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Immunotherapy for Metastatic Castration-Sensitive Prostate Cancer…Patients Want It!”

Immunotherapy for prostate cancer is a loaded topic. This is one of the first solid tumors to instill immunotherapy as a standard of care, with sipuleucel-T offering a survival benefit for patients with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer.1 To rewind even further back, our field of genitourinary oncology has been using immunotherapy, with Bacillus Calmette-Guerin (BCG), for non-invasive muscle invasive bladder cancer. Yet, the rest of the field of oncology has seen dramatic gains with immunotherapy, especially in the form of checkpoint inhibitors; its use has become common practice for most cancers. Unfortunately, prostate cancer has not seen major immunotherapy advances, with accumulation of many negative randomized phase 3 trial attempts, spanning vaccines, like Prostvac,2 and checkpoint inhibitors, like anti-PD-(L)13,4 or anti-CTLA-45,6 antibodies.

It is not completely clear why we have not seen as many immunotherapy successes in prostate cancer. However, enthusiasm for the potential of immunotherapy emanating from our patients has not waned. Those of us who are clinicians will seldom go much more than a week without a patient inquiring about why we aren’t using some way to harness the power of their immune system to fight their prostate cancer.

My answer to that is complex. It meanders through the discussion above, summarizing the modest victory of sipuleucel-T and the challenges with immune checkpoint inhibitors, to emphasizing the point that we lack good biomarkers for patient selection. I explain that we have only a limited number of patients who harbor mismatch repair deficiency, microsatellite instability, and/or hypermutation, features that firmly support the use of an immune checkpoint inhibitor, like pembrolizumab.7 Finally, I discuss how for some immunotherapies, e.g. vaccines, we may need to introduce the agent earlier in the disease course to maximize benefit.

Regardless, of whether it is the incorporation of better biomarkers, earlier introduction of immunotherapy, establishment of intelligent therapeutic agent combination partners, identification of superior immunotherapy targets, or whether we need to design better drugs and delivery systems, this field will not advance without taking a multi-pronged approach.

Below, I highlight ongoing, actively accruing trials that include immunotherapy for patients with the metastatic castration-sensitive prostate cancer disease state. Although we’ve made a huge number of advances with androgen pathway inhibitors and chemotherapy for patients with this disease state, earlier introduction of immunotherapy with promising new compounds is still warranted and frankly, it is demanded by our patient community. The immunotherapy trials below for patients with metastatic castration-sensitive prostate cancer include testing of novel drug mechanistic approaches, with vaccines or bispecific antibodies. There are also more attempts with anti-PD1 antibodies for unique, biomarker selected populations or for use in combination with chemotherapy as a consolidative therapy, a unique strategic approach.

Highlighted immunotherapy trials for patients with metastatic castration-sensitive prostate cancer

  • NCT04633252: Phase 1/2 trial of M9241 with docetaxel
  • NCT05733351: Phase 1 trial of vudalimab (XmAb20717) with abiraterone, enzalutamide, or abiraterone + docetaxel
  • NCT04126070: Phase 2 of nivolumab + docetaxel for DNA repair deficient, Immunoprofile inflamed, or biomarker negative cohorts
  • NCT05189457: First strike, second strike and consolidation with docetaxel plus tislelizumab (anti-PD1 antibody)

Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References: 

  1. Kantoff PW, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363:411-22.
  2. Gulley JL, et al. Phase III Trial of PROSTVAC in Asymptomatic or Minimally Symptomatic Metastatic Castration-resistant Prostate Cancer. J Clin Oncol 2019; 37:1051-61.
  3. Powles T, et al. Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nat Med 2022; 28:144-53.
  4. Antonarakis ES, et al. Pembrolizumab plus olaparib for patients with previously treated and biomarker-unselected metastatic castration-resistant prostate cancer: the randomized, open-label, phase III KEYLYNK-010 trial. J Clin Oncol 2023; 41:3839-50.
  5. Kwon ED, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2014; 15:700-12.
  6. Beer TM, et al. Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer. J Clin Oncol 2017; 35:40-7.
  7. Graham LS, Schweizer MT. Mismatch repair deficiency and clinical implications in prostate cancer. Prostate 2022; 82 Suppl 1:S37-S44.