UROLOGIE

CENTRUM UROLOGIE

ARTIKELS

ABSTRACT 1

Treatment of patients with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) in Belgium: a real world data analysis

Lambert E, Hollebosch S, Van Praet C, Van Bruwaene S, et al. Acta Clinica Belgica, 2021, doi: 10.1080/17843286.2021.2001999

ABSTRACT Abiraterone acetate + prednisone (AAP) and docetaxel have proven their efficacy in the treatment of patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) in clinical trials. However, real-world data are scarce.

The goal of this study is to evaluate real-world data on the efficacy and safety of these therapies in mHSPC patients. Records of 93 patients from 21 different centres were retrospectively reviewed. Primary and secondary endpoints were radiographic and PSA progression-free survival (RPFS – PSA-PFS) and cancer specific and overall survival (CSS – OS), respectively. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Differences in oncological outcome and AEs were evaluated between three treatment groups: ADT only (N=26) – ADT + AAP (N=48) – ADT + docetaxel (N=19). Survival analysis was performed using Kaplan–Meier statistics. Median RPFS was 13 months (95% confidence interval [CI]: 9–17) for ADT only, 21 months (95% CI: 19–23) for ADT + AAP and 12 months (95% CI: 11–14) for ADT + docetaxel (p = 0.004). The 1-year PSA-PFS, CSS and OS were 73.5%, 90.7% and 88.7%, respectively, with no significant differences between the three groups. Adverse events of grade 3 or higher were not observed more frequently.

Retrospective real-world data show a significantly longer RPFS for mHSPC patients treated with ADT + AAP compared to ADT only or ADT + docetaxel at short-term follow-up. This can aid in counselling of mHSPC patients in daily clinical practice. ABSTRACT 2

Multicentric prospective local treatment of metastatic prostate cancer (LoMP study)

Buelens S, Poelaert F, Claeys T, Billiet I, et al. BJU International, 2021, doi: 10.1111/bju.15553

ABSTRACT To investigate the role of cytoreductive radical prostatectomy in addition to standard of care for patients with newly diagnosed metastatic prostate cancer.

This multicentre, prospective study included asymptomatic patients from 2014 to 2018 (NCT02138721). Cytoreductive radical prostatectomy was offered to all fit patients with resectable tumours, resulting in 40 patients. Standard of care was administered to 40 patients who were ineligible or unwilling to undergo surgery. The primary endpoint was castration resistant cancer-free survival at the time point of ≥50% events.

The secondary endpoint was local event-free survival. Kaplan–Meier and Cox regression analyses with propensity-score analysis were applied. After a median (quartiles) follow-up of 35 (24–47) months, 42 patients became castration-resistant or died. The median castration resistant cancer-free survival was 53 (95% confidence interval [CI] 14–92) vs 21 (95% CI 15–27) months for cytoreductive radical prostatectomy compared to standard of care (P = 0.017). The 3-year estimates for local event-free survival were 83% (95% CI 71–95) vs 59% (95% CI 51–67) for cytoreductive radical prostatectomy compared to standard of care (P = 0.012). However, treatment group showed no significance in the multivariable models for castration resistant cancer-free survival (P = 0.5) or local event-free survival (P = 0.3), adjusted for propensity-score analysis. Complications were similar to the non-metastatic setting. Patients undergoing surgery were younger, with lower baseline prostate-specific antigen levels, alkaline phosphatase levels and metastatic burden.

The present LoMP study was unable to show a difference between the two inclusion groups regarding castration resistant cancer-free survival for asymptomatic patients with newly diagnosed metastatic prostate cancer. These results validate previous evidence that, in well-selected and informed patients, cytoreductive radical prostatectomy is feasible and safe, with corresponding continence rates compared to the non-metastatic, high-risk setting.

Whether cytoreductive radical prostatectomy could be a valuable option to achieve good local palliation needs to be further researched. Overall, the role of cytoreductive radical prostatectomy needs to be further explored in randomized studies to correct for potential bias.

PRESENTATIES/ CONGRESSEN

ABSTRACT 1

Hormone treatment–related adverse events with darolutamide in patients with nonmetastatic castration-resistant prostate cancer from the phase 3 ARAMIS study

Fizazi K, Shore, N, Smith M, Werbrouck P July 2021, Virtual

ABSTRACT Darolutamide is a structurally distinct and highly potent androgen receptor inhibitor (ARI) that has been demonstrated to significantly prolong metastasis-free survival and overall survival in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the phase 3 ARAMIS trial. Darolutamide improved MFS by almost 2 years and reduced the risk of death by 31% compared with placebo.

Men with nmCRPC are generally asymptomatic from their cancer, but they may experience cancer treatment-related adverse events (AEs) that can affect daily life. Darolutamide has a consistently favorable safety profile, with discontinuation rates due to AEs similar between darolutamide (8.9%) and placebo (8.7%) groups. Hormone treatment–related (HTR) AEs include fatigue, memory impairment, hypertension, falls, fractures, hot flush, gynecomastia, erectile dysfunction, anemia, diabetes, cardiac disorders, weight gain, and dyslipidemia.

Here, we present HTR AEs for darolutamide treatment and characterize their onset and occurrence over time versus placebo. ARAMIS was a global, multicenter, double-blind, randomized, phase 3 trial of darolutamide 600 mg twice daily (n=955) versus placebo (n=554) plus androgen deprivation therapy (ADT) in men with nmCRPC and prostate-specific antigen doubling time ≤10 months. HTR AE rates were determined by Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Cumulative incidences of HTR AEs were analyzed using Kaplan-Meier estimates. The observation period was truncated at 24 months to ensure ≥10% of the population was at risk of AEs in each cohort. During the double-blind period, time interval–specific new event rates of HTR AEs were determined for the time period between consecutive study visits.

Consistent with previous safety reports, darolutamide was well tolerated in patientswith nmCRPC. Most HTR AEs occurred at a low incidence with darolutamide and with similarincidence to that of placebo. Fatigue, hypertension, hot flush, falls, fractures, anemia, and coronary artery disorders showed minimal increase with continued darolutamide treatment.

ABSTRACT 2

Time course profile of adverse events of interest and serious adverse events with darolutamide in the ARAMIS Trial

Gratzke C, Fizazi K, Shore N, Werbrouck P, et al. September 2021, online

ABSTRACT Darolutamide is a structurally distinct and highly potent androgen-receptor inhibitor (ARI) that improved metastasis-free survival by almost 2 years and reduced the risk of death by 31% vs placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the phase 3 ARAMIS trial. Adverse events (AEs) of interest commonly associated with ARIs that can impact patient daily life include fatigue, falls, fractures, hypertension, mental impairment, and rash2-4.

Darolutamide has a consistently favorable safety and tolerability profile, with most AEs of interest showing ≤2% difference vs placebo. Fatigue was the only AE with an incidence with >10% in the darolutamide arm (13.2% vs 8.3% for placebo). Discontinuation rates due to AEs were similar between darolutamide (8.9%) and placebo (8.7%) groups and remained constant after longer follow-up. Patients with nmCRPC are generally asymptomatic from their cancer and may receive prolonged treatment with ARIs. Understanding the burden and time course of AEs commonly associated with ARIs that may impact patients’ daily lives will help inform optimal treatment selection for patients with nmCRPC.

Using data from ARAMIS, we present analyses of AEs of interest, grade 3/4 AEs, and serious AEs, characterizing their onset and occurrence over time. ARAMIS was a global, multicenter, double-blind, randomized, phase 3 trial of darolutamide 600 mg twice daily (n=955) vs placebo (n=554) plus androgen deprivation therapy in

patients with nmCRPC and prostate-specific antigen doubling time ≤10 months1,2. Cumulative incidences of AEs were analyzed using Kaplan–Meier estimates for the first 24 months of the double-blind period to ensure >10% of the population was at risk for AEs in each cohort.

Time interval–specific analysis determined new event rates of AEs at each scheduled study visit. During the first 24 months of the double-blind period, the incidence of AEs of interest with darolutamide was low and ≤2% different from that in the placebo group, except for fatigue (Figure 1). During the first month of darolutamide and placebo treatment, new event rates were very low and similar in the darolutamide and placebo arms for falls (0.2% and 0.7%), fractures (0.4% and 0.5%), mental impairment (0% and 0.4%), hypertension (1.7% and 1.1%), and rash (0.7% and 0.2%), respectively. In patients who had fatigue during the first 24 months (darolutamide, 12.6%; placebo, 8.3%), almost one-half experienced fatigue onset during the first month in both arms (darolutamide, 5.9%; placebo, 4.0%; Figure 2).

Cumulative incidence of fatigue minimally increased over time (Figure 2). Falls and fractures occurred mostly after the first month of treatment and had similar cumulative incidences for darolutamide and placebo (Figures 3 and 4). New-onset hypertension was not time interval–specific, and cumulative incidences of hypertension were similar between treatments (Figure 5). Mental impairment rarely occurred (<1% in each treatment group per time interval) and had similar cumulative incidences for darolutamide and placebo (Figure 6). Rash mostly occurred in the first 4 months of treatment and showed minimal increase over time (Figure 7). Rash was reported with worst grade of 1 or 2 in severity in almost all patients, except for 2 patients treated with darolutamide and 1 patient assigned to placebo who had rash of grade 3 severity Grade 3/4 AEs and Serious AEs. Rate of initial onset and cumulative incidence of grade 3/4 AEs and serious AEs were similar for darolutamide and placebo over 24 months (Figures 8 and 9). The time course profile of most AEs of interest, grade 3/4 AEs, and serious AEs confirms the safety profile of darolutamide, showing low incidence and a similar onset and cumulative incidence vs placebo.