New findings from the randomized, double-blind, phase III KEYNOTE-641 study reveal that adding the immunotherapy drug pembrolizumab to enzalutamide did not improve outcomes for patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Furthermore, the combination regimen was associated with additional toxicity.

Metastatic castration-resistant prostate cancer is a challenging disease, with patients often progressing after initial treatments. While standard-of-care options like abiraterone, enzalutamide, and taxane chemotherapy exist, almost all patients eventually experience disease progression. The KEYNOTE-641 study was designed to evaluate whether combining pembrolizumab, an immunotherapy, with enzalutamide, an established treatment, could offer improved efficacy compared to enzalutamide alone in this population.

The study enrolled male participants aged 18 or older with confirmed mCRPC who had not previously received chemotherapy, except for possible docetaxel treatment in the hormone-sensitive setting. Prior abiraterone treatment was permitted.
Participants were randomly assigned in a 1:1 ratio to one of two treatment arms: pembrolizumab 200 mg intravenously every three weeks for up to 35 cycles plus enzalutamide 160 mg orally daily, or a placebo intravenously every three weeks plus enzalutamide 160 mg orally daily.
The trial’s dual primary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS), assessed by blinded independent central review. Safety was evaluated as a secondary endpoint.

Between August 2019 and June 2022, a total of 1244 participants were randomly assigned to the treatment groups: 621 to pembrolizumab plus enzalutamide and 623 to placebo plus enzalutamide. At the data cutoff date in December 2022, the median follow-up duration was 27.6 months.
However, the study did not meet its primary endpoints. The median overall survival was 24.7 months in the pembrolizumab plus enzalutamide group compared to 27.3 months in the placebo plus enzalutamide group (hazard ratio [HR], 1.04; P=0.66). Similarly, median radiographic progression-free survival was 10.4 months with the combination versus 9.0 months with placebo plus enzalutamide (HR, 0.98; P=0.41).
Due to the lack of improvement in overall survival and having crossed the prespecified boundary for futility for this endpoint, the study was stopped.
Regarding safety, the addition of pembrolizumab resulted in more adverse events.
In summary, the KEYNOTE-641 trial demonstrated that adding pembrolizumab to enzalutamide did not enhance efficacy outcomes for individuals with chemotherapy-naive mCRPC and led to increased toxicity.

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