PREVAIL, a multinational phase 3 randomized trial, was halted after ENZA was shown to reduce risk of radiographic progression or death by 81% and risk of death by 29% compared with placebo (PBO) in a planned interim analysis (which became the final analysis). In this post-hoc analysis, we evaluated efficacy, with an extended analysis of radiographic progression-free survival (rPFS) and overall survival (OS), safety, and pharmacokinetics of ENZA in Japanese pts.
Asymptomatic or mildly symptomatic chemotherapy-naÃ¯ve pts with mCRPC progressing on androgen deprivation therapy were randomly assigned 1:1 to 160 mg/day oral ENZA or PBO until discontinuation upon unacceptable adverse event (AE), or radiographic progression or skeletal-related event and initiation of antineoplastic therapy. Coprimary endpoints were rPFS by central review and OS. Secondary endpoints included time to initiation of chemotherapy, time to prostate-specific antigen (PSA) progression and PSA response (≥50% decline). Plasma concentrations of ENZA were measured at 5, 13, and 25 weeks. Safety was analyzed in all randomized pts who received ≥1 dose of study drug.
61 Japanese pts were enrolled (ENZA: 28, PBO: 33). In the final analysis, ENZA showed benefit over PBO with hazard ratios (HRs) of 0.30 for rPFS (95% confidence interval [CI]: 0.03, 2.95), 0.59 for OS (95% CI: 0.20, 1.8), 0.46 for time to chemotherapy (95% CI: 0.22, 0.96), and 0.36 for time to PSA progression (95% CI: 0.17, 0.75). PSA responses were observed in 60.7% of ENZA- vs 21.2% of PBO-treated pts. Plasma concentrations of ENZA were higher in Japanese pts: geometric mean ratio of Japanese/non-Japanese pts = 1.126 (95% CI: 1.018, 1.245) at 13 weeks. Treatment-related AEs grade ≥3 occurred in 3.6% of ENZA- and 6.1% of PBO-treated pts. With an additional 4 months of exposure for rPFS by investigator review and 10 months for OS, and with some patients who crossed over from PBO to ENZA in the open-label extension, the HRs were 0.40 (95% CI: 0.18, 0.90) and 0.65 (95% CI: 0.28, 1.51), respectively.
Efficacy and safety results in Japanese pts were consistent with the overall PREVAIL trial.
Clinical trial identification
G. Kimura: grants and personal fees from Astellas, during the conduct of the study; grants and personal fees from Takeda, Pfizer, Bayer, Novartis, GlaxoSmithKline, and Ono Pharmaceutical, outside the submitted work
J. Yonese, T. Fukagai: grants from Astellas, during the conduct of the study. M. Nozawa: grants and personal fees from Astellas, during the conduct of the study. T. Parli: 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
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. 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. Ueda: other from Astellas, during the conduct of the study. All other authors have declared no conflicts of interest.