Pembrolizumab plus enzalutamide and androgen deprivation therapy versus placebo plus enzalutamide and androgen deprivation therapy for metastatic hormone-sensitive prostate cancer: the randomized, double-blind, phase III KEYNOTE-991 study

BACKGROUND: Despite treatment advances, most patients with metastatic hormone-sensitive prostate cancer (mHSPC) experience disease progression to castration-resistant disease within 5 years. The placebo-controlled, double-blind, phase III KEYNOTE-991 study evaluated the efficacy and safety of adding pembrolizumab to enzalutamide and androgen deprivation therapy (ADT) in participants with mHSPC. PATIENTS AND METHODS: Eligible participants were aged ≥18 years with next-generation hormonal agent-naive mHSPC. Participants were randomly assigned (1 : 1) to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for ≤35 cycles, with oral enzalutamide 160 mg and continuous ADT. Primary endpoints were radiographic progression-free survival (rPFS) and overall survival (OS). Safety was a secondary endpoint. RESULTS: Between 2 March 2020 and 9 August 2021, 626 participants were randomly assigned to receive pembrolizumab plus enzalutamide and ADT and 625 participants to receive placebo plus enzalutamide and ADT. At the first interim analysis, the median follow-up was 21.1 months (range 14.8-32.0 months). rPFS was not superior with pembrolizumab versus placebo [median not reached in both arms; hazard ratio (HR) 1.20, 95% confidence interval (CI) 0.96-1.49, P = 0.9467]. Median OS was not reached in either arm (HR 1.16, 95% CI 0.88-1.53; not formally statistically tested as per the multiplicity strategy). Grade ≥3 adverse events (AEs) and serious AEs (SAEs) were reported in 61.9% versus 38.1% and 40.3% versus 23.2% of participants in the pembrolizumab versus the placebo arm, respectively. Any-grade rash occurred at a higher frequency with pembrolizumab (25.1%) versus placebo (9.3%). CONCLUSIONS: KEYNOTE-991 did not meet its primary endpoint and was stopped for futility. The addition of pembrolizumab to enzalutamide and ADT was associated with higher frequencies of grade ≥3 AEs and SAEs than with placebo. Rash was identified as an additional safety signal with pembrolizumab plus enzalutamide and ADT.