PREVAIL, a phase 3 randomized trial, was halted after a planned interim analysis demonstrated a statistically significant improvement in overall survival (OS) for ENZA-treated men with mCRPC compared to placebo (PBO). We retrospectively evaluated efficacy, with an extended analysis of radiographic progression-free survival (rPFS) and OS, safety, and pharmacokinetic exposure of ENZA in patients from Japan and Republic of Korea.
Asymptomatic or mildly symptomatic chemotherapy-naÃ¯ve patients with mCRPC progressing on androgen deprivation therapy were randomly assigned 1:1 to ENZA 160 mg/day or PBO and treated until discontinuation upon unacceptable adverse event (AE), or radiographic progression or skeletal-related event and initiation of chemotherapy. Coprimary endpoints were rPFS by central review and OS. Prostate-specific antigen (PSA) response was defined as a confirmed ≥50% reduction from baseline to nadir. Plasma concentrations of ENZA were measured at weeks 5, 13, and 25. AEs were analyzed in all randomized patients who received ≥1 dose of study drug.
139 Asian patients were randomized (ENZA: 68, PBO: 71). In the final PREVAIL analysis, HRs for rPFS and OS in Asian patients were 0.30 (95%CI: 0.07-1.27) and 0.67 (95%CI: 0.32-1.41), respectively. Median time to chemotherapy was not yet reached with ENZA versus 10.4 months with PBO (HR, 0.32; 95%CI: 0.18-0.56). PSA responses were more common in patients receiving ENZA (66%) versus PBO (15%). Plasma concentrations of ENZA were slightly higher in the Asian subgroup (geometric mean Cmin = 14.7 Âµg/mL vs 12.1 Âµg/mL in non-Asian cohort at 13 weeks). AEs ≥ Grade 3 were more common with ENZA (32% vs 24% with PBO). Treatment-related AEs ≥ Grade 3 were reported in 1.5% of ENZA- and 2.8% of PBO-treated patients. In an extended analysis of rPFS determined by investigator and OS, which included 4 and 10 months of additional follow-up, respectively, HRs were 0.30 (95%CI: 0.18-0.51) and 0.69 (95%CI: 0.39-1.23).
Efficacy and safety results from the Asian subgroup were consistent with results from the overall PREVAIL trial.
Clinical trial identification
T. Ueda: other from Astellas, during the conduct of the study. J. Yonese, T. Fukagai: grants from Astellas, during the conduct of the study. E. Chiong: other from National University Hospital, from null, during the conduct of the study. S. Abhyankar: personal fees from Medivation, during the conduct of the study; personal fees from Medivation, Inc, outside the submitted work. A. Theeuwes: personal fees from Astellas, during the conduct of the study; personal fees from Astellas, outside the submitted work. B. Tombal: consulting fees from Amgen, Sanofi, and Astellas for honorarium, travel support, board membership; reports personal fees from Amgen, Ferring, Bayer Sanofi for board membership, consultancy, and speaker bureaus. T.M. Beer: consulting fees: Janssen Japan, Astellas; Research funding: Astellas, Medivation, Janssen Research & Development; payment from Research to Practice in Certified Nursing Education supported by Medivation and Astellas. G. Kimura: reports grants and personal fees from Astellas, during the conduct of the study; grants and personal fees from Takeda, Pfizer, Bayer, Novartis, GlaxoSmithKline, Ono pharmaceutical, outside the submitted work. All other authors have declared no conflicts of interest.