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

Alexander K Tsai1,2, Sana Kagalwalla1, Jenna Langer1

  • 1Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Masonic Cancer Center, Minneapolis, MN, USA.

Expert Opinion on Biological Therapy
|January 29, 2024
PubMed
Abstract

Insights

Pembrolizumab (a programmed-death 1 blocking antibody) did not improve outcomes for most metastatic prostate cancer patients. Response was not predicted by PD-L1 expression, highlighting the need for novel immunotherapy strategies.

Area of Science:

  • Oncology
  • Immunotherapy
  • Prostate Cancer Research

Background:

  • Immunotherapy, specifically programmed-death 1 (PD-1) blocking antibodies like pembrolizumab, has transformed cancer treatment.
  • Its application in prostate cancer is emerging, moving beyond specific genetic markers to broader patient populations.

Purpose of the Study:

  • To summarize findings from four phase III clinical trials of pembrolizumab in metastatic prostate cancer.
  • To review the role of PD-L1 expression and molecular defects in treatment response.
  • To discuss emerging combination strategies and future directions for immunotherapy in prostate cancer.

Main Methods:

  • Analysis of data from four key phase III clinical trials: KEYNOTE-641, KEYNOTE-921, KEYNOTE-991, and KEYLYNK-010.
  • Review of programmed death-ligand 1 (PD-L1) expression as a predictive biomarker.
  • Evaluation of pembrolizumab efficacy in combination with chemotherapy, next-generation hormonal agents (NHA), and poly(ADP-ribose) polymerase inhibitors (PARPi).

Main Results:

  • Pembrolizumab, when added to chemotherapy, NHA, or PARPi, did not benefit unselected metastatic prostate cancer patients.
  • Programmed death-ligand 1 (PD-L1) positivity did not reliably predict response to pembrolizumab in this patient group.
  • A small subset of patients showed benefit, likely due to rare genetic or molecular alterations.

Conclusions:

  • Current pembrolizumab-based regimens are ineffective for the majority of metastatic prostate cancer patients.
  • Novel combination strategies and alternative immuno-oncology approaches are essential to improve treatment outcomes.
  • Future research should focus on identifying predictive biomarkers and developing more effective immunotherapies beyond PD-1/PD-L1 inhibition.
Keywords:
KEYNOTEPD-1PD-L1clinical trialimmune checkpointimmunotherapymCRPCpembrolizumab

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