Photo Credit: iStock.com/ALIOUI Mohammed Elamine

The following is a summary of “Pembrolizumab plus enzalutamide versus placebo plus enzalutamide for chemotherapy-naive metastatic castration-resistant prostate cancer: the randomized, double-blind, phase III KEYNOTE-641 study,” published in the May 2025 issue of Annals of Oncology by Graff et al. 

Patients with metastatic castration-resistant prostate cancer (mCRPC), established first- and second-line standard-of-care treatments, including abiraterone, enzalutamide, and taxane chemotherapy, were available, but disease progression subsequently occurred in almost all patients.  

Researchers conducted a retrospective study to examine outcomes from the phase III KEYNOTE-641 trial, which compared pembrolizumab plus enzalutamide to placebo plus enzalutamide in individuals with chemotherapy-naive mCRPC.  

They enrolled males aged ≥18 years with confirmed mCRPC and no prior chemotherapy except docetaxel in the hormone-sensitive setting. Prior use of abiraterone was allowed. Participants were randomly allotted in a 1:1 ratio to receive either pembrolizumab 200 mg or placebo intravenously once every 3 weeks for up to 35 cycles, along with enzalutamide 160 mg taken orally each day. The dual primary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS), assessed per PCWG-modified RECIST v1.1 by blinded independent central review. Safety was evaluated as a secondary endpoint.  

The results showed that between August 21, 2019, and June 10, 2022, 1,244 participants were randomized to receive pembrolizumab plus enzalutamide (n=621) or placebo plus enzalutamide (n=623). At the data cutoff (December 12, 2022), the median follow-up was 27.6 months (range 6.1–39.8 months). The study did not meet the dual primary end points of OS or rPFS, with median OS of 24.7 vs 27.3 months (hazard ratio [HR], 1.04 [95% CI, 0.88–1.22]; P=0.66) and median rPFS of 10.4 vs 9.0 months (HR, 0.98 [0.84–1.14]; P=0.41) for pembrolizumab plus enzalutamide vs placebo plus enzalutamide. The prespecified futility boundary for OS was crossed, leading to the early termination of the trial. Grade ≥3 treatment-related adverse events (AEs) occurred in 192 of 615 (31.2%) participants receiving at least 1 dose of pembrolizumab plus enzalutamide and in 67 of 620 (10.8%) receiving at least 1 dose of placebo plus enzalutamide. Treatment discontinuation due to AEs occurred in 71 (11.5%) and 21 (3.4%) participants, respectively.  

Investigators concluded that pembrolizumab combined with enzalutamide did not enhance efficacy and was associated with increased toxicity in individuals with chemotherapy-naive mCRPC. 

Source: annalsofoncology.org/article/S0923-7534(25)00199-1/abstract