Final overall survival (OS) from PROSPER: A phase III, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC).

Abstract

5515 Background: PROSPER previously demonstrated a statistically significant and clinically meaningful improvement in metastasis-free survival (MFS) (hazard ratio [HR] 0.29; 95% CI 0.24-0.35; P < .001) in men with nmCRPC and rapidly rising prostate-specific antigen (PSA) who received ENZA. When first reported, OS was immature with only 165 of 596 (28%) prespecified deaths. Here we report results from the final OS analysis. Methods: Men with nmCRPC, PSA doubling time ≤ 10 mo, and PSA ≥ 2 ng/mL at screening continued androgen deprivation therapy (ADT) and were randomized 2:1 to ENZA 160 mg or PBO. OS treatment effect was assessed using a group sequential testing procedure with O’Brien-Fleming-type alpha spending function ( P ≤ .021 required for statistical significance). Medians were estimated using the Kaplan-Meier method; 95% CIs using a stratified Cox regression model. Results: As of Oct 15, 2019 (median follow-up ≈ 48 mo), there were 466 deaths (288 [30.9%] and 178 [38.0%] in the ENZA and PBO arms, respectively). ENZA significantly prolonged OS compared with PBO (HR 0.73; 95% CI 0.61-0.89; P = .0011). Median OS was 67.0 mo (95% CI 64.0-not reached) in the ENZA arm and 56.3 mo (95% CI 54.4-63.0) in the PBO arm. Subsequent antineoplastic therapies were initiated after treatment discontinuation by 310 (33%) men in the ENZA arm vs 303 (65%) in the PBO arm. Median duration of treatment was 33.9 mo vs 14.2 mo with ENZA vs PBO, respectively. Grade ≥ 3 adverse events (AEs) were reported by 48% of men in the ENZA arm vs 27% in the PBO arm (16% vs 6% were drug related, respectively). AEs with event rates per 100 patient-yr that were ≥ 2 points higher with ENZA vs PBO were falls (9 vs 4), fatigue (14 vs 12), and hypertension (7 vs 5). Conclusions: ENZA treatment resulted in a statistically significant 27% reduced risk of death compared with PBO, demonstrating that initiation of ENZA + ADT before the onset of detectable metastasis improves OS in men with CRPC and rapidly rising PSA. This OS benefit ensues despite crossover from the PBO arm to ENZA and higher rates of subsequent antineoplastic therapies in men from the PBO arm. Safety was consistent with previous clinical trials. This final OS analysis from PROSPER provides prospective validation of MFS as a potential surrogate endpoint for OS in nmCRPC and supports the continued use of ENZA + ADT as a standard of care in men with nmCRPC and rapidly rising PSA. Clinical trial information: NCT02003924 .

Bone health effects of androgen-deprivation therapy and androgen receptor inhibitors in patients with nonmetastatic castration-resistant prostate cancer

“…Clinical trial data for the approved ARIs apalutamide, darolutamide, and enzalutamide showed that falls and fractures occurred in a minority of patients with nmCRPC treated with these drugs; of the three, darolutamide was associated with the lowest incidence of falls and fractures (Table 1) [15,16,51]. However, this is not to say that one agent is associated with less fracture risk than the others, and as noted above updated data from these trials show that all three ARIs discussed are associated with increased overall survival compared with placebo, providing important treatment options for high-risk nmCRPC patients [27][28][29].…”

“…ADT in terms of statistically significant improvement in metastasis-free survival [15][16][17]. Updated data from the ARI trials also showed increase in overall survival compared with placebo (HR for apalutamide 0.78 [95% CI 0.64-0.96; P = 0.0161]) [27]; HR for darolutamide 0.69 [95% CI 0.53-0.88; P < 0.003] [28]; HR for enzalutamide 0.73 [95% CI 0.61-0.89; P = 0.001] [29].…”

Genitourinary cancers—best of ASCO 2020

“…Efficacy and safety update for darolutamide, enzalutamide and apalutamide Final survival data of three phase 3 trials (ARAMIS, PROSPER and SPARTAN) evaluating efficacy and patient risk-benefit of second-generation anti-androgens (darolutamide, enzalutamide and apalutamide) versus placebo for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) were presented [17][18][19]. A detailed overview of outcomes of all three randomized clinical trials are described in Table 3.…”

“…The secondary endpoint (PSA progression-free survival) has currently not met criteria to reject the null hypothesis (HR = 0.69; p = 0.02). Concerning side effects, the most Genitourinary cancers-best of ASCO 2020 K short review Table 3 Updated outcome and descriptive parameters of the three phase 3 trials evaluating efficacy of enzalutamide [17], darolutamide [18] and apalutamide [19] versus placebo in the treatment of nonmetastatic castration-resistant prostate cancer common from LuPSMA were dry eyes, dry mouth and thrombocytopenia. The most common grade 3 or 4 toxicity was thrombocytopenia (11%) [20].…”

Seizures and Neuropsychiatric Toxicity in Patients with Non-Metastatic CRPC Treated with New Antiandrogens: Systematic Review and Meta-Analysis

“…MFS had not previously been used as the primary outcome of clinical trials. The main reasons for administering these therapies in nmCPRC patients were: (1) delaying the onset of metastasis may increase OS; this has been demonstrated after increasing follow-up, and enzalutamide, apalutamide, and darolutamide have shown improvements in OS [12][13][14]; (2) a good tolerated and acceptable safety profile in terms of adverse events (AEs) and no evident loss of quality of life for patients.…”