Pembrolizumab-Olaparib Combination Did Not Improve Survival Outcomes Among Patients With Metastatic Castration-Resistant Prostate Cancer

Results from the Phase 3 KEYLINK-010 Trial

According to results from the KEYLINK-010 trial, pembrolizumab plus olaparib did not significantly improve the radiographic progression-free survival (PFS) or overall survival (OS) among patients with heavily pretreated, metastatic castration-resistant prostate cancer, compared with a next-generation hormonal agent (abiraterone or enzalutamide).

Emmanuel S. Antonarakis, MD, Masonic Cancer Center at University of Minnesota, Minneapolis, Minnesota, and coauthors wrote, “There is an unmet need for therapeutic options that prolong survival for patients with heavily pretreated, metastatic castration-resistant prostate cancer.” There is preclinical evidence to suggest that poly(ADP-ribose) polymerase (PARP) inhibitors may sensitize tumors to immune checkpoint inhibitor therapy, and among certain patients in the phase 1b/2 KEYNOTE-365 study, pembrolizumab plus olaparib showed antitumor activity.

In this open label, phase 3 trial, 793 patients with metastatic castration-resistant prostate cancer who were not preselected for HRR gene alterations and that had progression during continued ADT were enrolled. Patients were randomized on a 2-to-1 basis to receive either 200 mg pembrolizumab once every 3 weeks plus 300 mg olaparib twice daily (n = 529); or abiraterone acetate plus prednisone/prednisolone if they had previously received enzalutamide, or enzalutamide if they had previously received abiraterone (n = 264). Stratification was done based on prior next-generation hormone agent (abiraterone or enzalutamide) and whether there was the presence of measurable disease at baseline. The dual primary end points of this study were radiographic PFS and OS. A key secondary end point was time to first subsequent therapy with other secondary end points including objective response rate (ORR) and duration of response.

At the time of the final radiographic PFS analysis, the median radiographic PFS was 4.4 months in the pembrolizumab plus olaparib group vs 4.2 months in the next-generation hormonal agent group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.82 to 1.25; P = .55). At the time of the final OS analysis, the median OS was 15.8 months in the pembrolizumab plus olaparib group vs 14.6 months in the next-generational hormonal agent group (HR, 0.94; 95% CI, 0.77 to 1.14; P = .26). At the time of time to first subsequent therapy analysis, the median time to first subsequent therapy was 7.2 months and 5.7 months, respectively (HR, 0.86; 95% CI, 0.71 to 1.03). The ORR of the pembrolizumab plus olaparib group was 16.8% vs 5.9% in the next-generation hormonal agent group. Grade ≥3 treatment-related adverse events occurred in 34.6% and 9.0% of patients, respectively.

Dr Antonarakis et al concluded, “pembrolizumab plus olaparib did not significantly improve radiographic progression-free survival or overall survival versus [next-generation hormonal agent] switch.”

Associate editor for the Journal of Clinical Oncology, Michael A. Carducci, MD, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, explained that this study “reinforc[es] the challenges associated with the immunosuppressive tumor microenvironment found in prostate cancer.”

 Dr Carducci added, “continued exploration of immune checkpoint inhibitors with other novel agents based on preclinical and clinical studies such as this is needed.”

Source:

Antonarakis E, Park SH, Goh JC, et al. Pembrolizumab plus olaparib for patients with previously treated and biomarker-unselected metastatic castration-resistant prostate cancer: The randomized, open-label, phase III KEYLINK-010 trial. J Clin Oncol. Published on June 8, 2023. doi:10.1200/JCO.23.00233