Addition of Pembrolizumab Fails to Improve Outcomes for Chemotherapy-Naive Patients With Metastatic Castration-Resistant Prostate Cancer

According to results from the phase 3 KEYNOTE-641 study, the addition of pembrolizumab to enzalutamide did not improve outcomes compared to placebo plus enzalutamide among chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC). 

“Established first- and second-line standard-of-care treatment options (abiraterone, enzalutamide, taxane chemotherapy) are available for patients with metastatic castration-resistant prostate cancer, but almost all patients experience subsequent disease progression,” stated Julie Graff, MD, OHSU Knight Cancer Institute, Portland, Oregon, and coauthors. Here, researchers “evaluated pembrolizumab plus enzalutamide versus placebo plus enzalutamide in participants with chemotherapy-naive mCRPC.”

In this double-blind study, researchers randomized 1244 patients on a 1-to-1 basis to receive either 200 mg of pembrolizumab (n = 621) or placebo (n = 623) once every 3 weeks for ≤ 35 cycles plus 160 mg of daily enzalutamide. Primary end points included overall survival (OS) and radiographic progression-free survival (rPFS), by blinded independent central review. A key secondary end point was safety. 

At a median follow-up of 27.6 months, median OS was 24.7 months in the pembrolizumab arm and 27.3 months in the placebo arm (hazard ratio [HR] 1.04; 95% confidence interval [CI], 0.88 to 1.22; P = .66). Median rPFS was 10.4 months in the pembrolizumab arm and 9.0 months in the placebo arm (HR 0.98; 95% CI, 0.84 to 1.14; P = .41). Grade ≥s3 treatment-related adverse events occurred in 31.2% of patients who received ≥ 1 dose of pembrolizumab and 10.8% of patients who received ≥ 1 dose of placebo. Treatment discontinuation due to treatment-related adverse events occurred in 11.5% of patients in the pembrolizumab arm and 3.4% of patients in the placebo arm. 

“Adding pembrolizumab to enzalutamide did not improve efficacy outcomes for participants with chemotherapy-naive mCRPC,” concluded Dr Graff et al. “Additional toxicity was observed with the combination regimen.” 

Source: 

Graff JN, Burotto M, Fong PC, et al. Pembrolizumab plus enzalutamide versus placebo plus enzalutamide for chemotherapy-naive metastatic castration-resistant prostate cancer: The randomized, double-blind, phase III KEYNOTE-641 study. Ann Oncol. Published online: May 16, 2025. doi: 10.1016/j.annonc.2025.05.007