Metastatic Hormone-Sensitive Prostate Cancer and Combination Treatment Outcomes: A Review.

Importance: Metastatic hormone-sensitive prostate cancer is currently an incurable disease. Despite a high response rate to androgen-deprivation therapy, most cases progress to castration-resistant disease, the terminal phase. This review provides a summary of the most recent evidence for current and emerging management strategies, including treatment intensification with combinations of therapies. It also provides recommendations on applying the evidence in clinical practice to encourage appropriate treatment to improve survival outcomes among patients with metastatic hormone-sensitive prostate cancer. Observations: Androgen-deprivation therapy is the backbone of treatment for metastatic hormone-sensitive prostate cancer; however, it is insufficient alone to provide sustained disease control and long-term survival. Addition of an androgen receptor pathway inhibitor and/or docetaxel significantly improves survival, as demonstrated by several international phase 3 randomized clinical trials. Triplet therapy composed of androgen-deprivation therapy plus an androgen receptor pathway inhibitor plus docetaxel has been shown to improve overall survival over androgen-deprivation therapy plus docetaxel. In the ARASENS trial (darolutamide), the hazard ratios (HRs) were 0.68 (95% CI, 0.57-0.80) in the overall population; 0.71 (95% CI, 0.59-0.85) and 0.61 (95% CI, 0.35-1.05) in patients with de novo and recurrent disease, respectively; 0.69 (95% CI, 0.57-0.82) and 0.72 (95% CI, 0.41-1.13) in patients with high-volume and low-volume disease, respectively; and 0.71 (95% CI, 0.58-0.86) and 0.62 (95% CI, 0.42-0.90) in patients with high-risk and low-risk disease, respectively. In the PEACE-1 trial (abiraterone acetate + prednisone), the HRs were 0.75 (95% CI, 0.59-0.95; all de novo) in the overall population and 0.72 (95% CI, 0.55-0.95) and immature in the high-volume and low-volume subgroups, respectively. In the ENZAMET trial (enzalutamide), the HRs were 0.82 (95% CI, 0.63-1.06) in the overall population; 0.73 (95% CI, 0.55-0.99) and 1.10 (95% CI, 0.65-1.86) in the de novo and recurrent subgroups, respectively; and 0.87 (95% CI, 0.66-1.17) and 0.61 (95% CI, 0.33-1.10) in the high-volume and low-volume subgroups. Combination regimens are generally well tolerated, with adverse effects dependent on the profiles of the component drugs. Conclusions and relevance: The findings of this review show compelling evidence from phase 3 randomized clinical trials in favor of initiating triplet combination therapy for patients with metastatic hormone-sensitive prostate cancer for the best overall survival. Patients who are eligible for chemotherapy should be offered androgen-deprivation therapy plus an androgen receptor pathway inhibitor plus docetaxel, particularly patients with high-volume, high-risk, or de novo metastatic disease.

Deep and Durable Prostate-specific Antigen Response to Darolutamide with Androgen Deprivation Therapy and Docetaxel, and Association with Clinical Outcomes for Patients with High- or Low-volume Metastatic Hormone-sensitive Prostate Cancer: Analyses of the Randomized Phase 3 ARASENS Study.

BACKGROUND AND OBJECTIVE: Addition of darolutamide to androgen deprivation therapy (ADT) and docetaxel significantly improved overall survival (OS) in ARASENS (NCT02799602). Here we report on prostate-specific antigen (PSA) responses and their association with outcomes. METHODS: ARASENS is an international, double-blind, phase 3 study in patients with metastatic hormone-sensitive prostate cancer (mHSPC) randomized to darolutamide 600 mg orally twice daily (n = 651) or placebo (n = 654), both with ADT + docetaxel. The proportion of patients with undetectable PSA (<0.2 ng/ml) and time to PSA progression (≥25% relative and ≥2 ng/ml absolute increase from nadir) were compared between groups in prespecified exploratory analyses. PSA outcomes by disease volume and the association of undetectable PSA with OS and times to castration-resistant prostate cancer (CRPC) and PSA progression were assessed in post hoc analyses. KEY FINDINGS AND LIMITATIONS: The proportion of patients with undetectable PSA at any time was more than doubled with darolutamide versus placebo, at 67% versus 29% in the overall population, 62% versus 26% in the high-volume subgroup, and 84% versus 38% in the low-volume subgroup. Darolutamide delayed time to PSA progression versus placebo, with hazard ratios of 0.26 (95% confidence interval [CI] 0.21-0.31) in the overall population, 0.30 (95% CI 0.24-0.37) in the high-volume subgroup, and 0.093 (95% CI 0.047-0.18) in the low-volume subgroup. Undetectable PSA at 24 wk was associated with longer OS, with a hazard ratio of 0.49 (95% CI 0.37-0.65) in the darolutamide group, as well as longer times to CRPC and PSA progression, with similar findings in the disease volume subgroups. CONCLUSIONS AND CLINICAL IMPLICATIONS: Darolutamide + ADT + docetaxel led to deep and durable PSA responses in patients with high- or low-volume mHSPC. Achievement of undetectable PSA (<0.2 ng/ml) was correlated with better clinical outcomes. PATIENT SUMMARY: For patients with metastatic hormone-sensitive prostate cancer being treated with androgen deprivation therapy and docetaxel, PSA (prostate-specific antigen) became undetectable (below 0.2 ng/ml) in 67% of those also receiving darolutamide versus 29% of patients also receiving placebo. On average, patients achieving undetectable PSA lived longer than patients with detectable PSA.

Radiotherapy Combined with a Radiosensitizer for Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Carcinoma In Situ Bladder Cancer: An Open-label, Single-arm, Multicenter, Phase 2 European Organisation for Research and Treatment of Cancer Trial.

Radical cystectomy with pelvic lymph node dissection and urinary diversion is the standard of care for patients with bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). However, many patients are unwilling or unable to undergo such major surgery associated with high morbidity and a negative impact on quality of life. Chemoradiotherapy is an established treatment option for muscle-invasive bladder cancer. However, it has not been investigated adequately in NMIBC until now. The European Organisation for Research and Treatment of Cancer (EORTC) 2235 study (NCT06310369) is designed as a multicenter, prospective, international, phase 2 trial of moderate hypofractionated radiotherapy combined with a radiosensitizer in BCG-unresponsive NMIBC patients with carcinoma in situ (CIS) who are not eligible for or declined to undergo radical cystectomy. Patients who have received nadofaragene firadenovec or TAR-200 are eligible. The primary endpoint is the 6-mo complete response (CR) rate defined by the absence of CIS proven by a control biopsy of the bladder. The secondary endpoints include overall survival, progression-free survival, durability of CR, grade 3-4 adverse events rate, patients' quality of life, and organ preservation rate. PATIENT SUMMARY: Intravesical instillation of bacillus Calmette-Guérin is the standard treatment of non-muscle-invasive, also coined as superficial, bladder cancer. In case the cancer recurs, even superficially, there is no other proven treatment than a radical cystectomy-the surgical removal of the bladder. Although the surgical technique has improved dramatically over the past few years, it remains contraindicated in patients with severe comorbidities. In addition, because it affects the quality of life, patients may reject this option. This study will assess the efficacy of external beam radiotherapy, a robust alternative to surgery in muscle-invasive bladder cancer. Radiotherapy will be administered 5 d a week for 4 wk. It will be associated with a "radiosensitizer," an intravenous or oral drug, during the radiotherapy treatment. The study will measure the proportion of patients remaining recurrence free at 6 mo and thereafter. It will also evaluate the safety of the treatment and its impact on quality of life.

Efficacy and Safety of Radiotherapy Plus Relugolix in Men With Localized or Advanced Prostate Cancer.

Importance: Combination androgen deprivation therapy (ADT) with radiotherapy is commonly used for patients with localized and advanced prostate cancer. Objective: To assess the efficacy and safety of the oral gonadotropin-releasing hormone antagonist relugolix with radiotherapy for treating prostate cancer. Design, Setting, and Participants: This multicenter post hoc analysis of patients with localized and advanced prostate cancer receiving radiotherapy in 2 randomized clinical trials (a phase 2 trial of relugolix vs degarelix, and a subset of the phase 3 HERO trial of relugolix vs leuprolide acetate) included men who were receiving radiotherapy and short-term (24 weeks) ADT (n = 103) from 2014 to 2015 and men receiving radiotherapy and longer-term (48 weeks) ADT (n = 157) from 2017 to 2019. The data were analyzed in November 2022. Interventions: Patients receiving short-term ADT received relugolix, 120 mg, orally once daily (320-mg loading dose) or degarelix, 80 mg, 4-week depot (240-mg loading dose) for 24 weeks with 12 weeks of follow-up. Patients receiving longer-term ADT received relugolix, 120 mg, orally once daily (360-mg loading dose) or leuprolide acetate injections every 12 weeks for 48 weeks, with up to 90 days of follow-up. Main Outcomes and Measures: Castration rate (testosterone level <50 ng/dL [to convert to nmol/L, multiply by 0.0347) at all scheduled visits between weeks 5 and 25 for patients receiving short-term ADT and weeks 5 and 49 for patients receiving longer-term ADT. Results: Of 260 patients (38 Asian [14.6%], 23 Black or African American [8.8%], 21 Hispanic [8.1%], and 188 White [72.3%] individuals), 164 (63.1%) received relugolix. Relugolix achieved castration rates of 95% (95% CI, 87.1%-99.0%) and 97% (95% CI, 90.6%-99.0%) among patients receiving short-term and longer-term ADT, respectively. Twelve weeks post-short-term relugolix, 34 (52%) achieved testosterone levels to baseline or more than 280 ng/dL. Ninety days post longer-term ADT, mean (SD) testosterone levels were 310.5 (122.4) (106.7) ng/dL (relugolix; n = 15) vs 53.0 ng/dL (leuprolide acetate; n = 8) among the subset assessed for testosterone recovery. Castration resistance-free survival was not statistically different between the relugolix and leuprolide acetate cohorts (hazard ratio, 0.97; 95% CI, 0.35-2.72; P = .62). Adverse events grade 3 or greater for short-term or longer-term relugolix (headache, hypertension, and atrial fibrillation) were uncommon (less than 5%). Conclusions and Relevance: The results of these 2 randomized clinical trials suggest that relugolix rapidly achieves sustained castration in patients with localized and advanced prostate cancer receiving radiotherapy. No new safety concerns were identified when relugolix was used with radiotherapy.

Prognostic Impact of Prostate-Specific Antigen at 6 Months After Radiotherapy in Localized Prostate Cancer: An Individual Patient Data Analysis of Randomized Trials.

PURPOSE: We sought to evaluate the prognostic impact of prostate-specific antigen (PSA) at 6 months after completion of radiotherapy (RT) in patients treated with RT alone, RT plus short-term (st; 3-6 months), and RT plus long-term (lt; 24-36 months) androgen-deprivation therapy (ADT). PATIENTS AND METHODS: Individual patient data were obtained from 16 randomized trials evaluating RT ± ADT for localized prostate cancer (PCa) between 1987 and 2011. The lowest PSA recorded within 6 months after RT completion was identified and categorized as < or ≥0.1 ng/mL. The primary outcomes were metastasis-free survival (MFS), PCa-specific mortality (PCSM), and overall survival (OS), from 12 months after random assignment. RESULTS: Ninety-eight percent (n = 2,339/2,376) of patients allocated to RT alone, 84% (n = 4,756/5,658) allocated to RT + stADT, and 77% (n = 1,258/1,626) allocated to RT + ltADT had PSA ≥0.1 ng/mL within 6 months after completing RT. PSA ≥0.1 ng/mL was associated with lower MFS and OS and higher PCSM among patients allocated to RT ± ADT (RT - MFS: hazard ratio [HR], 2.24 [95% CI, 1.21 to 4.16]; PCSM: subdistribution hazard ratio [sHR], 1.82 [0.51 to 6.49]; OS: HR, 1.72 [0.97 to 3.05]; RT + stADT - MFS: HR, 1.27 [1.12 to 1.44]; PCSM: sHR, 2.10 [1.52 to 2.92]; OS: HR, 1.26 [1.11 to 1.44]; RT + ltADT - MFS: HR, 1.58 [1.27 to 1.96]; PCSM: sHR, 1.97 [1.11 to 3.49]; OS: HR, 1.59 [1.27 to 1.99]). Five-year MFS rates among patients allocated to RT, RT + stADT, and RT + ltADT were 91% versus 79%, 83% versus 76%, and 87% versus 74%, respectively, based on PSA < or ≥0.1 ng/mL. CONCLUSION: PSA ≥0.1 ng/mL within 6 months after RT completion was prognostic for lt outcomes in patients treated with RT ± ADT for localized PCa. This can be used to counsel patients treated with RT ± ADT and in guiding clinical trial design evaluating novel systemic therapies with RT + ADT as well as (de)intensification strategies.

Safety and effectiveness of the radium-223-taxane treatment sequence in patients with metastatic castration-resistant prostate cancer in a global observational study (REASSURE).

BACKGROUND: Radium-223 and taxane chemotherapy each improve survival of patients with metastatic castration-resistant prostate cancer (mCRPC). Whether the radium-223-taxane sequence could extend survival without cumulative toxicity was explored. METHODS: The global, prospective, observational REASSURE study (NCT02141438) assessed real-world safety and effectiveness of radium-223 in patients with mCRPC. Using data from the prespecified second interim analysis (data cutoff, March 20, 2019), hematologic events and overall survival (OS) were evaluated in patients who were chemotherapy-naive at radium-223 initiation and subsequently received taxane chemotherapy starting ≤90 days ("immediate") or >90 days ("delayed") after the last radium-223 dose. RESULTS: Following radium-223 therapy, 182 patients received docetaxel (172 [95%]) and/or cabazitaxel (44 [24%]); 34 patients (19%) received both. Seventy-three patients (40%) received immediate chemotherapy and 109 patients (60%) received delayed chemotherapy. Median time from last radium-223 dose to first taxane cycle was 3.6 months (range, 0.3-28.4). Median duration of first taxane was 3.7 months (range, 0-22.0). Fourteen patients (10 in the immediate and four in the delayed subgroup) had grade 3/4 hematologic events during taxane chemotherapy, including neutropenia in two patients in the delayed subgroup and thrombocytopenia in one patient in each subgroup. Median OS was 24.3 months from radium-223 initiation and 11.8 months from start of taxane therapy. CONCLUSIONS: In real-world clinical practice settings, a heterogeneous population of patients who received sequential radium-223-taxane therapy had a low incidence of hematologic events, with a median survival of 1 year from taxane initiation. Thus, taxane chemotherapy is a feasible option for those who progress after radium-223. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02141438. PLAIN LANGUAGE SUMMARY: Radium-223 and chemotherapy are treatment options for metastatic prostate cancer, which increase survival but may affect production of blood cells as a side effect. We wanted to know what would happen if patients received chemotherapy after radium-223. Among the 182 men treated with radium-223 who went on to receive chemotherapy, only two men had severe side effects affecting white blood cell production (neutropenia) during chemotherapy. On average, the 182 men lived for 2 years after starting radium-223 and 1 year after starting chemotherapy. In conclusion, patients may benefit from chemotherapy after radium-223 treatment without increasing the risk of side effects.

A Phase 2 Randomized Open-label Study of Oral Darolutamide Monotherapy Versus Androgen Deprivation Therapy in Men with Hormone-sensitive Prostate Cancer (EORTC-GUCG 1532).

BACKGROUND AND OBJECTIVE: Darolutamide is an androgen receptor inhibitor that increases overall survival in combination with androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive and nonmetastatic castration-resistant prostate cancer (PCa). This phase 2 study assessed the efficacy and safety of darolutamide as monotherapy without ADT in patients with eugonadal testosterone levels. METHODS: This was a 24-wk, open-label, randomized study of patients with hormone-sensitive, histologically confirmed PCa requiring gonadotropin-releasing hormone (GnRH); an Eastern Cooperative Oncology Group performance status score of 0/1; and life expectancy >1 yr. All patients received darolutamide 600 mg bid or a commercially available GnRH analog. The primary endpoint is a prostate-specific antigen (PSA) response, defined as a ≥80% decline at week 24 relative to baseline in the darolutamide study arm. The GnRH arm is used as an internal control. The secondary endpoints included changes in T levels, safety/tolerability, and quality of life. KEY FINDINGS AND LIMITATIONS: Among 61 men enrolled, the median (range) age was 72 yr (53-86 yr); 42.6% of them had metastases. In the darolutamide arm, the evaluable population with available PSA values at baseline and week 24 consisted of 23 patients. Twenty-three (100%) evaluable darolutamide patients achieved a PSA decline of >80% at week 24 (primary endpoint), with a median (range) decrease of -99.1% (-91.9%, -100%). Serum T levels increased by a median (range) of 44.3 (5.7-144.0) at week 24, compared with baseline. In the darolutamide arm, 48.4% of men reported drug-related adverse events (AEs; mostly grade 1 or 2). The most frequent treatment-emergent AEs included gynecomastia (35.5%), fatigue (12.9%), hot flush (12.9%), and hypertension (12.9%). Health-related quality of life measures are descriptive, and GnRH arm results will be presented as an internal reference. CONCLUSIONS AND CLINICAL IMPLICATIONS: Darolutamide monotherapy was associated with a significant PSA response in nearly all men with hormone-naïve PCa. Testosterone-level changes and most common AEs (gynecomastia, fatigue, hypertension, and hot flush) were consistent with potent androgen receptor inhibition. PATIENT SUMMARY: In this study, we report the first use of darolutamide, a novel antiandrogen, as monotherapy without androgen deprivation therapy (ADT). The study shows that darolutamide induce a profound suppression of prostate-specific antigen in all patients, with a safety profile different from that of ADT.

European Association of Nuclear Medicine Focus 5: Consensus on Molecular Imaging and Theranostics in Prostate Cancer.

BACKGROUND: In prostate cancer (PCa), questions remain on indications for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging and PSMA radioligand therapy, integration of advanced imaging in nomogram-based decision-making, dosimetry, and development of new theranostic applications. OBJECTIVE: We aimed to critically review developments in molecular hybrid imaging and systemic radioligand therapy, to reach a multidisciplinary consensus on the current state of the art in PCa. DESIGN, SETTING, AND PARTICIPANTS: The results of a systematic literature search informed a two-round Delphi process with a panel of 28 PCa experts in medical or radiation oncology, urology, radiology, medical physics, and nuclear medicine. The results were discussed and ratified in a consensus meeting. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Forty-eight statements were scored on a Likert agreement scale and six as ranking options. Agreement statements were analysed using the RAND appropriateness method. Ranking statements were analysed using weighted summed scores. RESULTS AND LIMITATIONS: After two Delphi rounds, there was consensus on 42/48 (87.5%) of the statements. The expert panel recommends PSMA PET to be used for staging the majority of patients with unfavourable intermediate and high risk, and for restaging of suspected recurrent PCa. There was consensus that oligometastatic disease should be defined as up to five metastases, even using advanced imaging modalities. The group agreed that [177Lu]Lu-PSMA should not be administered only after progression to cabazitaxel and that [223Ra]RaCl2 remains a valid therapeutic option in bone-only metastatic castration-resistant PCa. Uncertainty remains on various topics, including the need for concordant findings on both [18F]FDG and PSMA PET prior to [177Lu]Lu-PSMA therapy. CONCLUSIONS: There was a high proportion of agreement among a panel of experts on the use of molecular imaging and theranostics in PCa. Although consensus statements cannot replace high-certainty evidence, these can aid in the interpretation and dissemination of best practice from centres of excellence to the wider clinical community. PATIENT SUMMARY: There are situations when dealing with prostate cancer (PCa) where both the doctors who diagnose and track the disease development and response to treatment, and those who give treatments are unsure about what the best course of action is. Examples include what methods they should use to obtain images of the cancer and what to do when the cancer has returned or spread. We reviewed published research studies and provided a summary to a panel of experts in imaging and treating PCa. We also used the research summary to develop a questionnaire whereby we asked the experts to state whether or not they agreed with a list of statements. We used these results to provide guidance to other health care professionals on how best to image men with PCa and what treatments to give, when, and in what order, based on the information the images provide.

Treatment-Related Cognitive Impairment in Patients with Prostate Cancer: Patients' Real-World Insights for Optimizing Outcomes.

Cognitive impairment (CI) is an issue that needs to be at the forefront of unmet healthcare needs in patients with prostate cancer (PCa) as it can negatively impact quality of life during long-term care. CI in patients with prostate cancer is thought to be influenced by treatment, androgen deprivation therapy (ADT), and novel androgen receptor (AR) pathway inhibitors in particular; however, current understanding is limited on how treatment affects cognition. Additionally, the experience of patients with CI who are receiving PCa treatment is not well understood or represented in clinical literature, which is a barrier to optimal patient outcomes in managing prostate cancer treatment-related cognitive impairment (PCa-TRCI). To help understand the patient journey and elucidate management gaps in PCa-TRCI, an international roundtable of healthcare provider and patient panelists was convened. The panelists focused on four key topic areas: (1) the patient experience when afflicted with, or at risk of, PCa-TRCI, (2) the physical, emotional, and social impact of CI on patients' quality of life (QoL), (3) the challenges that patients with PCa-TRCI face, and their impact on clinical decision-making, and (4) ways in which managing PCa-TRCI should evolve to improve patient outcomes. The purpose of the roundtable was to include patients in a direct discussion with healthcare providers (HCPs) regarding the patient journey and highlight real-world evidence of areas where patient outcomes could be improved in the absence of clinical evidence. The resulting discussion highlighted important healthcare gaps for patients with, and at risk of, PCa-TRCI and offered potential solutions as a roadmap to effective medicine.

Efficacy and Safety of Darolutamide in Combination With Androgen-Deprivation Therapy and Docetaxel in Black Patients From the Randomized ARASENS Trial.

BACKGROUND: In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; P < .0001) compared with placebo plus ADT with docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We present efficacy and safety of darolutamide versus placebo in Black patients from ARASENS. PATIENTS AND METHODS: Patients with mHSPC were randomized 1:1 to darolutamide 600 mg or placebo twice daily in combination with ADT and docetaxel. The primary endpoint was overall survival. Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety. RESULTS: In ARASENS, 54 Black patients received darolutamide (n = 26) or placebo (n = 28) plus ADT and docetaxel. In Black patients, overall survival favored darolutamide versus placebo (median, not reached vs. 38.7 months; stratified HR, 0.41; 95% CI, 0.17-1.02), with 4-year survival rates of 62% versus 41%. The darolutamide group also had longer time to CRPC compared with the placebo group (median, not reached vs .12.6 months; HR, 0.09; 95% CI, 0.02-0.30). The safety profile of darolutamide in Black patients was consistent with that observed for the overall ARASENS population (grade 3/4 treatment-emergent adverse events, TEAEs: 61.5% vs. 66.1%; serious TEAEs: 42.3% vs. 44.8%). CONCLUSION: In this small population of Black patients with mHSPC from the ARASENS trial, darolutamide was associated with an improvement in survival and time to CRPC and was well tolerated. Efficacy and safety findings in Black patients were consistent with the overall ARASENS population.

Safety profile of darolutamide versus placebo: a systematic review and meta-analysis.

BACKGROUND: Darolutamide is an androgen receptor pathway inhibitor (ARPI) used in patients with prostate cancer (PC). In pivotal trials, it has demonstrated a favorable toxicity profile. There are no head-to-head comparison studies between the different ARPIs, but the efficacy of these drugs seems to be similar making the toxicity profile a key element for treatment selection. METHODS: We conducted a systematic review of all clinical trials assessing treatment with darolutamide for patients with PC using placebo as the control using the PubMed/Medline and Cochrane library databases. We also performed a meta-analysis to compare the safety of darolutamide versus placebo evaluating adverse events (AE) leading to treatment discontinuation and the rate of the AE reported as "AE of interest" in the ARAMIS trial. The comparison among darolutamide and the placebo group in terms of safety and tolerability was performed using odds ratio (OR) as meta-analytic outcome. RESULTS: We identified three articles comprising 2902 patients for the systematic review and meta-analysis (1652 treated with darolutamide and 1250 with placebo). Darolutamide did not increase AE leading to treatment discontinuation compared to placebo (pooled OR: 1.176, 95% CI 0.918-1.507, p = 0.633). Regarding the "AE of interest" there was no difference between darolutamide and placebo in terms of asthenia, cardiac arrhythmia, cardiac disorder, coronary artery disorder, depression mood disorder, falls, fatigue, heart failure, hot flushes, hypertension, mental-impairment disorder, rash, seizure and weight loss. The only "AE of interest" with a statistically significant difference in favor of placebo was bone fractures (pooled OR: 1.523, 95% CI 1.081-2.146). CONCLUSIONS: In our systematic review and meta-analysis, darolutamide showed a toxicity profile comparable to placebo with the exception of bone fractures. In the absence of head-to-head comparison studies between the different ARPIs, the results of our research suggest a preferred use of darolutamide in the approved settings.

Testosterone Recovery for Relugolix Versus Leuprolide in Men with Advanced Prostate Cancer: Results from the Phase 3 HERO Study.

BACKGROUND: In the HERO study, relugolix demonstrated sustained testosterone suppression superior to that of leuprolide acetate (97% vs 89%; difference 7.9% [95% confidence interval, 4.1-12%; p < 0.001]). OBJECTIVE: To analyze testosterone recovery in a prespecified subset of men from the HERO study not indicated to continue androgen deprivation therapy. DESIGN, SETTING, AND PARTICIPANTS: Men (N = 934) were randomized (2:1) to receive relugolix 120 mg orally daily or leuprolide acetate injections every 12 wk for 48 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Testosterone recovery was assessed in 184 men who completed 48 wk of treatment. During the 90-d recovery period, assessments included time to testosterone recovery (>280 ng/dl; ≥80% of baseline testosterone), serum levels of prostate-specific antigen and pituitary hormones, and adverse events. RESULTS AND LIMITATIONS: The cumulative incidence rate of testosterone recovery to >280 ng/dl at 90 d following drug discontinuation was significantly higher in the relugolix cohort (n = 137) than in the leuprolide acetate cohort (n = 47; 54% vs 3.2%; nominal p = 0.002). The median time to testosterone recovery was faster following relugolix treatment than with leuprolide acetate treatment (86.0 d vs 112.0 d). Compared with leuprolide acetate, more men treated with relugolix achieved ≥80% of baseline testosterone levels (39% vs 2.1%). Men ≤65 yr and those with baseline testosterone greater than the median had a higher incident rate of testosterone recovery. Adverse events were generally similar between treatment groups. One limitation is the short testosterone recovery follow-up period. CONCLUSIONS: Oral relugolix had faster and more complete recovery of testosterone to normal levels after treatment discontinuation than leuprolide acetate in a subset of men from the HERO study. The clinical implications of a faster testosterone recovery with relugolix may be significant for men being treated with androgen deprivation therapy and influence treatment decisions. PATIENT SUMMARY: The male hormone testosterone is reduced during androgen deprivation therapy for prostate cancer. Reduced testosterone levels cause side effects, impacting patient quality of life. When treatment is stopped, the side effects lessen over time as the levels of testosterone come back to pretreatment range (testosterone recovery). In this study, we found that the time to testosterone recovery was faster with relugolix than with leuprolide acetate.

Cardiovascular Effects of GnRH Antagonists Compared With Agonists in Prostate Cancer: A Systematic Review.

Background: Androgen deprivation therapy is the cornerstone of treatment for patients with advanced prostate cancer. Meta-analysis of small, oncology-focused trials suggest gonadotropin-releasing hormone (GnRH) antagonists may be associated with fewer adverse cardiovascular outcomes compared with GnRH agonists. Objectives: This study sought to determine whether GnRH antagonists were associated with fewer major adverse cardiovascular events compared with GnRH agonists. Methods: Electronic databases were searched for all prospective, randomized trials comparing GnRH antagonists with agonists. The primary outcome was a major adverse cardiovascular event as defined by the following standardized Medical Dictionary for Regulatory Activities terms: "myocardial infarction," "central nervous system hemorrhages and cerebrovascular conditions," and all-cause mortality. Bayesian meta-analysis models with random effects were fitted. Results: A total of 11 eligible studies of a maximum duration of 3 to 36 months (median = 12 months) enrolling 4,248 participants were included. Only 1 trial used a blinded, adjudicated event process, whereas potential bias persisted in all trials given their open-label design. A total of 152 patients with primary outcome events were observed, 76 of 2,655 (2.9%) in GnRH antagonist-treated participants and 76 of 1,593 (4.8%) in agonist-treated individuals. Compared with GnRH agonists, the pooled OR of GnRH antagonists for the primary endpoint was 0.57 (95% credible interval: 0.37-0.86) and 0.58 (95% credible interval: 0.32-1.08) for all-cause death. Conclusions: Despite the addition of the largest, dedicated cardiovascular outcome trial, the volume and quality of available data to definitively answer this question remain suboptimal. Notwithstanding these limitations, the available data suggest that GnRH antagonists are associated with fewer cardiovascular events, and possibly mortality, compared with GnRH agonists.

Impact of Relugolix Versus Leuprolide on the Quality of Life of Men with Advanced Prostate Cancer: Results from the Phase 3 HERO Study.

BACKGROUND: Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, demonstrated testosterone suppression to castrate levels in men with advanced prostate cancer (PCa) in the HERO study. Since advanced PCa and its treatments can impact patients' daily life, it is imperative to understand the impact of systemic therapy on patient health-related quality of life (HRQOL). OBJECTIVE: To report the HRQOL for patients on relugolix compared with those on leuprolide in on-treatment and testosterone recovery periods of the HERO study. DESIGN, SETTING, AND PARTICIPANTS: A phase 3 randomized controlled study was conducted in 934 patients with advanced PCa. INTERVENTION: Patients underwent 2:1 randomization and received relugolix 120 mg orally once daily or leuprolide 3-mo injections for 48 wk. Testosterone recovery was evaluated in a patient subset. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: HRQOL evaluations were based on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30) and the Prostate Cancer Module (EORTC QLQ-PR25) during treatment and testosterone recovery phases. In a post hoc analysis, predictors of HRQOL deterioration were evaluated. RESULTS AND LIMITATIONS: No statistically significant differences between the two groups were found in changes from baseline to the end of treatment in either the EORTC QLQ-C30 or the EORTC QLQ-PR25 instrument. During the testosterone recovery phase, hormonal treatment-related symptoms scores were lower for relugolix than for leuprolide, suggesting a lower burden of hormone-related symptoms associated with a treatment that has more rapid testosterone recovery after treatment cessation. Limitations include low patient numbers in the testosterone recovery group. CONCLUSIONS: Oral relugolix is a therapeutic option with similar patient-reported HRQOL to leuprolide, providing an oral option for androgen deprivation therapy associated with a more rapid testosterone reduction. PATIENT SUMMARY: In men with advanced prostate cancer, relugolix had similar health-related quality of life to leuprolide.

Relugolix vs. Leuprolide Effects on Castration Resistance-Free Survival from the Phase 3 HERO Study in Men with Advanced Prostate Cancer.

Background: Relugolix is an oral GnRH receptor antagonist approved for men with advanced prostate cancer. Relugolix treatment has demonstrated an ability to lower testosterone to sustained castration levels in the phase 4 HERO study. Herein, we describe the results of a secondary endpoint of castration resistance-free survival (CRFS) during 48 weeks of treatment and profile patients with castration-resistant prostate cancer (CRPC). Methods: Subjects were 2:1 randomized to either relugolix 120 mg orally once daily (after a single 360 mg loading dose) or 3-monthly injections of leuprolide for 48 weeks. CRFS, defined as the time from the date of first dose to the date of confirmed prostate-specific antigen progression while castrated or death due to any reason was conducted in the metastatic disease population and the overall modified intention-to-treat (mITT) populations. Results: The CRFS analysis (mITT population) included 1074 men (relugolix: n = 717; leuprolide: n = 357) with advanced prostate cancer as well as 434 men (relugolix: n = 290; leuprolide: n = 144) with metastatic prostate cancer. In the metastatic disease populations, CRFS rates were 74.3% (95% CI: 68.6%, 79.2%) and 75.3% (95% CI: 66.7%, 81.9%) in the relugolix and leuprolide groups, respectively (hazard ratio: 1.03 [0.68, 1.57]; p = 0.84) at week 48. Results in the overall mITT population were similar to the metastatic population. No new safety findings were identified. Conclusions: In men with metastatic disease or in the overall population of the HERO study, CRFS assessed during the 48-week treatment with relugolix was not significantly different than standard-of-care leuprolide. Relugolix had similar efficacy for men with/without CRFS progression events.

Discrete-Choice Experiment to Understand the Preferences of Patients with Hormone-Sensitive Prostate Cancer in the USA, Canada, and the UK.

BACKGROUND: Treatment options for patients with metastatic hormone-sensitive prostate cancer (mHSPC) have broadened, and treatment decisions can have a long-lasting impact on patients' quality of life. Data on patient preferences can improve therapeutic decision-making by helping physicians suggest treatments that align with patients' values and needs. OBJECTIVE: This study aims to quantify patient preferences for attributes of chemohormonal therapies among patients with mHSPC in the USA, Canada, and the UK. METHODS: A discrete-choice experiment survey instrument was developed and administered to patients with high- and very-high-risk localized prostate cancer and mHSPC. Patients chose between baseline androgen-deprivation therapy (ADT) alone and experimentally designed, hypothetical treatment alternatives representing chemohormonal therapies. Choices were analyzed using logit models to derive the relative importance of attributes for each country and to evaluate differences and similarities among patients across countries. RESULTS: A total of 550 respondents completed the survey (USA, 200; Canada, 200; UK, 150); the mean age of respondents was 64.3 years. Treatment choices revealed that patients were most concerned with treatment efficacy. However, treatment-related convenience factors, such as route of drug administration and frequency of monitoring visits, were as important as some treatment-related side effects, such as skin rash, nausea, and fatigue. Patient preferences across countries were similar, although patients in Canada appeared to be more affected by concomitant steroid use. CONCLUSION: Patients with mHSPC believe the use of ADT alone is insufficient when more effective treatments are available. Efficacy is the most significant driver of patient choices. Treatment-related convenience factors can be as important as safety concerns for patients.

Which patients with metastatic hormone-sensitive prostate cancer benefit from docetaxel: a systematic review and meta-analysis of individual participant data from randomised trials.

BACKGROUND: Adding docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer, but uncertainty remains about who benefits most. We therefore aimed to obtain up-to-date estimates of the overall effects of docetaxel and to assess whether these effects varied according to prespecified characteristics of the patients or their tumours. METHODS: The STOPCAP M1 collaboration conducted a systematic review and meta-analysis of individual participant data. We searched MEDLINE (from database inception to March 31, 2022), Embase (from database inception to March 31, 2022), the Cochrane Central Register of Controlled Trials (from database inception to March 31, 2022), proceedings of relevant conferences (from Jan 1, 1990, to Dec 31, 2022), and ClinicalTrials.gov (from database inception to March 28, 2023) to identify eligible randomised trials that assessed docetaxel plus ADT compared with ADT alone in patients with metastatic, hormone-sensitive prostate cancer. Detailed and updated individual participant data were requested directly from study investigators or through relevant repositories. The primary outcome was overall survival. Secondary outcomes were progression-free survival and failure-free survival. Overall pooled effects were estimated using an adjusted, intention-to-treat, two-stage, fixed-effect meta-analysis, with one-stage and random-effects sensitivity analyses. Missing covariate values were imputed. Differences in effect by participant characteristics were estimated using adjusted two-stage, fixed-effect meta-analysis of within-trial interactions on the basis of progression-free survival to maximise power. Identified effect modifiers were also assessed on the basis of overall survival. To explore multiple subgroup interactions and derive subgroup-specific absolute treatment effects we used one-stage flexible parametric modelling and regression standardisation. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool. This study is registered with PROSPERO, CRD42019140591. FINDINGS: We obtained individual participant data from 2261 patients (98% of those randomised) from three eligible trials (GETUG-AFU15, CHAARTED, and STAMPEDE trials), with a median follow-up of 72 months (IQR 55-85). Individual participant data were not obtained from two additional small trials. Based on all included trials and patients, there were clear benefits of docetaxel on overall survival (hazard ratio [HR] 0·79, 95% CI 0·70 to 0·88; p<0·0001), progression-free survival (0·70, 0·63 to 0·77; p<0·0001), and failure-free survival (0·64, 0·58 to 0·71; p<0·0001), representing 5-year absolute improvements of around 9-11%. The overall risk of bias was assessed to be low, and there was no strong evidence of differences in effect between trials for all three main outcomes. The relative effect of docetaxel on progression-free survival appeared to be greater with increasing clinical T stage (pinteraction=0·0019), higher volume of metastases (pinteraction=0·020), and, to a lesser extent, synchronous diagnosis of metastatic disease (pinteraction=0·077). Taking into account the other interactions, the effect of docetaxel was independently modified by volume and clinical T stage, but not timing. There was no strong evidence that docetaxel improved absolute effects at 5 years for patients with low-volume, metachronous disease (-1%, 95% CI -15 to 12, for progression-free survival; 0%, -10 to 12, for overall survival). The largest absolute improvement at 5 years was observed for those with high-volume, clinical T stage 4 disease (27%, 95% CI 17 to 37, for progression-free survival; 35%, 24 to 47, for overall survival). INTERPRETATION: The addition of docetaxel to hormone therapy is best suited to patients with poorer prognosis for metastatic, hormone-sensitive prostate cancer based on a high volume of disease and potentially the bulkiness of the primary tumour. There is no evidence of meaningful benefit for patients with metachronous, low-volume disease who should therefore be managed differently. These results will better characterise patients most and, importantly, least likely to gain benefit from docetaxel, potentially changing international practice, guiding clinical decision making, better informing treatment policy, and improving patient outcomes. FUNDING: UK Medical Research Council and Prostate Cancer UK.