KEYNOTE-641: Does Pembrolizumab Plus Enzalutamide Improve Outcomes for mCRPC?

Results of the KEYNOTE-641 study on the effects of pembrolizumab plus enzalutamide in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) with or without prior abiraterone treatment were presented by Julie N. Graff, MD, of Oregon Health & Science University, at the European Society for Medical Oncology Congress 2023.

Patients with mCRPC who experience progressive disease after second-generation hormonal agent therapy do not often receive further chemotherapy. Novel treatment approaches are needed in this setting, and early studies suggest that pembrolizumab plus enzalutamide has antitumor activity in pretreated mCRPC.

Dr. Graff and colleagues designed the KEYNOTE-641 study to compare pembrolizumab plus enzalutamide versus placebo plus enzalutamide in 1244 patients with chemotherapy-naïve mCRPC with or without prior abiraterone treatment. Patients were randomized (1:1) to pembrolizumab (200 mg) or placebo (intravenously once every 3 weeks for ≤35 cycles) plus enzalutamide (160 mg daily).

The dual primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Key secondary end points included time to initiation of first subsequent anticancer therapy (TFST), safety, and tolerability.

After a median follow-up time at first interim analysis of 27.6 months, the dual primary end points of rPFS and OS were not met; the median rPFS was 10.4 months in the pembrolizumab arm versus 9.0 months in the placebo arm (hazard ratio [HR], 0.98; 95% CI, 0.84-1.14; P=.41), and the median OS was 24.7 months versus 27.3 months, respectively (HR, 1.04; 95% CI, 0.88-1.22; P=.66). Additionally, Dr. Graff noted the prespecified boundary for futility for OS was crossed and the study was stopped.

The median TFST was 13.2 months versus 12.6 months, respectively (HR, 0.95; 95% CI, 0.83-1.09).

Dr. Graff added that any-grade and grade 3 or higher treatment-related adverse events occurred in 77.9% and 31.2%, respectively, of patients who had received at least 1 dose of pembrolizumab plus enzalutamide and 61.6% and 10.8%, respectively, of patients who had received at least 1 dose of placebo plus enzalutamide.

Three treatment-related deaths occurred in the pembrolizumab arm. No deaths were reported in the placebo arm.

Results of KEYNOTE-641 led Dr. Graff to conclude that “pembrolizumab plus enzalutamide does not significantly improve efficacy outcomes…in patients with mCRPC with or without prior abiraterone treatment.”