The primary completion of a PHASE3 trial for pembrolizumab (KEYNOTE-641) in metastatic castration-resistant prostate cancer (mCRPC) was reported on December 12, 2022. The study found that the combination of pembrolizumab plus enzalutamide did not improve overall survival, with a median OS of 24.7 months compared to 27.3 months for placebo plus enzalutamide. This result indicates that the trial did not meet its primary endpoint for overall survival.

Background

Pembrolizumab (Keytruda) is an immunotherapy drug. The trial investigated its use in combination with enzalutamide for participants with metastatic castration-resistant prostate cancer (mCRPC). This condition affects men whose prostate cancer has spread and no longer responds to treatments that lower testosterone.

Trial design

The study, identified as NCT03834493 (KEYNOTE-641), was a PHASE3 trial designed to assess the efficacy and safety of pembrolizumab plus enzalutamide compared to placebo plus enzalutamide. It enrolled 1244 participants with metastatic castration-resistant prostate cancer (mCRPC) who had not received chemotherapy for mCRPC, were abiraterone-naïve, or were intolerant to or progressed on abiraterone acetate. The primary study hypotheses were that the combination of pembrolizumab plus enzalutamide would be superior to placebo plus enzalutamide with respect to Overall Survival (OS) and Radiographic Progression-free Survival (rPFS).

Key results

The PHASE3 KEYNOTE-641 trial reported median Overall Survival (OS) of 24.7 months for the pembrolizumab plus enzalutamide arm, compared to 27.3 months for the placebo plus enzalutamide arm. The hazard ratio (HR) for OS was 1.04 (95% Confidence Interval [CI]: 0.88, 1.22), with a p-value of 0.6621, indicating no statistically significant improvement in OS with the addition of pembrolizumab.

For Radiographic Progression-free Survival (rPFS), the median was 10.4 months in the pembrolizumab plus enzalutamide arm versus 9.0 months in the placebo plus enzalutamide arm. The HR for rPFS was 0.98 (95% CI: 0.84, 1.14), with a p-value of 0.4073, also not reaching statistical significance.

Other measured outcomes included:

  • Median Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST) was 13.2 months for pembrolizumab plus enzalutamide versus 12.6 months for placebo plus enzalutamide (HR: 0.95, 95% CI: 0.83, 1.09).
  • The Prostate-specific Antigen (PSA) Response Rate was 49.0% for the pembrolizumab combination versus 45.1% for the placebo combination, a difference of 3.4% (95% CI: -1.5%, 8.3%).
  • Objective Response (OR) was observed in 12.2% of participants in the pembrolizumab combination arm compared to 9.3% in the placebo combination arm, a difference of 2.9% (95% CI: -0.2%, 6.1%).
  • The Prostate-specific Antigen (PSA) Undetectable Rate was 13.1% for pembrolizumab plus enzalutamide versus 12.6% for placebo plus enzalutamide, a difference of 0.3% (95% CI: -3.4%, 4.1%).

What this means

The results from the PHASE3 KEYNOTE-641 trial indicate that the addition of pembrolizumab to enzalutamide did not demonstrate a statistically significant improvement in Overall Survival (OS) or Radiographic Progression-free Survival (rPFS) in participants with metastatic castration-resistant prostate cancer. The numerically lower median OS in the pembrolizumab combination arm compared to the placebo combination arm, along with non-significant hazard ratios for both primary endpoints, suggests that the trial did not meet its primary objectives. While some secondary endpoints like rPFS showed a numerical increase, the lack of statistical significance across key efficacy measures implies that the combination did not provide a clear clinical benefit over enzalutamide alone in this patient population.

Source

These trial results were reported as a primary completion on ClinicalTrials.gov on December 12, 2022. The full details of the study, NCT03834493, are available on clinicaltrials.gov.