Pembrolizumab Plus Enzalutamide and Androgen Deprivation Therapy Fails to Improve Survival for Patients With Metastatic Hormone-Sensitive Prostate Cancer

According to results from the phase 3 KEYNOTE-991 study, pembrolizumab plus enzalutamide and continuous androgen deprivation therapy did not improve survival results among patients with metastatic hormone-sensitive prostate cancer. 

“Despite treatment advances, most patients with metastatic hormone-sensitive prostate cancer experience disease progression to castration-resistant disease within 5 years,” stated Christian Gratzke, MD, University Hospital Freiburg, Freiburg, Germany, and coauthors. 

In this double-blind study, 1251 patients who had not yet received next-generation hormonal agents were randomized on a 1-to-1 basis to receive either 200 mg of pembrolizumab (n = 626) or placebo (n = 625) every 3 weeks for up to 35 cycles, plus 160 mg of enzalutamide and continuous androgen deprivation therapy. Primary end points included radiographic progression-free survival (rPFS) and overall survival (OS). A key secondary end point was safety. 

At a median follow-up of 21.1 months, median rPFS was not achieved in either treatment arm and rPFS was not superior with pembrolizumab compared to placebo (hazard ratio [HR] 1.20; 95% confidence interval [CI], 0.96 to 1.49; P = .9467). Median OS was not achieved in either treatment arm (HR 1.16; 95% CI, 0.88 to 1.53). Grade ≥3 adverse events were reported in 61.9% of patients in the pembrolizumab arm and 38.1% of patients in the placebo arm. Serious adverse events were reported in 40.3% and 23.2% of patients, respectively. Any-grade rash occurred in 25.1% of patients in the pembrolizumab arm and 9.3% in the placebo arm. 

“KEYNOTE-991 did not meet its primary end point and was stopped for futility,” concluded Dr Gratzke et al. “The addition of pembrolizumab to enzalutamide and [androgen deprivation therapy] was associated with higher frequencies of grade ≥3 [adverse events] and serious [adverse events] than with placebo.”

Source: 

Gratzke C, Özgüroğlu M, Peer A, et al. 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. Ann Oncol. Published online: May 16, 2025. doi: 10.1016/j.annonc.2025.05.008