Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer

Abstract

Background: Men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising prostate-specific antigen (PSA) level are at high risk for metastasis. We hypothesized that enzalutamide, which prolongs overall survival among patients with metastatic, castration-resistant prostate cancer, would delay metastasis in men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level.

Methods: In this double-blind, phase 3 trial, we randomly assigned, in a 2:1 ratio, men with nonmetastatic, castration-resistant prostate cancer and a PSA doubling time of 10 months or less who were continuing androgen-deprivation therapy to receive enzalutamide (at a dose of 160 mg) or placebo once daily. The primary end point was metastasis-free survival (defined as the time from randomization to radiographic progression or as the time to death without radiographic progression).

Results: A total of 1401 patients (median PSA doubling time, 3.7 months) underwent randomization. As of June 28, 2017, a total of 219 of 933 patients (23%) in the enzalutamide group had metastasis or had died, as compared with 228 of 468 (49%) in the placebo group. The median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group (hazard ratio for metastasis or death, 0.29; 95% confidence interval, 0.24 to 0.35; P<0.001). The time to the first use of a subsequent antineoplastic therapy was longer with enzalutamide treatment than with placebo (39.6 vs. 17.7 months; hazard ratio, 0.21; P<0.001; such therapy was used in 15% vs. 48% of patients) as was the time to PSA progression (37.2 vs. 3.9 months; hazard ratio, 0.07; P<0.001; progression occurred in 22% vs. 69% of patients). At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died. Adverse events of grade 3 or higher occurred in 31% of the patients receiving enzalutamide, as compared with 23% of those receiving placebo.

Conclusions: Among men with nonmetastatic, castration-resistant prostate cancer with a rapidly rising PSA level, enzalutamide treatment led to a clinically meaningful and significant 71% lower risk of metastasis or death than placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924 .).

Figure 1.. Kaplan–Meier Estimate of Metastasis-free Survival.

Shown are data for the primary end point of metastasis-free survival. The dashed line indicates the median. The hazard ratio was based on a Cox regression model that was stratified according to the prostate-specific antigen (PSA) doubling time (<6 months vs. ≥6 months) and previous or current use of a bone-targeting agent (yes vs. no), with trial group as the only covariate and a value less than 1.00 favoring enzalutamide treatment. Symbols indicate censored data. NR denotes not reached.

Figure 2.. Kaplan–Meier Estimates of the Time to PSA Progression and the Time to the First Use of Subsequent Antineoplastic Therapy.

Shown are data for the secondary efficacy end points: the time to PSA progression (Panel A) and the time to the first use of a subsequent antineoplastic therapy (Panel B). The dashed line in each panel indicates the median. Hazard ratios were based on Cox regression models that were stratified according to the PSA doubling time (<6 months vs. ≥6 months) and previous or current use of a bone-targeting agent (yes vs. no), with trial group as the only covariate and values less than 1.00 favoring enzalutamide treatment. Symbols indicate censored data.