Urology Practice Management February 2015

FOR UROLOGISTS, PRACTICE MANAGERS, FINANCIAL COUNSELORS, AND REIMBURSEMENT SPECIALISTS™

February 2015

www.UroPracticeManagement.com

Predictors of Hormone Responsiveness in Prostate Cancer

By Pongwut Danchaivijitr, MD, and Saby George, MD

Pongwut Danchaivijitr, MD

Saby George, MD

P

rostate cancer is the most common noncutaneous cancer in men and the second most common cause of cancer-related death.1 Normal prostate cells and prostate cancer cells require the presence of androgen for growth and survival. In advanced prostate cancer, androgen deprivation therapy (ADT), medically or surgically, has been the mainstay.

Continued on page 11

Volume 4 • Number 1

Prostate Cancer Progression May Be Predicted by a Novel Gene Panel

By Rosemary Frei, MSc

A

novel gene panel is showing promise for determining which treatment-naïve patients with prostate cancer could benefit from intensified treatment. A new study indicates that a 100-gene-loci panel can identify which patients with prostate cancer are most likely to fail treatment within 18 months, with a multivariable

analysis yielding a hazard ratio of 2.9 for relapse (Lalonde E, et al. Lancet Oncol.

2014;15:1521-1532).

The study was not powered to analyze cancer-specific mortality and overall survival. However, its results will be the basis for further analyses of the impact of adjuvant treatment on the DNA panel’s performance.

Continued on page 10

Preserving Sexual Function with Vessel-Sparing Radiation Therapy

By Phoebe Starr

I

n men with prostate cancer undergoing curative radiation therapy, it may be possible to preserve sexual function by using a vessel-sparing radiation technique, according to the 5-year follow-up results from a study of men who underwent vessel-sparing radiation therapy in this setting.

At the 2014 American Society for Radiation Oncology meeting, Patrick W. McLaughlin, MD, Professor of Radiation Oncology, University of Michigan, Novi, presented the results of the 5-year follow-up on patients treated with the technique.

In 2005, Dr McLaughlin and colleagues defined the vessel-sparing technique.

Continued on page 10

r ke ac ate r t st

© 2015 Engage Healthcare Communications, LLC

o al n Pr tive i tr ay i rac 5 l a r W Ove r…2 c i de r, de lin ls Un nce lad C ia Ca B Tr

FOR UROLOGISTS, PRACTICE MANAGERS, FINANCIAL COUNSELORS, AND REIMBURSEMENT SPECIALISTS™

Call for Papers

Do you have a practice management story to share

?

In your background as a urology practice manager, it’s likely there’s one business experience—and maybe more—that practice managers across the nation would want to read about.

High-interest topics include: the solution you found to a practice management challenge, reimbursement, your experience with EMR, Medicare audits, a memorable encounter that shaped the way you now run your business and/or practice medicine, or how you successfully integrated ancillary products and services into your practice as a revenue generator.

Send us your ideas!

Submit a 600- to 1500-word original article to Urology Practice Management that your fellow practice managers will want to read.

Submit to: info@the-lynx-group.com UPM_73114

In mCRPC therapy…

Is there more to the story?

INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia.

Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken.

Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials.

Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. mCRPC=metastatic castration-resistant prostate cancer; AST=aspartate aminotransferase; ALT=alanine aminotransferase.

Please see additional Important Safety Information on the next page.

Please see brief summary of full Prescribing Information on subsequent pages.

For men with mCRPC who progressed on ADT

In a clinical trial, patients had a median overall survival on ZYTIGA® (abiraterone acetate) of…*

More than 1,000 days.

And every day tells a story.

35.3 IMPROVEMENT IN MEDIAN OVERALL SURVIVAL 5.2 MONTHS compared with placebo plus prednisone.

MONTHS MEDIAN OVERALL SURVIVAL FOR ZYTIGA® plus prednisone† vs 30.1 MONTHS with placebo plus prednisone (active compound).‡

Co-primary end point—overall survival: hazard ratio (HR)=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified value for statistical significance not reached.

Co-primary end point—radiographic progression-free survival: median not reached for ZYTIGA® plus prednisone vs a median of 8.28 months for placebo plus prednisone. HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

IMPORTANT SAFETY INFORMATION (cont) Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken.

Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter.

Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were overall survival (OS) and radiographic progression-free survival.

ADT=androgen-deprivation therapy.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2014 6/14 016819-140612

Please see brief summary of full Prescribing Information on subsequent pages.

B:11.125 in

003307-130924

S:10.375 in

T:10.875 in

Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C). †At a prespecified interim analysis for OS, 37% (200/546) of patients treated with ZYTIGA® plus prednisone compared with 43% (234/542) of patients treated with placebo plus prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

Learn more today at

www.zytigahcp.com.

Every day tells a story.

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information].

In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ZYTIGA® (abiraterone acetate) Tablets ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

• Increased ZYTIGA Exposures with Food [see Warnings and Precautions].

Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia,

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Musculoskeletal discomfort, and Musculoskeletal stiffness terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 4 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo.

The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%).

Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine).

If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

Based on its mechanism of action, ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.

• Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.

• Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information.

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: May 2014 015924-140528

In This Issue

FEATURES PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Vice President, Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Director, Client Services Zach Ceretelle zceretelle@the-lynx-group.com Editorial Directors Dalia Buffery dbuffery@the-lynx-group.com Anne M. Cooper acooper@the-lynx-group.com Senior Production Manager Lynn Hamilton

Predictors of Hormone Responsiveness in Prostate Cancer............................. 1

The Lynx Group

Clinical Trials for Prostate Cancer, Overactive Bladder....................................25

President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistants Lora LaRocca Wayne Williams Director, Digital Media Anthony Romano Jr Digital Media Specialist Charles Easton IV Web Content Manager Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Mezzacappa Project Manager Deanna Martinez Project Coordinator Rachael Baranoski IT Manager Kashif Javaid Administrative Team Leader Allison Ingram Administrative Assistant Amanda Hedman Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

By Pongwut Danchaivijitr, MD, and Saby George, MD

Prostate Cancer Progression May Be Predicted by a Novel Gene Panel....................................................................................................... 1

By Rosemary Frei, MSc

Preserving Sexual Function with Vessel-Sparing Radiation Therapy…................ 1

By Phoebe Starr

Developments in Oncology Reimbursement.................................................. 20

By Gail Thompson

Building the Oncology System of the Future........................................................21

By Gail Thompson

How to Choose a 529 College Savings Plan........................................................23

By W. Ben Utley, CFP®, and Lawrence B. Keller, CFP®, CLU®, ChFC®, RHU®, LUTCF

Editorial Advisory Board Neil Baum, MD Practicing Urologist New Orleans, LA Cheris Craig, MBA, CMPE Chief Administrative Officer Urology of Greater Atlanta, LLC Atlanta, GA Michael deWitt Clayton, MD, FACS Urology Associates of San Luis Obispo, CA Rick Janss, MBA, CMPE Practice Administrator Clinical Urology Associates Gadsden, AL

John McMann, MS Administrator Advanced Urology Specialists, LLC Oxford, FL

James A. Sylora, MD Urologist AUS–Midwest Urology Evergreen Park, IL

Jonathan Oppenheimer, MD, FCAP Medical Director, Chief Pathologist Oppenheimer Urologic Reference Laboratory Nashville, TN

Sean M. Weiss, CCP-P, CCA-P, ACS-EM, CPC, CPC-P Vice President & Chief Compliance Officer DecisionHealth/Professional Services Gaithersburg, MD

Jonathan Rubenstein, MD Director of Coding and Compliance Chesapeake Urology Baltimore, MD

Mission Statement Urology healthcare requires providers to focus attention on financial concerns and strategic decisions that affect the bottom line. To continue to provide the high-quality care urology patients deserve, providers must master the ever-changing business of urology. Urology Practice Management offers process solutions for members of the urology care team—medical, surgical, and radiation urologists, as well as executives, administrators, and coders/billers—to assist them in reimbursement, staffing, electronic health records, REMS, and compliance with state and federal regulations.

Urology Practice Management™, ISSN 2374-0752 (print); 2374-0760 (online), is published 6 times a year

by Engage Healthcare Communications, LLC, 1249 South River Road, Cranbury, NJ 08512. Copyright © 2015 by Engage Healthcare Communications, LLC. All rights reserved. Urology Practice Management™ is a trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

The ideas and opinions expressed in Urology Practice Management™ do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Urology Practice Management™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Urology Practice Management™, 1249 South River Road, Cranbury, NJ 08512.

Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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Prostate Cancer

Prostate Cancer Progression May Be... Continued from the cover “We will be culling out patients with the gene signature into novel clinical trials that will compare adjuvant treatment versus no adjuvant treatment, with the end point being biochemical failure at 18 months and local control, using postradiotherapy biopsies,” lead investigator Robert G. Bristow, MD, PhD, clinician scientist at Princess Margaret Cancer Centre, Toronto, Ontario, Canada, told Urology Practice Management. “If the intensified treatment is more successful than the standard treatment for signature-positive patients, then our prognostic signature turns into a predictive signature.”

Dr Bristow; colead investigator Paul C. Boutros, PhD, of the Ontario Institute for Cancer Research, Toronto; and their coinvestigators, first extracted DNA from 126 preradiotherapy biopsies from patients with low or intermediate risk for prostate cancer progression.

They identified 4 distinct genetic profiles or subtypes based on the resulting gene-alteration panel. Patients with subtype 4 had an 89% 5-year biochemical relapse-free survival rate compared with 53% to 58% rates for the other 3 subtypes. The team also determined that the test’s prognostic power comes from the presence of specific gene alterations and general genomic instability.

Furthermore, tissue hypoxia, which had already been well-established as linked to worse prognosis, is associated with accuracy of the genomic panel. Patients with a high proportion of gene alteration and high hypoxia had the worse prognosis, whereas those with only high hypoxia did well after radical prostatectomy.

The researchers then created the 100-loci DNA signature and validated its ability to identify patients at risk for cancer progression using radical prostatectomy samples from pa-

tients treated at Memorial Sloan Kettering Cancer Center (MSKCC) and in Cambridge, United Kingdom.

The hazard ratio for biochemical relapse was 2.8 among patients with a Gleason score of 7. The gene panel was also highly prognostic for low-risk patients and those who went on to develop metastases; for example, 89% of low- to intermediate-risk patients at MSKCC who were classified by the gene panel as having a good prognosis were relapse free at 5 years compared with 58% of those who were classified as having a poor prognosis.

Further validation yielded a 2.9 hazard ratio for progression in patients deemed by the gene panel to have a poor prognosis versus those with a good prognosis.

The team also found that the genomic signature provided better prognostication than 23 RNA panels that had been previously investigated by other researchers. l

Preserving Sexual Function with... Continued from the cover

10

“Using MRI [magnetic resonance imaging] to define patient’s anatomy, the vessels involved in maintaining an erection can be spared in some patients,” said Dr McLaughlin.

“This is not possible in all patients; for example, those with prostate cancer at the apex of the prostate,” Dr McLaughlin said.

The study included 90 men diagnosed with prostate cancer, approximately 50% of whom underwent external beam radiation therapy (EBRT) alone and 50% who received EBRT plus brachytherapy.

None of the patients received androgen deprivation therapy.

All forms of cancer therapy affect sexual function, Dr McLaughlin said.

A 2009 study showed that among patients with good baseline erectile capacity, after 36 months of prostate

cancer therapy, erectile capacity was present in only approximately 30% of those treated with prostatectomy, 50% of those who received EBRT, and 80% of patients who underwent brachytherapy (Chen RC, et al. J Clin Oncol. 2009;27:3916-3922).

Two patient-reported metrics were used to assess sexual function—Metric A, which measured erections suf­ ficient for sexual intercourse, and Metric B, which was more general regarding any form of sexual activity.

Using Metric A, which only examined erectile function sufficient for sexual intercourse, at 2 years erectile capacity was achieved in 16.5% of patients of the radiation therapy– alone group and in 20.8% in the group receiving radiation therapy plus brachytherapy. At 5 years, 15.4% and 16.9% of patients, respectively, were

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February 2015

able to maintain an erection.

Using Metric B, erectile function sufficient for sexual activity with or without aids was preserved in 78.6% of patients receiving radiation therapy alone and in 91.8% who received radiation therapy plus brachytherapy at 5 years.

Dr McLaughlin said that as people age, sexuality changes and many couples engage in sexual activity other than intercourse, which can be painful to women after menopause—this is why he thinks Metric B is more reflective of sexuality in older people.

The cure rates at the 5-year follow-up were excellent. The cure rates were 98% among low-risk men (55% of patients), 96% among intermediate-risk men (30% of patients), and 87% in high-risk men (5% of patients). l

Personalized Medicine

Predictors of Hormone Responsiveness... Continued from the cover Initially, androgen-sensitive prostate cancer cells stop dividing and undergo apoptosis. Eventually, some cells evolve to become castration-­ resistant prostate cancer (CRPC).2 Once CRPC develops, treatment options are limited along with shortened overall survival (OS). To date, despite extensive research, there is no clinically meaningful predictive biomarker available for selecting treatment for prostate cancer. Here we conduct a review of existing markers that can potentially predict response to ADT.

Gleason Score The Gleason score (GS) grading system is a dominant prognostic factor for both localized and metastatic prostate cancer, both hormone-sensitive and castration-resistant disease, and an independent predictor of duration of hormone sensitivity.3-10 Traditionally, GS is classified homogenously into low/ intermediate risk (GS ≤7) and high risk (GS ≥8). Rusthoven et al collected data through the Surveillance, Epidemiology, and End Results database to assess outcomes of prostate cancer based on GS. ADT was utilized in a majority of patients.

At 4 years of follow-up, there were highly significant differences between GS 7 versus 8, 8 versus 9, and 9 versus 10 (all P<.001) in multivariate analysis for both OS and prostate cancer–specific survival. Gleason pattern of 5 in GS of 6 to 10 was an independent poor prognostic factor.11 Benaim et al conducted a retrospective study in 150 patients with advanced prostate cancer treated with ADT. A GS of 8 to 10 was also associated with shorter response to ADT in metastatic hormone-sensitive prostate cancer.9 Printed with permission from Personalized Medicine in Oncology.

Minor Histologic Subtypes Adenocarcinoma comprises more than 95% of prostate cancer. Most prostate cancer treatment studies are based on adenocarcinoma histologic subtype. Minor histologic subtypes include neuroendocrine (small cell)

types are usually associated with relatively lower prostate-specific antigen (PSA) values despite the presence of distant metastatic disease.

PSA and PSA Kinetics PSA is the most utilized biomarker to diagnose, classify risk, and monitor treatment response of prostate cancer. It could also serve as a predictive marker for duration of response after ADT.15 Data from Southwest Oncology Group Trial 9346 (SWOG 9346, INT-0162) demonstrated that patients who achieved PSA nadir (<0.2 ng/mL) at 7 months after ADT had significantly better OS compared with patients who did not (hazard ratio [HR] 0.17; P<.0001). Patients who achieved a PSA between 0.2 and 4.0 ng/mL also had significantly better OS (HR 0.30; P<.0001).16 Sasaki et al conducted a study of primary continuous ADT in patients with bone metastasis. Patients who achieved PSA nadir (<0.2 ng/mL) had a significantly longer OS (HR 3.73; P=.003). Time to nadir (TTN) PSA was also a good predictive marker for disease progression. In the same study, TTN >9 months was associated with increased OS compared with TTN <9 months both in patients who achieved PSA nadir and those who did not.17 Many studies have report-

The adrenal gland produces androgens, which could contribute to prostate cancer cell growth after initiating ADT. carcinoma, transitional cell carcinoma, ductal prostate cancer, basal cell carcinoma, carcinosarcoma, and stromal sarcoma. These usually do not respond to ADT and are characterized by rapid clinical progression.

Most patients die within 2 years despite aggressive chemotherapeutic regimens. Neuroendocrine carcinoma is one of the most common of the minor subtypes and can present as a primary tumor or transformed after ADT. These correlate with poor prognosis due to activation of multiple signaling pathways and lack of androgen receptor.12-14 These sub-

Key Points n In the genomic era, more genetic variants could be discovered and incorporated into the prognostic/predictive model along with traditional biomarkers n Currently the only “biomarker-guided” strategy for advanced prostate cancer treatment is up-front androgen deprivation therapy n Developing strategies to identify tumors that would respond to firstline and second-line hormonal manipulations would allow for the appropriate early use of cytotoxic agents in the other group of patients n With appropriate early application of cytotoxic agents in the adjuvant or neoadjuvant setting, we could see higher rates of cures in this disease in the near future Continued on page 12 February 2015

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Personalized Medicine

Predictors of Hormone Responsiveness... Continued from page 11 ed different significant PSA nadir and TTN to predict OS18,19 and androgen-independent progression.20,21 PSA nadir <0.1 ng/mL was shown to be a predictive marker for better response and delayed development of CRPC in intermittent ADT.22 To date, there is no optimal PSA nadir or TTN cutoff after ADT to predict OS. In general, we believe that rapid PSA reduction correlates with more prostate cancer cell death, a longer remission period, and increased OS. Many studies have shown that longer TTN correlates with longer OS. The possible explanation is tumor heterogeneity which contains a large number of PSA producing CRPC, which was initially suppressed with ADT then a subset of aggressive cancer cells regrow rapidly in low androgen environment.18,23 This knowledge could be used to select second-line hormonal manipulations versus chemotherapies.

Androgen, Androgen Receptor, and AndrogenResponsive Elements Androgen is the main driver of prostate cancer cell growth. Measuring 6-month post-ADT testosterone

level showed a positive correlation with survival along with GS and 6-month post-ADT PSA.24 However, the adrenal gland produces androgens, which could contribute to prostate cancer cell growth after initiating

The androgen/AR complex binds to a specific promoter region of AREs in order to regulate gene expression and cell growth.

ADT.25 In a later stage, the prostate cancer cell can produce androgen intracellularly and stimulate cell proliferation. Measuring intratumoral androgen could be a potential marker of response, but data have been inconsistent.26,27 To date, there is no recommendation for using the androgen level to measure response to second-line hormonal manipulation.

Unlike breast cancer, in which the

estrogen receptor has been well established as a prognostic and predictive marker, the androgen receptor (AR) in prostate cancer has not been validated in large studies to be a predictive marker of ADT. AR expression was uniformly positive in all pretreated prostate cancer but was lost in CRPC and more frequently lost in neuroendocrine-differentiated cancer cells.28 In pretreated patients, high AR content is a favorable prognostic factor29 and predictor of response.30 It was also demonstrated that lower GS cancer cells have a higher level of AR expression.29 The same study also showed that patients with tumors that had more than 48% AR-expressing cells had a better outcome. This clearly demonstrates that there is cell heterogeneity in a tumor that may have higher-grade (low AR-expressing) and lower-grade (high AR-expressing) elements.

This leads to the hypothesis that the higher the percentage of high-grade cells in a tumor (which are essentially less sensitive to hormonal manipulation by ADT), the faster that tumor becomes castration resistant.

However, Sun et al studied variations of AR and estrogen receptor

Proposed Algorithm for Systemic Therapy Considerations

Gleason Score 7 (3+4)

ADT Followed by Second-Line Therapies

Gleason Score 8-10 and (4+3 with tertiary 5 pattern)

ADT + Chemotherapy as First-Line Treatment. Then Second-Line Strategies.

Adenocarcinoma

Metastatic Prostate Cancer

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Neuroendocrine

Chemotherapy

Other Histologic Subtypes

Chemotherapy vs Clinical Trial

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Personalized Medicine

alpha and beta by using single nucleotide polymorphisms (SNPs), and results showed that common genetic variations were not associated with aggressiveness and response to ADT.31 AR expression and function can be changed over the course of treatment. In post-ADT, resistant mechanisms develop as follows: 1. Increased AR gene amplification: Tumor adapts to grow in a low androgen state and up-regulates AR by gene amplification, especially a tumor that has initially responded well to ADT and has a response duration of more than 12 months.32,33 2. AR gene mutations: This mechanism helps prostate cancer cells evade ADT. Mutation occurs in multiple sites of AR gene.34,35 Mutated AR can be activated by many types of hormonal agonists/ antagonists or even the absence of steroid.35,36

accurately predict outcome of prostate cancer patients receiving ADT. Once a patient is diagnosed as having CRPC, abiraterone and enzalutamide are approved agents for treatment in the pre- and postdocetaxel setting. Antonarakis et al studied androgen-receptor isoform encoded by splice variant 7 (AR-V7) in circulating tumor cells, which lack a ligand-binding domain but has an active transcription factor. Patients who had positive AR-V7 had a poor PSA response to both abiraterone and enzalutamide compared with patients with negative AR-V7 (0% vs 68%; P=.004, and 0% vs 53%; P=.004, respectively). These findings translate into shorter progression-free survival and OS in both groups.40 However, this study was done in a small patient population and requires a larger-scale prospective validation.

Androgen-Responsive Elements (AREs): After Androgen Binds to AR The androgen/AR complex binds to a specific promoter region of AREs in order to regulate gene expression and cell growth.37 Huang et al studied 55 common SNPs within AREs in 601 patients treated with ADT. After multivariate analysis, FBOX32 rs7830622 (HR 1.69; P=.004) and FLT1 rs9508016 (HR 1.52; P=.028) remained as significant predictive factors for all-cause mortality. Combination of SNPs showed a higher HR of 3.33, P<.001. However, this study was conducted in a Chinese population.38 Bao et al studied 19 prostate cancer variants in the same patient cohort. After multivariate analysis, rs16901979 remained a significant predictor for prostate cancerâ&#x20AC;&#x201C;specific mortality (HR 0.58; P=.002) and all-cause mortality (HR 0.64; P=.002).39 These results suggest that an integrated conventional and genetic variant predictive model can

After selective candidate gene products, PSA and prostate-specific membrane antigen remained markers consistently up-regulated following AR activation and AR suppression, respectively.

survival of 20.7 months versus 9.5 months for patients whose CTC did not decline. Okegawa et al conducted a single-institution study in treatment-naive metastatic prostate cancer in Japan that showed CTC â&#x2030;Ľ5 cells/7.5 mL of blood was associated with a shorter androgen responsiveness time of 17 months compared with 32 months in patients with CTC <5 cells/7.5 mL.42 Goodman Jr et al conducted a prospective study in 33 treatment-naive metastatic prostate cancer patients in a western population. After multivariate analysis, baseline CTC remained an independent predictive marker for duration and depth of responsiveness to ADT. This study also suggested a CTC cutpoint of 3 cells/7.5 mL of blood instead of the traditional 5 cells/7.5 mL of blood in a treatment-naive group in order to maximize a predictive value. However, this was a very small patient cohort, and more prospective studies are needed to validate this finding.43 The androgen signaling pathway was also studied in CTC. After selective candidate gene products, PSA and prostate-specific membrane antigen remained markers consistently up-regulated following AR activation and AR suppression, respectively.44 Miyamoto et al studied an androgen signaling pattern using a combination of these markers in both treatment-naive and CRPC patients. Results showed that the androgen signaling pathway was uniformly expressed in treatment-naive patients and heterogeneously expressed in CRPC patients, likely due to acquired resistance, which led to inconsistent response to ADT. However, active AR signaling during a treatment with abiraterone was also associated with poor treatment outcome.45

Circulating Tumor Cells Initially, circulating tumor cells (CTCs) were utilized as a prognostic and predictive marker in mCRPC after chemotherapy. Patients who had CTC â&#x2030;Ľ5 cells/7.5 mL of blood had significantly poorer prognosis (median OS 11.5 vs 21.7 months; P<.001).41 Patients who had CTC <5 cells/7.5 mL after chemotherapy demonstrated an increased median

Germline Mutation Due to insufficient predictive factors for ADT responsiveness, genetic Continued on page 14

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Personalized Medicine

Predictors of Hormone Responsiveness... Continued from page 13 variations were studied using SNPs. Yang et al studied androgen transporter genes in 538 patients receiving ADT. Patients who carried SLCO2B1 and SLCO2B3 genotypes had a significantly shorter time to progression on ADT.46 Kohli et al studied germline mutations associated with sex steroid biosynthesis and metabolisms using a total of 746 SNPs in 304 patients with advanced prostate cancer

There is an unmet need to develop strategies to identify the tumors that would respond to firstline and second-line hormonal manipulations for long periods. receiving ADT. After multivariate analysis and censor for false discovery rates of 0.10 or more, 2 of the 4 TRMT11-tagged SNPs (rs1268121 and rs6900796) were found to be associated with time to ADT failure.47 Fraga et al studied variants of hypoxia-inducible factor 1 alpha (HIF1A), which regulates cellular response to hypoxia and induces cancer progression, in 754 prostate cancer patients.

Results showed that patients who carried the HIF1A +1722 T-allele had an increased risk for developing resistance to ADT after multivariate analysis (odds ratio [OR] 6.0; P=.001) and for developing distant metastasis (OR 2.0; P=.027).48

Conclusion Prostate cancer usually has heterogeneity in the cells that comprise the tumor. Although many biomarkers have been studied, none has been validated in a prospective fashion. In

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the genomic era, with the assistance of high-throughput sequencing and data management, more genetic variants could be discovered and incorporated into the prognostic/predictive model along with traditional biomarkers. So far, there is no biomarker-guided strategy for advanced prostate cancer treatment except up-front ADT. Data suggest that lower GS cancers tend to express more AR and thus may be associated with better outcomes from hormone manipulation. Higher GS cancers tend to express lower AR and are thus less amenable to a good outcome. This is consistent with the outcome strictly based on the biology/morphology of the disease. This is substantiated by the recently reported ECOG-3805 trial by Sweeney et al that demonstrated a significant survival advantage to applying docetaxel up-front with ADT in hormone-sensitive metastatic prostate cancer when compared with ADT alone (HR 0.61; median OS 57.6 vs 44 months; P=.0003).49 There is an unmet need to develop strategies to identify the tumors that would respond to first-line and second-line hormonal manipulations for long periods. This would also allow for the appropriate early use of cytotoxic agents in the other group of patients.

The aggressive cancer cells tend to be of Gleason grades 4 and 5 pattern and the unusual histologies per the available data. Despite that knowledge, there is a lack of enthusiasm to apply cytotoxic chemotherapies up-front in those patients with high-grade disease, especially when the tumor volume is low. If high-grade elements could be eliminated by early application of cytotoxic agents in the adjuvant or neoadjuvant setting, we could see higher rates of cures in this disease in the near future. l Dr Danchaivijitr is a Hematology/ Oncology Fellow at Roswell Park

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Cancer Institute. His clinical interests are genitourinary cancer and new drug developments.

Dr George is a Medical Oncologist, Assistant Professor of Medicine and Oncology at Roswell Park Cancer Institute. He is a clinical/translational investigator with focus on prostate and kidney cancer. His interests include aggressive variants of prostate cancer and developing novel treatment strategies in both prostate and kidney cancer.

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2. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001; 1:34-45.

3. Pierorazio PM, Walsh PC, Partin AW, et al. Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU Int. 2013;111:753-760.

4. Glass TR, Tangen CM, Crawford ED, et al. Metastatic carcinoma of the prostate: identifying prognostic groups using recursive partitioning. J Urol. 2003;169: 164-169.

5. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25:1596-1605.

6. Halabi S, Small EJ, Kantoff PW, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol. 2003; 21:1232-1237.

7. Nakabayashi M, Hayes J, Taplin ME, et al. Clinical predictors of survival in men with castration-resistant prostate cancer: evidence that Gleason score 6 cancer can evolve to lethal disease. Cancer. 2013;119:2990-2998.

8. Smaletz O, Scher HI, Small EJ, et al. Nomogram for overall survival of patients with progressive metastatic prostate cancer after castration. J Clin Oncol. 2002;20: 3972-3982.

9. Benaim EA, Pace CM, Roehrborn CG. Gleason score predicts androgen independent progression after androgen deprivation therapy. Eur Urol. 2002;42:12-17.

10. Humphrey PA. Gleason grading and prognostic factors in carcinoma of the prostate. Mod Pathol. 2004; 17:292-306.

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Front Oncol. 2014;4:60.

13. Hansel DE, Nakayama M, Luo J, et al. Shared TP53 gene mutation in morphologically and phenotypically distinct concurrent primary small cell neuroendocrine carcinoma and adenocarcinoma of the prostate. Prostate. 2009;69:603-609.

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The androgen receptor status of neuroendocrine cells in human benign and malignant prostatic tissue. Cancer Res. 1993;53:1967-1970.

15. Oosterlinck W, Mattelaer J, Derde MP, et al. Prognostic factors in advanced prostatic carcinoma treated with total androgen blockade. Flutamide with orchiectomy or with LHRH analogues. A Belgian multicentric

Personalized Medicine

study of 546 patients. Acta Urol Belg. 1995;63:1-9.

16. Hussain M, Tangen CM, Higano C, et al. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol.

2006;24:3984-3990.

17. Sasaki T, Onishi T, Hoshina A. Nadir PSA level and time to PSA nadir following primary androgen deprivation therapy are the early survival predictors for prostate cancer patients with bone metastasis. Prostate Cancer Prostatic Dis. 2011;14:248-252.

18. Choueiri TK, Xie W, D’Amico AV, et al. Time to prostate-specific antigen nadir independently predicts overall survival in patients who have metastatic hormone-sensitive prostate cancer treated with androgen-deprivation therapy. Cancer. 2009;115:981-987.

19. Tomioka S, Shimbo M, Amiya Y, et al. Outcome of patients with hormone-refractory prostate cancer: prognostic significance of prostate-specific antigen-­ doubling time and nadir prostate-specific antigen. Jpn J Clin Oncol. 2008;38:36-42.

20. Kwak C, Jeong SJ, Park MS, et al. Prognostic significance of the nadir prostate specific antigen level after hormone therapy for prostate cancer. J Urol. 2002;168: 995-1000.

21. Morote J, Esquena S, Abascal JM, et al. Usefulness of prostate-specific antigen nadir as predictor of androgen-­ independent progression of metastatic prostate cancer.

Int J Biol Markers. 2005;20:209-216.

22. Sciarra A, Cattarino S, Gentilucci A, et al. Predictors for response to intermittent androgen deprivation (IAD) in prostate cancer cases with biochemical progression after surgery. Urol Oncol. 2013;31:607-614.

23. Hori S, Jabbar T, Kachroo N, et al. Outcomes and predictive factors for biochemical relapse following primary androgen deprivation therapy in men with bone scan negative prostate cancer. J Cancer Res Clin Oncol. 2011;137:235-241.

24. Perachino M, Cavalli V, Bravi F. Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: prognostic significance? BJU Int. 2010;105:648-651.

25. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17:337-345.

26. van der Sluis TM, Vis AN, van Moorselaar RJ, et al. Intraprostatic testosterone and dihydrotestosterone.

Part I: concentrations and methods of determination in men with benign prostatic hyperplasia and prostate cancer. BJU Int. 2012;109:176-182.

27. van der Sluis TM, Meuleman EJ, van Moorselaar RJ, et al. Intraprostatic testosterone and dihydrotestosterone. Part II: concentrations after androgen hormonal manipulation in men with benign prostatic hyperplasia and prostate cancer. BJU Int. 2012;109:183-188.

28. Komiya A, Yasuda K, Watanabe A, et al. The prognostic significance of loss of the androgen receptor and neuroendocrine differentiation in prostate biopsy specimens among castration-resistant prostate cancer patients. Mol Clin Oncol. 2013;1:257-262.

29. Takeda H, Akakura K, Masai M, et al. Androgen receptor content of prostate carcinoma cells estimated by immunohistochemistry is related to prognosis of patients with stage D2 prostate carcinoma. Cancer. 1996; 77:934-940.

30. Trachtenberg J, Walsh PC. Correlation of prostatic nuclear androgen receptor content with duration of response and survival following hormonal therapy in advanced prostatic cancer. J Urol. 1982;127:466-471.

31. Sun T, Lee GS, Werner L, et al. Inherited variations in AR, ESR1, and ESR2 genes are not associated with prostate cancer aggressiveness or with efficacy of androgen deprivation therapy. Cancer Epidemiol Biomarkers Prev. 2010;19:1871-1878.

32. Koivisto P, Kononen J, Palmberg C, et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 1997;57:314-319.

33. Koivisto P, Hyytinen E, Palmberg C, et al. Analysis of genetic changes underlying local recurrence of prostate carcinoma during androgen deprivation therapy.

Am J Pathol. 1995;147:1608-1614.

34. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer.

2001;1:34-45.

35. Steinkamp MP, O’Mahony OA, Brogley M, et al.

Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Res. 2009;69:4434-4442.

36. Culig Z, Hobisch A, Cronauer MV, et al. Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Mol Endocrinol. 1993;7:1541-1550.

37. Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25:276-308.

38. Huang CN, Huang SP, Pao JB, et al. Genetic polymorphisms in androgen receptor-binding sites predict

survival in prostate cancer patients receiving androgen-deprivation therapy. Ann Oncol. 2012;23:707-713.

39. Bao BY, Pao JB, Huang CN, et al. Significant associations of prostate cancer susceptibility variants with survival in patients treated with androgen-deprivation therapy. Int J Cancer. 2012;130:876-884.

40. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371:1028-1038.

41. de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer.

Clin Cancer Res. 2008;14:6302-6309.

42. Okegawa T, Nutahara K, Higashihara E. Immunomagnetic quantification of circulating tumor cells as a prognostic factor of androgen deprivation responsiveness in patients with hormone naive metastatic prostate cancer. J Urol. 2008;180:1342-1347.

43. Goodman OB Jr, Symanowski JT, Loudyi A, et al.

Circulating tumor cells as a predictive biomarker in patients with hormone-sensitive prostate cancer. Clin Genitourin Cancer. 2011;9:31-38.

44. Evans MJ, Smith-Jones PM, Wongvipat J, et al.

Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen. Proc Natl Acad Sci U S A. 2011;108:9578-9582.

45. Miyamoto DT, Lee RJ, Stott SL, et al. Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer. Cancer Discov. 2012;2:995-1003.

46. Yang M, Xie W, Mostaghel E, et al. SLCO2B1 and SLCO1B3 may determine time to progression for patients receiving androgen deprivation therapy for prostate cancer. J Clin Oncol. 2011;29:2565-2573.

47. Kohli M, Riska SM, Mahoney DW, et al. Germline predictors of androgen deprivation therapy response in advanced prostate cancer. Mayo Clin Proc.

2012;87:240-246.

48. Fraga A, Ribeiro R, Príncipe P, et al. The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration. Eur J Cancer.

2014;50:359-365.

49. Sweeney C, Chen Y-H, Carducci MA, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): an ECOG-led phase III randomized trial. J Clin Oncol. 2014;32(suppl).

Abstract LBA2.

REGISTER TH

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ANNUAL CONFERENCE

M AY 3-6, 2015 Omni Shoreham Hotel Washington, DC

AVBCConline.org/conference February 2015

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Your Patients, Your Practice…

Helping Your Practice This comprehensive financial assistance program offers ongoing support across the reimbursement spectrum to help you help your patients.

Complete Provider Assistance Benefits verification Prior authorization tracking Regionally dedicated case managers Local access and reimbursement specialists Denied claims assistance Indication XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Important Safety Information Contraindications XTANDI (enzalutamide) capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of patients who were treated with XTANDI and 0% treated with placebo. In Study 2, conducted in patients with chemotherapy-naïve metastatic CRPC, seizure occurred in 0.1% of patients who were treated with XTANDI and 0.1% treated with placebo. Patients experiencing a seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited clinical trial experience in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold, whereas Study 2 permitted the use of these medications.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Adverse Reactions The most common adverse reactions (≥ 10%) reported from the two combined clinical trials that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/ vertigo.

Other Adverse Reactions include: • Laboratory Abnormalities: In the two studies, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI

We’ve Got You Covered Helping Your Patients Financial assistance is available for patients.* Private Insurance $5000/month copay assistance, up to $12,000/year

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(0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).

• Infections: In Study 1, 1% of XTANDI versus 0.3% of placebo patients and in Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

• Falls: In the two studies, falls including fall-related injuries occurred in 9% of XTANDI patients vs 4% treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients and included non-pathologic fractures, joint injuries, and hematomas.

• Hypertension: In the two studies, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of XTANDI or placebo treated patients.

Drug Interactions • Effect of Other Drugs on XTANDI – Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible.

If co-administration of XTANDI cannot be avoided,

XTANDISupportSolutions.com

reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers may alter the plasma exposure of XTANDI and should be avoided if possible.

• Effect of XTANDI on Other Drugs – XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

PLEASE SEE BRIEF SUMMARY OF COMPLETE PRESCRIBING INFORMATION ON FOLLOWING PAGES.

XTANDI Support SolutionsSM, a component of Astellas Access ServicesSM 1-855-8XTANDI (1-855-898-2634); Fax 1-855-982-6341; XTANDISupportSolutions.com ©2014 Astellas Pharma US, Inc. All rights reserved. 076-0329-PM 9/14 Printed in USA XTANDI, Astellas, and the flying star logo are trademarks of Astellas Pharma, Inc.

XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information.

INDICATIONS AND USAGE

Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in Study 1 (cont.)

Respiratory Disorders

Table 1. Adverse Reactions in Study 1

Seizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience readministering XTANDI to patients who experienced seizure.

Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids.

The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

0.1

1.3

0.3

26.4

5.3

24.3

4.0

Arthralgia 20.5 Musculoskeletal 15.0 Pain Muscular 9.8 Weakness Musculoskeletal 2.6 Stiffness Gastrointestinal Disorders

2.5

17.3

1.8

1.3

11.5

0.3

Table 2. Adverse Reactions in Study 2

1.5

6.8

1.8

0.3

0.3

0.0

21.8

1.1

17.5

0.3

Hot Flush

20.3

0.0

10.3

0.0

Hypertension

6.4

2.1

2.8

1.3

Grade 1-4a (%)

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

3.3

CTCAE v4 Includes asthenia and fatigue.

Includes dizziness and vertigo.

Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Study 2: Chemotherapy-naive Metastatic CastrationResistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDItreated patients and 37% of placebo-treated patients.

Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

XTANDI N = 800

XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)].

Epistaxis a b c d

General Disorders Asthenic Conditionsb Peripheral Edema

Placebo N = 399

Grade Grade Grade 3-4 1-4 3-4 (%) (%) (%)

50.6

9.0

44.4

9.3

15.4

1.0

13.3

0.8

Musculoskeletal And Connective Tissue Disorders Back Pain

Diarrhea Vascular Disorders

Nervous System Disorders Headache

12.1

0.9

5.5

0.0

Dizzinessc Spinal Cord Compression and Cauda Equina Syndrome Paresthesia Mental Impairment Disordersd Hypoesthesia

9.5

0.5

7.5

0.5

XTANDI N = 871 Grade 1-4a (%)

Grade 3-4 (%)

Placebo N = 844 Grade 1-4 (%)

Grade 3-4 (%)

General Disorders Asthenic 46.9 3.4 33.0 2.8 Conditionsb Peripheral 11.5 0.2 8.2 0.4 Edema Musculoskeletal And Connective Tissue Disorders Back Pain

28.6

2.5

22.4

3.0

Arthralgia

21.4

1.6

16.1

1.1

Gastrointestinal Disorders 7.4

6.6

4.5

3.8

6.6

0.0

4.5

0.0

4.3

0.3

1.8

0.0

4.0

0.3

1.8

0.0

0.0

6.5

0.3

Infections And Infestations Upper Respiratory Tract 10.9 Infectione Lower Respiratory 8.5 Tract And Lung Infectionf Psychiatric Disorders

2.4

4.8

1.3

Insomnia

8.8

0.0

6.0

0.5

Anxiety

6.5

0.3

4.0

0.0

Renal And Urinary Disorders Hematuria

6.9

1.8

4.5

1.0

Pollakiuria

4.8

0.0

2.5

0.0

Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 Non-pathologic 4.0 1.4 0.8 Fractures Skin And Subcutaneous Tissue Disorders

0.0 0.3

Pruritus

3.8

0.0

1.3

0.0

Dry Skin

3.5

0.0

1.3

0.0

Constipation

23.2

0.7

17.3

0.4

Diarrhea

16.8

0.3

14.3

0.4

Vascular Disorders Hot Flush

18.0

0.1

7.8

0.0

Hypertension

14.2

7.2

4.1

2.3

Nervous System Disorders Dizzinessc

11.3

0.3

7.1

0.0

Headache

11.0

0.2

7.0

0.4

Dysgeusia

7.6

0.1

3.7

0.0

5.7

0.0

1.3

0.1

2.1

0.1

0.4

0.0

0.6

8.5

0.6

10.5

0.0

4.7

1.1

5.7

0.0

Mental Impairment Disordersd Restless Legs Syndrome

Respiratory Disorders Dyspneae

11.0

Infections And Infestations Upper Respiratory 16.4 0.0 Tract Infectionf Lower Respiratory Tract And 7.9 1.5 Lung g Infection Psychiatric Disorders Insomnia

8.2

0.1

Table 2. Adverse Reactions in Study 2 (cont.)

Renal And Urinary Disorders Hematuria

8.8

1.3

5.8

1.3

Injury, Poisoning And Procedural Complications Fall

12.7

1.6

5.3

NonPathological 8.8 2.1 3.0 Fracture Metabolism and Nutrition Disorders Decreased 18.9 0.3 16.4 Appetite

0.7 1.1

0.7

Investigations Weight Decreased

12.4

0.8

8.5

0.2

Reproductive System and Breast Disorders Gynecomastia

3.4

0.0

1.4

0.0

a b c d

CTCAE v4 Includes asthenia and fatigue.

Includes dizziness and vertigo.

Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes dyspnea, exertional dyspnea, and dyspnea at rest. f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4).

The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).

Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls and Fall-related Injuries In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo.

Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible.

Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology (12.3)].

Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl

enzalutamide by 1.3-fold in healthy volunteers [see Clinical Pharmacology (12.3)].

The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo.

Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible.

Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology (12.3)].

Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category X [see Contraindications (4)].

Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryofetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC).

Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.

Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical

experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted.

Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)].

Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function.

The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology (12.3)].

OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.

Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Revised: September 2014 14B006-XTA-BRFS Rx Only © 2014 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

076-0472-PM

Cancer Center Business Summit

Developments in Oncology Reimbursement

By Gail Thompson

C

hanges in oncology payment and reimbursement as well as delivery models were reviewed recently by an expert panel at the Cancer Center Business Summit (CCBS). Providers, payers, industry representatives, and thought leaders were on hand to share their thoughts and experiences.

Moderated by Marc Samuels, JD, MPH, Chief Executive Officer, ADVI, the panel included Michael Kolodziej, MD, National Medical Director, Oncology Solutions, Aetna; Kavita Patel, MD, MS, Fellow and Managing Director, Engelberg Center for Health Care Reform, The Brookings Institution; Denise Pierce, President and Chief Executive Officer, DK Pierce & Associates; Larry Strieff, MD, Specialty Medical Director, Hill Physicians Medical Group; and Robin Zon, MD, FACP, FASCO, Michiana Hematology Oncology, and Chair, Clinical Practice Committee, American Society of Clinical Oncology (ASCO).

Dr Kolodziej shared with the audience that moving forward, transparency in care, pricing, utilization, and costs will be mandatory from all stakeholders: providers, payers, patients, and employers. While everything must be on the table for review in order to develop workable solutions, he noted that reform will not work unless physicians are holding the reins, so collaboration rather than conflict between payers and providers is essential. Aetna has explored several models for oncology, and has decided on the parameters of a model based upon the oncology medical home. This meets the companyâ&#x20AC;&#x2122;s needs and expectations for transparency and quality, and should allow oncology practices to meet those deliverables as well.

Dr Patel explored alternative pay-

ment models under review by the Centers for Medicare & Medicaid Services (CMS). One of the models CMS is considering identifies patients with specific cancers and builds an episode-based payment on a per-month basis, plus another payment that is risk-adjusted for care coordination. When an episode is complete, quality measures will be reviewed with the potential for a

While everything must be on the table for review in order to develop workable solutions, Dr Kolodziej noted that reform will not work unless physicians are holding the reins, so collaboration rather than conflict between payers and providers is essential. bonus performance payment or a negative payment element for poor performance. CMS would like to include private payers in this implementation, but has not yet identified any collaborators. Some of the current challenges for this model include defining a cancer type, defining a finite period of time coverage, and other issues that have arisen with control of Medicare Part D, Part A, and Part B costs.

Employer perspectives on cancer management were presented by Ms Pierce, based upon qualitative and quantitative research completed recently with employers across the

United States. Cancer has become one of the top 3 disease concerns for many employers, some of whom are starting to take action themselves, rather than to wait for a payment reform model. Ms Pierce discussed the efforts of employers that are exploring a solid tumor mapping program, the use of nurse navigators, value-based payment design, among other options to manage cancer treatment costs. In a specific example, she discussed collaborations between MD Anderson Cancer Center and Shell Oil Company through a voluntary program that offers cancer information and prevention services to Shell employees utilizing a case manager. She indicated that business coalitions are also starting to become more engaged not just in contracting for services, but in benefit design and analytics coordination.

The Hill Physicians Medical Group has built a bundled payment model for oncology patients in California.

Dr Strieff described the utilization experience, the development of the case rate, and the necessary addition of stop-loss programs to financially protect the physicians. The group is monitoring quality by using ASCOâ&#x20AC;&#x2122;s Quality Oncology Practice Initiative program. To date, the model has led to performance improvements, increased satisfaction compared with a standard fee-for-service model, and improvements in cost.

Dr Zon outlined the details of Consolidated Payments for Oncology Care (CPOC), ASCOâ&#x20AC;&#x2122;s proposed payment reform model. This model would replace current codes with new codes that are billable for physician services for new patients, for each month of active treatment, for monitoring patients not in active treatment, for services related to transitions of care, and for additional Continued on page 22

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Cancer Center Business Summit

Building the Oncology System of the Future

By Gail Thompson

P

ractice managers, physicians, and members of industry gathered recently at the Cancer Center Business Summit (CCBS) to consider the state of cancer care delivery and its future. A panel discussion among key thought leaders featured perspectives from the oncology community as well as national policy advisors.

Paul H. Keckley, PhD, Managing Director of the Navigant Center for Healthcare Research and Policy Analysis, joined Allen S. Lichter, MD, FASCO, Chief Executive Officer of the American Society of Clinical Oncology (ASCO); Lindsay Conway, MSEd, Practice Manager of the Oncology Roundtable at The Advisory Board Company; and Gary H. Lyman, MD, MPH, Codirector of the Fred Hutchison Institute for Cancer Outcomes Research, for the discussion.

In his presentation, Dr Keckley shared that the pressure to reduce healthcare spending will not dissipate, even if reform is challenging, because costs and the growth of costs in healthcare continue to adversely affect the economy. There are examples of large systems (eg, investor-owned healthcare) that have fared fairly well since the passage of the Patient Protection and Affordable Care Act (ACA); these systems have not yet overtly addressed cancer care, but he expects that they will in the future.

The Patient-Centered Outcomes Research Institute, established through the ACA, has the potential to provide a substantial shift in the delivery of cancer care, Dr Keckley stated. The institute was charged with supporting comparative clinical effectiveness research that helps patients, caregivers, clinicians, employers, and insurers make informed health decisions. The open market is already responding with announcements of

technical gadgets and a biometrics revolution of what we wear and how it interacts with us physicallyâ&#x20AC;&#x201D;representing a movement toward putting more health information directly in consumersâ&#x20AC;&#x2122; hands.

Dr Keckley summarized with his vision that it is conceivable to have just 80 to 100 integrated health systems across the United States within the next 10 years, paid on a capitated basis, with responsibility for early disease detection as well as longterm care. Such a scenario would inevitably change the dynamics of cancer care.

said. He also noted that in the future, the utility of treatment will be driven by real-time analysis of realworld data from active clinical care, rather than by clinical trials and research alone.

Ms Conway shared trends that the Oncology Roundtable has seen to be shaping community hospitals and cancer care. Patients will become more demanding and discerning healthcare consumers by 2018, she said, driven by new insurance plans, activist employers, new financial incentives, and growth in private health markets. Shrinking health insurance networks will exclude providers, and the providers who find themselves outside of or within key networks will have to find ways either to survive out of network or to conform to the greater cost sensitivities within them, respectively. Treatment decisions are likely to change as providers begin to stratify patients for management choices based on risk assessments.

In the northwest United States, the Fred Hutchison Institute for Cancer Outcomes Research, as a leading area cancer provider, has been involved in a regional collaborative network looking at cancer outcomes with 60 regional employer and plan stakeholders. Dr Lyman shared that from an initial list of more than 100 recommendations for factors to consider when studying cancer care outcomes, the network has narrowed those choices to a list of 6. These data will be tracked over the next year and benchmarked for adherence; he indicated that perhaps this approach could extend to other regions or nationwide. Currently, 2 specific interventions are moving forward: one involves capturing data before and after a patient-centered education campaign,

The pressure to reduce healthcare spending will not dissipate, even if reform is challenging, because costs and the growth of costs in healthcare continue to adversely affect the economy.

Dr Lichter presented the initiatives that ASCO has considered to build the delivery system of the future. Solutions include at least 3 simultaneous revolutions: cancer panomics, big data, and the cost structure and valuation of healthcare, with a possible fourth revolution related to patient engagement.

He emphasized a growing recognition of treatment value (compared with cost only) as the primary driver for innovation in clinical practice.

ASCO is actively engaged to move these revolutions forward, but it is not easy or fast to accomplish, he

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Cancer Center Business Summit

Building the Oncology System... Continued from page 21 and the other involves tracking the use of growth factors.

General consensus among participants was that major networks and growing systems of healthcare providers will transition treatment choices from individual physician–patient interactions to a more global care continuum focus. Increasing attention to the total cost of care will change discussions regarding the definition of appropriate treatments. Pathways, while continuing to emerge as an essential element in the growing process of care delivery, will serve as just one tool in the larger discussion of relative value, efficacy, total cost, and impact of decisions on care outcomes.

Manufacturers of cancer care drugs will need to equip their teams with the ability to adapt to rapidly changing delivery leaders in individual markets, and to tailor materials and support for a variety of perspectives.

Some leaders in providing care will

be more focused on the role of products in the total cost of the care continuum, whereas health plan decision makers and policy makers may request proof of value to the employer or plan to better meet the needs of insured patients. Increasingly, patients, treating physicians, and health

During an audience question-and­answer session, one point summarized the status of the future healthcare delivery model debate: there is a need to innovate in drugs, but also to recognize that a focus on the cost of drugs, especially multiple combinations of drugs, comes with reduced

All stakeholders need to come together to determine how to balance the needs of patients and providers with the efforts of the pharmaceutical industry and the concept of value. plans are likely to ask manufacturers of new products for comparisons to other market alternatives and even to other delivery or site-of-care models that may be supported by the treatment options (home care, oral medicines, pumps, self-administration, or even decisions to not treat).

sustainability of cancer therapy. All stakeholders need to come together to determine how to balance the needs of patients and providers with the efforts of the pharmaceutical industry and the concept of value.

We do not, however, have any definitive answers yet. l

Developments in Oncology Reimbursement... Continued from page 20 payment adjustments related to utilization and performance on quality measures, adherence and use of certified pathways, resource utilization (oncology medical home, hospitalization, and emergency department admissions), and participation in clinical trials. The CPOC model is not yet tested; ASCO hopes to begin practice testing this year.

Presenters generally agreed that CMS will be a major driver of change for provider payments. It is likely that private payers will begin collaborating with CMS, increasing the rapidity of changes on oncology payments across a wide variety of markets. In addition, it is expected that drug costs will be targeted and probably removed as a driver of cancer treatment choices; rather, patient outcomes and allowable cost

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CMS will be a major driver of change for provider payments. It is likely that private payers will begin collaborating with CMS, increasing the rapidity of changes on oncology payments across a wide variety of markets. parameters will become targeted drivers of treatment choice. Several oncology payment reform models are under consideration by public and private entities, but none have

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been identified as primary solutions at this time. The consensus among presenters was that the current system is not sustainable, and private insurers and CMS have committed to change.

In addition, employers were mentioned as a rising catalyst—rather than a passive participant—in the oncology payment and management reform arena. Escalating prices for insurance premiums are pushing small to medium employers to turn to exchange plans for employee health insurance benefits, a move that has far-reaching implications for coverage and access.

Despite the variety of pilots and proposed models, the panel emphasized that the future of oncology reimbursement is a work in progress, and one clear solution is yet to emerge. l

Wealth Management

How to Choose a 529 College Savings Plan

By W. Ben Utley, CFP®, and Lawrence B. Keller, CFP®, CLU®, ChFC®, RHU®, LUTCF

S

ection 529 College Savings plans are tax-advantaged college savings vehicles, and one of the most popular ways to save for college today. Known officially as “qualified tuition programs,” 529 college savings plans have changed the world of tuition savings, much like the way 401(k) plans changed the world of retirement savings a few decades ago. While a 529 plan may be the best vehicle to save for college, you will need to understand the basics in order to make the right choice.

The Basics of 529 Plans Congress created 529 plans in 1996 and named them after Section 529 of the Internal Revenue code. A 529 plan is state-operated and offers tax advantages as well as other potential incentives to ease saving for college or postsecondary training for a designated beneficiary, such as a child or grandchild. Eligible educational institutions generally include colleges, universities, vocational schools, or other postsecondary educational institutions eligible to participate in a student aid program administered by the US Department of Education.

When establishing a 529 plan, you can name anyone as a beneficiary, including a relative, a friend, or yourself. There are no income restrictions on you as the contributor, or on the beneficiary, and there is also no limit to the number of 529 plans you can establish. College savings plans are established by individual states and typically managed by an experienced financial institution that the state has designated. All 50 states and the District of Columbia sponsor at least 1 type of 529 plan.

The main advantage to these plans is that earnings are not subject to federal tax—and generally not sub-

ject to state tax—when the designated beneficiary uses the money for “qualified higher education expenses” (eg, tuition, fees, books, room and board). If you make a nonqualified withdrawal (ie, a withdrawal used for something other than the beneficiary’s qualified higher education expenses), then the earnings portion of the withdrawal will be taxed at the federal level at the rate of the person who receives the distribution (usually the account owner). State taxes will likely apply in addition to a penalty; specifically, the earnings portion of the withdrawal will be subject to a 10% federal penalty.

The majority of plans are open to residents of any state. This means you can shop for the plan with the best money manager, overall performance record, investment options, fees, and customer service. Keep in mind, however, that many states limit their tax benefits to residents who participate in an in-state college savings plan.

Opening a 529 plan is simple: complete a short application, designate a beneficiary, and contribute the required minimum amount. Most plans also offer automatic deductions or electronic fund transfers to make future saving even easier. Once the account is open, you or anyone else can contribute as much money to the account as you wish, subject to the plan’s specific limits. Some plans may require a minimum amount to open the account, have a minimum amount for each contribution, or restrict the total contributions allowed per year. All plans have total lifetime contribution limits; however, most states generally have limits in excess of $300,000.

You can roll over your existing college savings plan account to a new 529 plan account once every 12

W. Ben Utley

Lawrence B. Keller

months without any federal tax penalty and without having to change the beneficiary. There may be state income tax consequences (and, in some cases, state-imposed penalties) that result from such a rollover. This option lets you leave a plan with few investment choices or one that has earned poor returns for a plan with more investment flexibility or a better track record. If you are satisfied with the plan but want to change the way your existing assets are invested, this can be done twice each calendar year, or whenever the account beneficiary changes. You do have the ability to change how your future contributions are allocated at any time.

If your child receives a college scholarship, you can withdraw money without penalty as long as your withdrawals during the year don’t exceed the annual scholarship amount. However, you will owe federal and state income taxes on the earnings portion of each withdrawal.

If the beneficiary doesn’t use the money in the account for college, you can use the savings for graduate school or other higher education later, transfer the balance without penalty to another eligible family member (including a parent, step-sibling, half-sibling, or, in some cases, an inlaw of the original beneficiary), or simply make a nonqualified withdrawal as described earlier.

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Wealth Management

How to Choose a 529... Continued from page 23 Section 529 plans yield another valuable break: estate taxes. Contributions to the plan are considered a completed gift under estate tax code, so your contribution qualifies for the $14,000 annual gift tax exclusion amount. In fact, you can contribute up to $70,000 per child and then elect to treat the contribution as if it were made over a 5-year period. This means a physician’s family with 2 children could move as much as $280,000 into the plan, and out of their estate, in a year.

Now that you understand the basics, let’s look at the steps you will need to take as you do your financial planning for college.

1

Determine whether your state offers a tax advantage for 529 plan contributions. Colorado, Georgia, Idaho, Iowa, Kansas, Louisiana, Maryland, Michigan, Mississippi, Missouri, Montana, Nebraska, New Mexico, New York, Ohio, Oklahoma, Oregon, Rhode Island, South Carolina, Utah, Virginia, West Virginia, and Wisconsin offer tax benefits for 529 contributions made by taxpayers residing in those states.

you forgot (or didn’t know) to make a contribution last year.

3

Research investment results and expenses for in-state and out-of-state plans. If your state offers a tax break for 529 plan contributions, it might seem like this is the best option. But what if the performance of your state’s plan is poor? The cost of lower returns may outweigh the benefit of the tax break, so do a little digging and run a quick calculation.

The majority of plans are open to residents of any state. This means you can shop for the plan with the best money manager, overall performance record, investment options, fees, and customer service.

4

Calculate the performance gap: this is the difference in total return between your in-state plan and the out-of-state plan.

2

Learn how your state’s tax break works. Contact your tax specialist and ask these 3 questions: • How much money do I need to contribute to my state’s 529 plan to get the maximum tax benefit?

• How much will I save in taxes when I make my contribution?

• What is the deadline for making a contribution?

Note that some states will only allow you to deduct calendar year contributions from your tax return, while others will allow you to contribute up until the time your return is filed (as is the case with IRA contributions). If you discover this article in March, this means you might still have a chance to save taxes if

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Think about the amount of money you will have in the plan.

If you are targeting a 4-year private university at a cost of $200,000 per student, and your family has nothing saved today, the average balance between now and then will probably be about $100,000.

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Calculate the opportunity cost of using the in-state plan: multiply the average amount you’ll have invested by the performance gap.

Amount Invested × Performance Gap = Opportunity Cost

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7

Let the opportunity cost help you choose your plan. If the tax benefit outweighs the opportunity cost, consider using your state’s plan.

If the opportunity cost is much larger than the tax benefit, then the out-ofstate plan might be a better choice.

We say “might be” because there’s one more thing you need to consider as you choose your plan: asset protection. Some state plans confer a measure of protection against the claims of creditors, and in some states this protection only extends to physicians who live in that state and contribute to the in-state 529 plan. The law on this issue varies from state to state, so you might want to seek legal counsel if you are at all concerned about the protections your plan may (or may not) afford.

Joseph F. Hurley, CPA, founder of www.savingforcollege.com and the nation’s expert on saving for college, hails the 529 plan as the best way to save for college. Even though the tax benefits, creditor protection, and kid-friendly usability were intended for everyone’s benefit, these features make 529 plans the best way for families of physicians to save for college, too. Choosing the right 529 plan is not as easy as it appears, but these steps will help you make the right choice for your family. l Lawrence B. Keller, CFP®, CLU®, ChFC®, RHU®, LUTCF, is the founder of Physician Financial Services, a New York–based firm specializing in income protection and wealth accumulation strategies for physicians. He can be reached by calling 516-677-6211 or by e-mail to Lkeller@physicianfinancialservices.com.

W. Ben Utley, CFP®, is the lead advisor with Physician Family Financial Advisors, a fee-only financial planning firm helping doctors throughout the United States to save for college and invest for retirement.

He can be reached by calling 541-463-0899 or by e-mail to ben@physicianfamily.com.

Clinical Trial Tracker

Clinical Trials for Prostate Cancer, Overactive Bladder

T

he following clinical trials are currently recruiting patients with urologic conditions for inclusion in several investigations.

Each trial description includes the NLM Identifier to use as reference with ClinicalTrials.gov.

Prostate Cancer

1

Radiation With or Without Androgen Deprivation Therapy This phase 3, parallel-assignment, open-label study examines the effectiveness of radiation therapy when it is given with or without androgen deprivation therapy comprising a lutein­ izing hormone-releasing hormone (LHRH). Patients aged ≥18 years with prostate cancer may enroll if other criteria are met. Patients are randomized to receive (1) external-beam radiation therapy once daily on days 1 to 5 or (2) an LHRH agonist subcutaneously or as an injection every 1 to 3 months with oral flutamide or bicalu­tamide for 6 months. Beginning 8 weeks after the first LHRH injection, patients will undergo radiotherapy as in the non-LHRH group.

The primary objective is overall survival (OS), measured from the date of randomization to the date of death due to any cause. Secondary outcome measures include biochemical failure, local or regional disease recurrence, and distant metastasis. This study is expected to enroll 1520 patients at sites throughout the United States. For more information, contact Alvaro Martinez, MD, FACR, at 248-5530606 or alvaro.martinez@rtsx.com.

The NLM Identifier is NCT00936390.

2

Safety and Efficacy of Enzalutamide This phase 3, parallel-assignment, double-blind study assesses the safety and efficacy of enzalutamide in patients with nonmetastatic prostate

cancer. Patients aged ≥18 years who have ongoing androgen deprivation therapy with a gonadotropin-releasing hormone agonist/antagonist or prior bilateral orchiectomy may enroll if other criteria are met. Patients are randomized to placebo or 160 mg of enzalutamide daily.

The primary outcome measure is metastasis-free survival. Secondary outcome measures include OS, time to pain progression, or time to opiate use for prostate cancer pain. Time to first use of cytotoxic chemotherapy or new antineoplastic therapy, and time to prostate-specific antigen (PSA) progression are also collected. This study is expected to enroll 1560 patients at sites throughout the United States. For more information, contact Mohammad Hirmand, MD, at 415543-3470 or mohammad.hirmand@ medivation.com, or Kristina Wilson at 415-543-3470 or kristina.wilson@ medivation.com. The NLM Identifier is NCT02003924.

survival (PFS), and duration to PSA progression and skeletal-related events. This trial is expected to enroll 1170 patients at several sites throughout the United States. For more information, contact Richard Kapsa at kapsa@sotio.com. The NLM Identifier is NCT02111577.

4

Enzalutamide and Mifepristone This phase 1/2 trial studies the side effects, efficacy, and best dose of enzalutamide and mifepristone combination therapy. Patients aged ≥18 years with metastatic hormone-resistant prostate cancer, an Eastern Cooperative Oncology Group performance status of ≤2, and evidence of castrate testosterone levels at <50 ng/dL may enroll if other criteria are met. Patients are randomized to receive either enzalutamide alone or in combination with mifepristone.

Primary outcomes are the recommended phase 2 dose, defined as the highest mifepristone dose in combination with enzalutamide, and PFS. Secondary outcome measures include OS, radiographic PFS, pharmacokinetic parameters of the 2 drugs, and the androgen and glucocorticoid receptors’ expressions within circulating tumor cells. This study is expected to enroll 108 patients in Chicago, IL. For more information, contact Kelly O’Connor at 773-7024653 or koconnor@medicine.bsd. uchicago.edu. The NLM Identifier is NCT02012296.

3

DCVAC Added to Standard Chemotherapy The objective of this phase 3, parallel-assignment, double-blind study is to determine whether DCVAC/PCa added to standard-ofcare chemotherapy can improve survival times for patients with metastatic castration-resistant prostate cancer. Patients aged ≥18 years with disease progression despite androgen deprivation therapy, a life expectancy of ≥6 months, and an Eastern Cooperative Oncology Group performance status of 0 to 2 may enroll if other criteria are met. Patients are randomized to receive either DCVAC or placebo with standardof-care therapy consisting of docetaxel and prednisone.

The primary outcome is OS, measured over a time frame of 124 weeks.

Secondary outcome measures include radiographic progression-free

5

Enzalutamide plus Dutasteride as First-Line Treatment The objective of this phase 2, open-label, single-group assignment study is to determine the effect of enzalutamide and dutasteride on the time to PSA level increase. Patients aged 65 to 85 years with prostate cancer who have a serum testosterone level of >1.7 nmol/L at time of screening and an Eastern Cooperative OnContinued on page 26

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Clinical Trial Tracker

Clinical Trials for Prostate Cancer... Continued from page 25 cology Group performance status of 0 to 2 may enroll if other criteria are met. All patients will receive daily enzalutamide and dutasteride orally.

The primary outcome measure is PSA levels, measured from blood drawn every 6 weeks for 103 weeks.

This trial is expected to enroll 40 patients in Rochester, NY, and Milwaukee, WI. For more information, contact Chunkit Fung, MD, at 585-275-9319 or chunkit_fung@urmc.rochester.edu, or Ayesha Khan at 585-275-3351 or ayesha_khan@urmc.rochester.edu.

The NLM Identifier is NCT02213107.

FACP, at 877-275-7724 or askrpci@ roswellpark.org. The NLM Identifier is NCT00536991.

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Calcitriol, Ketoconazole, and Hydrocortisone This single-arm, phase 1/2 trial studies the side effects, best dose, and efficacy of calcitriol when given in combination with ketoconazole and hydrocortisone in patients with advanced or recurrent prostate cancer. Patients aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0 to 2 or a Karnofsky performance score of 60% to 100%, a life expectancy >3 months, and hemoglobin ≥8 g/dL may enroll if other criteria are met. All patients will receive oral calcitriol daily according to protocol.

Patients will receive ketoconazole orally 3 times a day on days 1 to 24 and days 4 to 24 in phase 1 and 2 of the trial, respectively. Oral hydrocortisone is given in phase 1 of the trial only. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Primary outcome measures include the maximum tolerated dose of calcitriol as well as PSA response rate. Secondary outcome measures are toxicity and objective tumor response as measured by a monthly physical exam and radiographic evaluation every 12 weeks. This study is expected to enroll 51 patients in Buffalo, NY. For more information, contact Donald L. Trump, MD,

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Myrbetriq versus Detrol LA This phase 4, crossover-assignment, double-blind, safety and efficacy study assesses the tolerability of Myrbetriq compared with Detrol LA in patients with overactive bladder (OAB), defined as symptoms of urinary frequency and urgency with or without incontinence. Patients aged ≥18 years who have had OAB for ≥3 months and are treatment-naïve to pharmaceutical agents for OAB may enroll if they are willing to complete a micturition diary and questionnaires, and if other criteria are met. Patients are randomized to one of the following sequences: (1) Myrbetriq/Detrol LA, (2) Detrol LA/Myrbetriq, (3) Myrbetriq/Myrbetriq, or (4) Detrol LA/Detrol LA. The primary outcome measure is patient tolerability as assessed by the Tolerability Scale of Overactive Bladder-satisfaction (OAB-S) questionnaire at weeks 8 and 18. Secondary outcome measures include patient preference at week 18 based on a 5-point scale, scaled ratings from the OAB-S questionnaire assessed at weeks 8 and 18, and the change from baseline in the number of incontinence episodes and micturitions per 24 hours as assessed at weeks 8 and 18. This study is expected to enroll 360 patients at sites throughout the United States. For more information, contact Astellas Pharma Global Development at 800-888-7704, extension 5473, or astellas.registra tion@astellas.com. The NLM Identifier is NCT02138747.

8

Mirabegron in Older Adults This phase 4, parallel-assignment, double-blind trial assesses

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the safety, efficacy, and tolerability of mirabegron versus placebo in older patients with OAB. Patients aged ≥65 years who have had symptoms of wet OAB—ie, urinary frequency and urgency with incontinence—for ≥3 months may enroll if other criteria are met. Patients are randomized to mirabegron or placebo, and they may not participate in another interventional study from the time of screening until the final study visit.

Primary outcome measures are the change in mean number of micturitions and incontinence episodes per 24 hours based on a 3-day micturition diary, the change in the mean volume voided per micturition, and quality-of-life scores as assessed by questionnaire. The change in patient perception of his or her bladder condition is also measured. Data are collected at baseline and 12 weeks.

This study is expected to enroll 800 patients at sites throughout the United States. For more information, contact Astellas Scientific & Medical Affairs, Inc, at 800-8887704, extension 5473, or astellas. registration@astellas.com. The NLM Identifier is NCT02216214.

9

Urinary Incontinence in Pediatric Patients This phase 3, parallel-assignment, double-blind trial evaluates the safety and efficacy of onabotulinumtoxinA for the treatment of urinary incontinence due to OAB. Patients aged 12 to 17 years who have had OAB with urinary incontinence for ≥6 months and whose symptoms are not adequately managed with ≥1 anticholinergic agent may enroll if other criteria are met.

Patients will be randomized to 1 of 3 treatment drug doses. The experimental drug is injected into the detrusor wall of the bladder on day 1 and is readministered as needed at intervals of ≥12 weeks.

The primary outcome measure is

Clinical Trial Tracker

the change from baseline in the number of daily episodes of urinary incontinence. Secondary outcome measures include the change from baseline in number of daytime micturition and urgency episodes; the change from baseline to scores on the 20-Item Pediatric Incontinence Questionnaire; the percentage of patients with nighttime urinary incontinence and a positive treatment response on the modified treatment benefit scale; and the volume that is voided per micturition. The time to a patient’s request or qualification for retreatment is also assessed. This study is expected to enroll patients within the United States as well as internationally. For more information, contact Allergan, Inc, at clinic altrials@allergan.com. The NLM Identifier is NCT02097121.

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Urinary Incontinence in Adults This phase 4, parallel-assignment, double-blind study evaluates the efficacy and safety of onabotulinumtoxinA versus placebo in achieving a 100% reduction in urinary incontinence in patients with OAB. Patients aged ≥18 years who have had OAB with urinary incontinence for ≥6 months that is not properly managed with an anticholinergic may enroll if other criteria are met. Patients are randomized to receive either onabotulinumtoxinA or placebo (normal saline) injected into the detrusor wall of the bladder on day 1, followed by an injection of onabotulinumtoxinA after ≥12 weeks. The second injection is provided as needed.

Primary outcome measures are (1) the percentage of patients who achieve a 100% reduction in urinary incontinence, and (2) the change from baseline in the number of episodes of urinary incontinence; measures are assessed at baseline and week 12. Secondary outcome measures include the number of micturitions, daily urgency episodes, and

istered alone or a placebo in the treatment of patients with OAB. Patients aged ≥18 years who have had symptoms of urinary frequency and urgency with incontinence for ≥3 months may enroll if they are able to (1) complete a micturition diary and questionnaires, (2) measure their vital signs at home at stipulated time points, and (3) meet other inclusion and exclusion criteria.

Patients are randomized to receive solifenacin succinate–mirabegron combination therapy, either medication alone, or a placebo.

Primary outcome measures are the change from baseline in the mean number of incontinence episodes and micturitions per 24 hours at the end of treatment. Secondary outcome measures are the change in the mean volume voided per micturition, symptom bother as assessed by questionnaire, and patient satisfaction. These end points are collected at baseline and 12 weeks. This trial is expected to enroll 3392 patients at sites throughout the United States.

For more information, contact Global Clinical Science at astellas. registration@astellas.com. The NLM Identifier is NCT01972841.

nocturia episodes at week 12. This investigation is expected to enroll 258 patients in Shreveport, LA, and Mountlake Terrace, WA. For more information, contact Allergan, Inc, at clinicaltrials@allergan.com. The NLM Identifier is NCT01945489.

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Fesoterodine in Children Aged 6 to 17 Years This phase 3, parallel-assignment, open-label, safety and efficacy study will assess whether fesoterodine is a useful treatment in children with bladder muscle overactivity caused by a neurological condition. Patients aged 6 to 17 years may enroll if they have stable neurological disease and stable neurogenic detrusor overactivity, if other criteria are met. Patients will be randomized to receive fesoterodine PR 4 mg or 8 mg, oxybutynin extended release, or fesoterodine BIC 2 mg or 4 mg.

The primary outcome measure is maximum cystometric bladder capacity. Secondary outcome measures include detrusor pressure at maximum bladder capacity, the presence of involuntary detrusor contractions, bladder volume at first involuntary detrusor contraction, and bladder compliance. The mean number of micturitions and/or catheterizations per day, incontinence episodes per day, and urgency episodes per day, and the mean volume voided per micturition or catheterization are also measured. All end points are assessed over a time frame of 12 weeks. This trial is expected to enroll 132 patients at locations throughout the United States. For more information, contact Pfizer’s clinical trials call center at 800-718-1021. The NLM Identifier is NCT01557244.

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Oxybutynin Topical Gel in Pediatric Patients This phase 4, parallel-­ group, double-blind study evaluates the safety and efficacy of oxybutynin topical gel in children with neurogenic OAB. Patients aged 6 to 16 years may enroll if they are diagnosed with neurogenic bladder and meet additional criteria. Patients will receive either 10% oxybutynin chloride topical gel or placebo. The primary outcome is the percentage of catheterizations without a leaking accident over a time frame of 6 weeks. The trial is expected to enroll 96 patients at sites throughout the United States. For more information, contact Jaime May at 201-427-8853 or jaime.may@frx. com, or Branka Palic at 973-659-2171 or branka.palic@actavis.com. The NLM Identifier is NCT01192568. l

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Solifenacin Succinate and Mirabegron This phase 3, parallel-assignment, double-blind study examines the effectiveness of solifenacin succinate–mirabegron combination therapy versus either medicine adminFebruary 2015

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ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information].

In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ZYTIGA® (abiraterone acetate) Tablets ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

• Increased ZYTIGA Exposures with Food [see Warnings and Precautions].

Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia,

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Musculoskeletal discomfort, and Musculoskeletal stiffness terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 4 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo.

The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%).

Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine).

If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

Based on its mechanism of action, ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.

• Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.

• Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information.

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: May 2014 015924-140528

INDICATION and IMPORTANT SAFETY INFORMATION about ZYTIGA® (abiraterone acetate) INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

IMPORTANT SAFETY INFORMATION

003307-130924

Contraindications ZYTIGA® (abiraterone acetate) is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI) AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Increased ZYTIGA® Exposures with Food ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10- fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adverse Reactions The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Drug Interactions Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Use in Specific Populations Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

Please see Brief Summary of Prescribing Information on adjacent pages. © Janssen Biotech, Inc. 2014

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006076-141015

Our goal is to help make access to ZYTIGA®(abiraterone acetate) easy.

Support for you: 4-6

Support for your patients:

Rapid investigation and assessment of patient eligibility and coverage • Prior authorization support • Information on cost support options, including updates on independent foundation funding status • Electronic enrollment through an online portal • Identification of a Specialty Pharmacy Provider (SPP) • Access to medication order information • A personally-assigned Site Coordinator Business Hours

• Explanation of benefits from a personally-assigned Care Coordinator • Referral to cost support options, including the ZytigaOne® Instant Savings Program for eligible patients • Upon request, follow-up status calls to those referred for cost support • Coordination with SPP for processing and delivery of medication • Educational materials and personalized prescription reminders, if requested

Take advantage of ZytigaOne® Support today.

1-855-ZYTIGA-1 (998-4421) Monday–Friday, 8:00 AM–8:00 PM ET

ACCESS TO ZYTIGA® SIMPLIFIED FOR YOU AND YOUR PATIENTS More information at ZYTIGAHCP.com

Please see Important Safety Information on back, and Brief Summary of Prescribing Information on adjacent pages.

Patient insurance benefit investigation is provided as a service by The Lash Group, Inc., under contract for Janssen Biotech, Inc. In this regard, The Lash Group, lnc., assists healthcare professionals in the determination of whether treatment could be covered by the applicable third-party payer based on coverage guidelines provided by the payer and patient information provided by the healthcare provider under appropriate authorization following the provider’s exclusive determination of medical necessity. This reimbursement support service has no independent value to providers apart from the product and is included within the cost of the product.

Importantly, insurance verification is the ultimate responsibility of the provider. Third-party reimbursement is affected by many factors. This document is presented for informational purposes only and is not intended to provide reimbursement or legal advice and does not promise or guarantee coverage, levels of reimbursement, payment or charge. Similarly, all CPT and HCPCS codes are supplied for informational purposes only and represent no promise or guarantee that these codes will be appropriate or that reimbursement will be made. It is not intended to increase or maximize reimbursement by any payer. Laws, regulations and policies concerning reimbursement are complex and are updated frequently. While we have made an effort to be current as of the issue date of this document the information may not be as current or comprehensive when you view it. We strongly recommend you consult with your counsel, payer organization, or reimbursement specialist for any reimbursement or billing questions. While The Lash Group, Inc., attempts to provide correct information, they and Janssen Biotech, Inc., make no representations or warranties, expressed or implied, as to the accuracy of the information. In no event shall The Lash Group, Inc., Janssen Biotech, Inc., or its employees or agents be liable for any damages resulting from or relating to the services. All providers and other users of this information agree that they accept responsibility for the use of this service. © Janssen Biotech, Inc. 2014 11/14 006076-141015