Combination Strategies with PD-1/PD-L1 Inhibition for Patients with Metastatic Castration-Sensitive Prostate Cancer

The clinical data surrounding inhibition of PD-1/PD-L1 in prostate cancer is evolving.  In the past, I have written a couple of articles about both single-agent and combination approaches for metastatic castration-resistant prostate cancer (mCRPC).1, 2  The field has evolved to the point where we recognize that single-agent PD-1/PD-L1 inhibition is unlikely to yield a major benefit for an unselected population.  In the KEYNOTE-199 trial, pembrolizumab yielded 5% and 3% objective response rates in patients with PD-L1 positive and negative tumors, respectively.3  

Similarly, in the IMbassador250 randomized phase 3 trial, atezolizumab did not offer an overall survival advantage when combined with enzalutamide over enzalutamide alone.4  With that said, there are still multiple randomized phase 3 trials for patients with mCRPC that have pending results.  For example, KEYNOTE-641, KEYNOTE-921, and KEYLYNK-010 are testing whether pembrolizumab combined with enzalutamide, docetaxel, or olaparib, respectively, for unselected populations, will lead to patient benefit (NCT03834493, NCT03834506, and NCT03834519).

The challenge is that it is difficult in an immunologically “cold” tumor like prostate cancer for PD-1/PD-L1 antibody therapy to work well.  The Cancer Genome Atlas data points towards prostate cancers to generally have low inflammation levels and prostate cancer was defined as immunologically “ignorant” tumors.5, 6  However, one situation where this is not accurate is the microsatellite unstable, mismatch repair deficient and/or hypermutated prostate cancer.7  As a result, there are broad FDA labels for patients who harbor solid tumors with one or more of these enriched molecular features for use of pembrolizumab.8-10  Unfortunately, there are few patients with prostate cancer who harbor these features,11 and there is no prospective clinical trial data that enrolled prostate cancer patients with these enrichment features to PD-1/PD-L1 antibody therapy to properly guide us.

Essentially, our greatest hope remains with combination therapy, as described above.  With the mCRPC portfolio quite well covered, we turn towards the metastatic castration-sensitive prostate cancer (mCSPC) disease state with hopes for future success.  Theoretically, initial androgen deprivation therapy with treatment intensification may be a time point in the treatment of prostate cancer where significant initial apoptosis is induced.  This could cause an inflammatory response that would be conducive to checkpoint inhibition with PD-1/PD-L1 inhibitors.  For example, the randomized phase 3 KEYNOTE-991 trial has completed accrual with androgen deprivation and enzalutamide with or without pembrolizumab for this mCSPC unselected population (NCT04191096).

The future of PD-1/PD-L1 inhibition in prostate cancer will depend heavily upon both ideal patient selection and better understanding of tumor biologic characteristics that harbor an appealing environment for checkpoint inhibitor therapy.  Outside of an enriched biomarker population, single-agent activity is very low, yet we remain committed to studying PD-1/PD-L1 inhibition in earlier disease states and with multiple rational combinations.  This includes attempts at inducing abscopal effect with either radiation or chemotherapy or use of antiangiogenic agents to attempt to create leakier blood vessels in the tumor microenvironment to facilitate T cell entry.  Below, I have highlighted trials with PD-1/PD-L1 antibody agents in combination with conventional androgen deprivation therapy and various methods of treatment intensification.  

Highlighted Trials for patients with mCSPC

  • KEYNOTE 991 (China extension) – Randomized phase 3 trial of androgen deprivation therapy and enzalutamide with or without pembrolizumab (NCT04934722)
  • SAABR – Phase 2 study of abiraterone, atezolizumab, GnRH analog, and Stereotactic Body Radiotherapy (SBRT) to the prostate in new mCSPC (NCT04262154)
  • Phase 2 study of ADT, docetaxel and nivolumab for those with DNA repair deficiency, mismatch repair deficiency or Immunoprofile enriched mCSPC patients (NCT04126070)
  • CABIOS – Phase 1 trial of ADT, abiraterone, cabozantinib and nivolumab for previously untreated mCSPC (NCT04477512)


Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington

References

  1. Yu EY. "Does PD-1/PD-L1 Inhibition Really Work in Prostate Cancer?." Urotoday Clinical Trials Portal. On-line: August 14, 2017
  2. Yu EY. "PARP with PD-1/PD-L1 inhibition: Is There Any Magic to the Combination in a Molecularly Unselected Patient Population?" Urotoday Clinical Trials Portal.On-line: February 15, 2019.
  3. Antonarakis ES, et al. Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J Clin Oncol (2020);38:395-405.
  4. Sweeney CJ, et al.2020 AACR Virtual Annual Meeting.Abstract CT014.  Presented April 27, 2020.
  5. Danaher P, et al."Pan-cancer adaptive immune resistance as defined by the Tumor Inflammation Signature (TIS): Results from The Cancer Genome Atlas (TCGA)" J Immunother Cancer (2018); 6:63.
  6. Bou-Dargham MJ, et al." Immune landscape of human prostate cancer: immune evasion mechanisms and biomarkers for personalized immunotherapy." BMC Cancer 2020; 20:572.
  7. Pritchard CC et al." Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer." Nat Commun (2014); 5:4988.
  8. Le T et al." PD-1 Blockade in Tumors with Mismatch-Repair Deficiency." N Engl J Med (2015); 372:2509-20.
  9. Federal Drug Administration. (2017, May 23). FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication [Press release]. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication.
  10. Federal Drug Administration. (2020, June 16). FDA approves pembrolizumab for adults and children with TMB-H solid tumors. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors.
  11. Robinson D et al. Integrative clinical genomics of advanced prostate cancer. Cell (2015);161(5):1215-1228
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