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

ABSTRACT

Introduction

Immunotherapies 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 covered

The 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 opinion

Pembrolizumab 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.

KEYWORDS:

• clinical trial
• immune checkpoint
• immunotherapy
• KEYNOTE
• mCRPC
• PD-1
• PD-L1
• pembrolizumab

Article highlights

• Pembrolizumab does not improve outcomes when combined with other standard-of-care therapies in molecularly unselected metastatic prostate cancer patients.

• PD-L1 is expressed at low levels in prostate cancer and is not a biomarker of sensitivity to pembrolizumab.

• A rare subset of prostate cancer patients with mismatch repair deficiency/microsatellite instability may benefit from pembrolizumab and other immune checkpoint inhibitors, but prospective trials in this small population are lacking.

• Additional or alternative approaches are needed to yield effective immunotherapies in prostate cancer and to overcome an immunosuppressive microenvironment.

Declaration of interest

AK Tsai is partially funded by the National Institutes of Health (NIH) grant (T32 CA009138). ES Antonarakis is partially funded by the NIH grant (P30 CA077598) and U.S. Department of Defense (DOD) grant (W81XWH-22-2-0025). ES Antonarakis has served as a paid consultant/advisor to Aikido Pharma, Constellation, Corcept Therapeutics, EcoR1, Exact Sciences, Foundation Medicine, Global Life Sciences, Hookipa Pharma, KeyQuest Health, Menarini Silicon Biosystems, Propella Therapeutics, z-Alpha, Research to Practice, and Blue Earth Diagnostics; has received research funding (to his institution) from Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Clovis, Constellation Pharma, MacroGenics, Merck, Orion, Sanofi, Aadi Biosciences, Amgen, Janssen, Pfizer, and Tempus; and is a co-inventor of a patented AR-V7 biomarker technology that has been licensed to Qiagen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.