Circuit Newsletter September 2014

September 2014 We are Epic Pharmacy For the best part of 28 years we have been APHS or Australian Pharmaceutical Healthcare Systems.

This is the name under which we have delivered a service we are truly proud of; a service focused on best outcomes for our partners and their clients. But APHS as a name has never encapsulated the spirit of our organisation, it is a healthcare acronym that’s easily lost in the crowd. And that’s why on September 9, we launched our new brand and will commence a future with a name that truly reflects our spirit and ambitions — Epic Pharmacy.

Epic is a word that’s really important to us. It relates back to our four company values: Energy, Purpose, Innovate and Connect. Our people live and breathe these values and strive to meet them in every facet of their working life. Epic is in our DNA and future; a future focused on engaging our partners and customers with an epic service and epic digital healthcare solutions.

We are an organisation with a spirit like no other.

We’re a healthcare company that promises to deliver healthcare in an Epic way. We can’t wait to show you our new look as we transition to Epic Pharmacy.

This will be commencing from January 2015.

For now here is a sneak-peak at our bright, bold new look and uniforms.

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If you have any queries regarding Circuit content and authors please contact the APHS Pharmacy Practice Unit by email: circuit.editor@aphs.com.au Every effort has been made to ensure this newsletter is free from error or omission.

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clinical initiatives, research and current updates in treatment Pharmacological Management of Castration-Resistant Prostate Cancer Mina Kirollos and Jordan Hamlet APHS Pharmacy Toowoomba Diagnoses of prostate cancer have doubled between 1998 and 2008 and, by 2020, reported cases are likely to be 50% higher than current levels.1 Prostate cancer (PCA) is the most common cancer amongst Australian men (excluding non-melanoma skin cancers) and accounts for around 30% of all new cancers diagnosed.1 PCA is the second most common cause of cancer death after lung cancer.2 Compared with other cancers, sufferers of prostate cancer have a relatively good five year survival rate at 92%.1 As a result the number of patients in Australia living with PCA is around 120,000 but could rise to 267,000 by as soon as 2017.1 Pharmacological management of prostate cancer initially involves reducing circulating testosterone levels commonly known as androgen deprivation therapy (ADT) or chemical castration. This is usually achieved through the use of luteinising hormone releasing hormone agonists such as goserelin or leuprorelin. This can also be achieved surgically.

Despite these treatments, overtime cancer cells can survive and flourish and disease progression can become androgen independent. It is thought that, following androgen deprivation therapy, circulating testosterone can remain at around 10% of normal levels as a result of adrenal steroid conversion. Additionally, tissue levels of androgen may be sufficient to stimulate androgen receptors and an increased expression of the androgen receptor may also lead to what is now termed castration-resistant prostate cancer. Previous terms such as hormone-refractory or androgen-independent have been recently superseded.5 Castration-resistant prostate cancer can be defined as disease progression despite ADT and may present as one or any combination of, a continuous rise in serum levels of prostate-specific antigen (PSA), progression of pre-existing disease or the appearance of new metastases.3 Although most men are diagnosed in the early stage of disease, the inevitable progression to metastatic castrate resistant prostate cancer (mCRPC) is associated with poor prognosis and survival of 8-16 months.5 Therapies aimed at prolonging survival Cytotoxic therapies For more than 40 years it was thought that mCRPC was resistant to chemotherapy.

First-line cytotoxic therapy is usually with docetaxel, a taxane that binds and stabilises tubulin, inducing cell–cycle arrest and inhibiting cell proliferation.6 Docetaxel given three weekly with prednisone has proven benefits over mitozantrone including superior survival and response rates in terms of pain, serum PSA level and quality of life.6

Recently at the American Society of Clinical Oncology Annual Scientific Meeting (June 2014), the results of the “CHAARTED” trial were presented. This trial examined introducing docetaxel earlier: at the commencement of ADT before the cancer becomes castrate-resistant. Overall survival (OS) in the study population was significantly improved, with a median survival of 57.6 months for the docetaxel plus ADT group versus 44.0 months for the ADT alone group.12 That is an improvement in median survival of 13.6 months, far more than what is seen when docetaxel is used in the castrate-resistant setting.12 Currently docetaxel is only PBS-reimbursed in castrate-resistant disease.

Cabazitaxel is another taxane that has recently shown improved OS compared with mitozantrone (15.1 vs. 12.7 months) in patients for whom prior treatment with docetaxel has failed.7 This validates the cancer cell’s microtubule as a target for future therapies. Progression-free survival was almost doubled with cabazitaxel over mitozantrone (2.8 vs. 1.4 months).7 However, recipients of cabazitaxel experienced significant toxicities compared with mitozantrone: diarrhoea (6% vs. <1%), neutropenia (82% vs. 58%), febrile neutropenia (8% vs. 1%), and toxic death (4.9% vs. <1%).7 New Hormonal therapies Patients whose disease progressed on ADT were long thought to be unresponsive to further hormone therapy. Scientific data has demonstrated the tumour’s ability to activate the androgen receptor via many mechanisms including overexpression, extragonadal production of androgens, mutation and androgen-receptor amplification. More potent suppression of androgen receptor signalling is now an important therapeutic target.6 Abiraterone is an irreversible inhibitor of an enzyme that is critical in the production of extragonadal and testicular androgen synthesis. Inhibition of this enzyme also leads to reduced cortisol production and associated problems.7 To supplement endogenous cortisol, a daily dose of 10mg of prednisone/prednisolone (usually as 5mg twice daily) is given during abiraterone therapy.7 The COU-AA-301 study evaluated abiraterone against placebo in a post-docetaxel mCRPC cohort. Its endpoints were a median OS of 14.8 months compared with 10.9 months for the placebo. Also a significantly higher PSA response rate (total – 38.5% vs 10.1%) was seen in the abiraterone arm of COU-AA-301.7 Abiraterone is an oral tablet taken once daily on an empty stomach. This is important as co-administration with food has been associated with up to a 17-fold increase in plasma concentration over fasting administration levels.8 Side effects most commonly seen were related to mineralocorticoid excess: hypokalemia, hypertension, and fluid retention.9 Currently abiraterone is PBS-listed for mCRPC post-docetaxel failure as monotherapy with prednisone/prednisolone.

A more recent study (COU-AA-302) has evaluated abiraterone usage in chemonaïve patients.9 Asymptomatic mCRPC patients may be reluctant to receive cytotoxic therapy but a less toxic oral option may be more appealing. Mean progressionfree survival was 16.5 months for abiraterone plus prednisone compared with 8.3 months for placebo plus prednisone.9 Abiraterone plus prednisone showed superiority over prednisone alone with respect to time to initiation of cytotoxic

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September 2014

chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status.9 Abiraterone therapy before chemotherapy is TGA approved but not currently PBS subsidised but is subsidised by the drug sponsor whilst it is being considered for PBS subsidy for this indication.

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Enzalutamide = 18.4 Placebo = 13.6 HR = 0.63 (p<0.001)

Enzalutamide is an oral, androgen receptor (AR) inhibitor that targets multiple steps in the androgen-receptor-signalling pathway. As illustrated in Figure 1, when enzalutamide binds to the receptor, it decreases nuclear translocation, impairs AR binding to DNA and co-activators, then blocks cell proliferation.7,10 It also induces tumour cell apoptosis, and has no agonist activity.7

In the pre-chemotherapy setting, the PREVAIL trial demonstrated that enzalutamide significantly reduced the risk of death by 29% and slashed the risk of radiographic progression or death compared with placebo by 81%.11 Arguably the most impressive finding was enzalutamide’s ability to delay the median time to initiate cytotoxic chemotherapy by 17 months (28 months vs 10.8 months with placebo).11 Adverse events that occurred more frequently with enzalutamide versus placebo included all-grade fatigue (36% vs. 26%), back pain (27% vs. 22%), constipation (22% vs. 17%), and arthralgia (20% vs. 16%).11 Future directions in therapy Multiple new agents have been shown to improve survival in mCRPC, and new discoveries surrounding the timing of docetaxel treatment has led to questions regarding the best way to sequence these new agents and our current treatments.

Choice and sequence of agents depends on multiple factors (e.g. symptoms, toxicity profile in relation to the patient condition and previous treatments).

Currently no head to head trials exist directly comparing these newer agents. The optimal time to administer abiraterone remains unclear: while currently limited to post-docetaxel administration, the COU-AA-302 trial suggests abiraterone is of benefit before chemotherapy.7 Enzalutamide has recently been approved in Australia in the post-docetaxel setting and whilst not currently PBS-subsidised, it is available compassionately to eligible patients. Questions surrounding its sequencing remain unanswered. Docetaxel and ADT together may yet become a mainstay of therapy. Given these relatively rapid advances in treatment options for mCRPC, once these outstanding questions are resolved there will be a need for clear guidelines to optimise patient outcomes.

Androgen receptor (AR)

Testosterone

AR after conformational change due to testosterone or bicalutamide binding

Bicalutamide

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Bone Health in Cancer Chris Henry, APHS Holy Spirit Northside Hospital Pharmacy Bone is a dynamic tissue that is remodelled constantly throughout life. Remodelling is accomplished by two distinct cell types: osteoblasts which produce the bone matrix, and osteoclasts which reabsorb or break down the bone matrix.1 Bone metastases can cause symptoms that negatively impact patient quality of life, including pain (particularly with motion) as well as a number of complications, collectively referred to as skeletal related events (SREs). These include fractures, loss of skeletal integrity and spinal cord compression. SREs are a major contributor to morbidity in cancer, often requiring pharmacological or surgical treatment.3 Hypercalcaemia can also occur in metastatic bone disease as large amounts of calcium are liberated from bone and introduced into the circulation during the degradation process. Hypercalcaemia is considered a medical emergency and patients with hypercalcaemia can present with polyuria, polydipsia, dehydration, anorexia, nausea and muscle weakness.

These symptoms may further progress to more significant events requiring urgent intervention (such as kidney stones, seizures or coma).10 The timely management of bone metastases is a critically important factor in the care of patients with metastatic cancer and bone involvement.

60 OS (%)

In 2012, enzalutamide was approved by the FDA in the post-docetaxel setting based on results from a placebo-controlled phase III trial (AFFIRM). The median OS was 18.4 months with enzalutamide versus 13.6 months with placebo (see Figure 2), representing a 37% reduction in risk of death.7

Median OS (months)

40

20

0 0

3

6

9

12

15

18

21

24

Months Figure 2 Survival benefit of enzalutamide in post chemotherapy mCRPC (The AFFIRM Study)13

References available on request.

Enzalutamide

1. Enzalutamide inhibits AR-testosterone binding with higher affinity than bicalutamide.

2. Enzalutamide receptor inhibition blocks the activational change induced by AR-testosterone binding.

3. Enzalutamide inhibits AR-testosterone nuclear translocation and DNA transcription

4. Enzalutamide lacks partial AR agonist activity that occurs with bicalutamide resistance.

The treatment of bone metastases requires a co-ordinated approach between a range of medical specialties (surgical, medical oncology, radiation oncology and palliative care) and allied health providers to ensure optimised patient outcomes. Management strategies include the use of chemotherapy, radiation therapy, bone targeting drugs, surgical fixation and supportive care interventions (analgesia).4 Currently, a number of drugs are available in Australia which target the bone degradation process to reduce bone loss and subsequent complications.

Denosumab (Xgeva©) is a human monoclonal antibody which binds to the RANK ligand (the essential regulator of osteoclast formation, function and survival).5 It inhibits osteoclast activity in the bone, inhibiting bone resorption and increasing the structural integrity of the bone. Denosumab is given by subcutaneous injection once every four weeks. Currently, the PBS restricts the use to the treatment of giant cell tumour of the bone or treatment of bone metastases in patients with breast cancer or castration-resistant prostate cancer.6 Bisphosphonates are a group of drugs that decrease bone resorption by inhibiting osteoclastic activity.5 Zoledronic acid (Zometa©) is administered by intravenous infusion over at least 15 minutes once every three to four weeks and is the most potent bisphosphonate available.5 Currently, the PBS restricts the use of zoledronic acid to the treatment of multiple myeloma, the treatment of bone metastases due to breast cancer or castration-resistant prostate cancer and the treatment of hypercalcaemia of malignancy refractory to antineoplastic therapy.7 Pamidronate (Aredia© or Pamisol©) is administered by intravenous infusion over two to four hours once every three to four weeks.5 The PBS limits the use of pamidronate to the treatment of multiple myeloma, the treatment of bone metastases caused by breast cancer and hypercalcaemia of malignancy refractory to anti-neoplastic therapy.7 Ibandronic acid (Bondronat©) is administered by intravenous infusion over at least 15 minutes once every four weeks.5 Alternatively, the oral tablets can be taken once daily (with a full glass of water, at least 30 minutes before food or other oral medications).5 The PBS restricts the use of ibandronic acid to bone metastases due to breast cancer.7 Clodronate (Bonefos©) is taken orally once daily (with a full glass of water, at least one hour before or two hours after food or other medicines).5 Under the PBS it has restricted the use of clodronate to maintenance treatment of hypercalcaemia of malignancy refractory to anti-neoplastic therapy, treatment of multiple myeloma and treatment of bone metastases due to breast cancer.7 Denosumab is generally considered the first line choice and zoledronic acid the first alternative for patients with bone metastases from breast or prostate cancer.9 These drugs are both easily administered once per month and are reasonably well tolerated by patients.5

For patients who require bone targeting drugs, pre-existing hypocalcaemia and/or vitamin D deficiency should be corrected prior to treatment and patients should be counselled regarding adequate intake of calcium and vitamin D.9 The optimal dose of calcium and vitamin D supplementation is unclear; however current Australian Ttherapeutic Gguidelines recommend 600 mg of elemental calcium and 1000-2000 international units of cholecalciferol (vitamin D) daily.8 One rare but serious complication of bone targeting drugs is osteonecrosis of the jaw (ONJ).8 ONJ can occur in patients receiving intravenous bisphosphonates or denosumab.8 An assessment of dental hygiene is recommended before starting treatment with any bone targeting drug, however a formal examination by a dentist is not required.8 The risk of ONJ is increased after dental extractions and in those with periodontal disease. It is recommended that, if possible, dental treatment should be completed before starting bisphosphonate or denosumab therapy.8 In addition, all patients should be counselled to follow up with a dental provider at regular intervals to ensure oral health is maintained.9 Skeletal bone is a common site of metastatic spread in cancer. The pathological activation of bone reabsorbing cells leads to accelerated bone loss and a variety of detrimental events. Health professionals caring for patients with metastatic disease should be aware of the consequences of bone metastases and common treatment options. Bone targeting drugs like zoledronic acid and denosumab are effective in preventing SREs, but it is important to be aware of the rare association with ONJ.

References available on request.

New Drug brief: Mirabegron Stefan Sieradzan, APHS Pharmacy Port Macquarie Mirabegron is a beta-3-adrenoceptor agonist, which acts to relax the detrusor smooth muscle, thereby affecting urine storage in the bladder. It is selective for beta-3 receptors, improving bladder storage capacity without affecting other systems.1 The clinical indication for mirabegron is “overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.”1,2,3 Mirabegron has produced positive results in three double-blind randomised studies.2 Its pharmacokinetic and pharmacodynamic parameters show significant inter-individual variability, but the therapeutic window is wide.

Dosing should commence at 25mg daily for eight weeks (regardless of age), at which point 50mg may be considered.2,3 Patients with mild-moderate renal or hepatic impairment should not exceed 25mg daily, however no recommendations exist regarding patients with severe impairments, children or pregnant/breastfeeding individuals.2,4,5 QT prolongation, bladder obstruction and hypertensive states are all issues to consider before prescribing.2 The tablets can be taken regardless of food and should be swallowed whole.2 It is intended as monotherapy.6 Mirabegron’s most common side effects are hypertension (9-11%), UTI (3-6%), nasopharyngitis (4%) and headache (4%).1 Moderate CYP2D6 inhibitor, increasing plasma concentrations (and hence side effects) of other CYP2D6 substrates. It is also a weak CYP3A4 inhibitor, increasing the exposure of other CYP3A4 substrates.1,2,3,5 First-line treatment is still oxybutynin or solifenacin.7 Patients should always be counselled on bladder training, avoiding irritants and preventing constipation.8

References available on request.

Figure 1 Enzalutamide Mechanism of Action10

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