Pembrolizumab for metastatic castration-resistant prostate cancer: trials and tribulations

IntroductionImmunotherapies have revolutionized the management of various malignancies but have only recently been evaluated systematically in prostate cancer. Pembrolizumab, a programmed-death 1 (PD-1) blocking antibody, has been utilized in a small subset of prostate cancer patients with mismatch repair deficiency/microsatellite instability, but has now been assessed in broader populations of metastatic prostate cancer patients.Areas coveredThe results of four pembrolizumab-based phase III clinical trials for metastatic castration-resistant prostate cancer (mCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC) patients, including KEYNOTE-641, KEYNOTE-921, KEYNOTE-991, and KEYLYNK-010 are summarized. Programmed death-ligand 1 (PD-L1) expression, the efficacy of pembrolizumab in prostate cancer patients with certain molecular defects, and emerging pembrolizumab-based therapeutic combinations are also reviewed.Expert opinionPembrolizumab has not benefitted unselected metastatic prostate cancer patients when combined with chemotherapy, next-generation hormonal agents (NHA), or poly(ADP-ribose) polymerase inhibitors (PARPi). PD-L1 positivity does not predict the response to pembrolizumab in this disease. A small number of responding patients can likely be explained by rare genetic and molecular defects, and more innovative combination strategies are needed to improve outcomes in prostate cancer patients who are not sensitive to pembrolizumab. Emphasis should be placed on developing additional or alternative immuno-oncology approaches beyond classical immune checkpoint inhibition.