Immunotherapy in metastatic castration-resistant prostate cancer: transformative for the few, not for all

Despite advances in hormonal therapies, chemotherapy, and radioligand agents, metastatic castration-resistant prostate cancer (mCRPC) remains a therapeutic challenge. Most patients ultimately progress, and outcomes remain poor (1,2). Against the backdrop of successes in melanoma, lung, and bladder cancer, immunotherapy (IO) was expected to deliver similar gains in prostate cancer. Yet, in unselected populations, checkpoint inhibitors have shown limited responses and minimal clinical benefit (1,2).

This lack of efficacy reflects the biology of prostate cancer, often described as a “cold tumor”. It is characterized by a low mutation rate, restricted neoantigen formation, and limited immune cell infiltration, which drive primary resistance to programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blockade (3-5).

However, rare molecular subsets, including mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H), high mutational burden (TMB-high), and CDK12 loss, demonstrate enhanced sensitivity to IO (3,5). These represent critical niches where checkpoint blockade can offer substantial benefit.

The PERSEUS1 trial

PERSEUS1, an open-label, investigator-initiated phase 2 trial, prospectively evaluated pembrolizumab in mCRPC patients with immunosensitive alterations (dMMR/MSI-H, TMB-high, CDK12 loss, POLE/POLD1 mutations) (6). The primary endpoint was objective response rate; secondary endpoints included survival and safety.

Among 25 treated patients, responses were observed in 28% (7/25): 5 with dMMR and two with CDK12 loss. Median progression-free survival (PFS) was 2.8 months, overall survival (OS) was 16 months, and some responses exceeded 5 years. Toxicity was manageable, with grade 3–4 events in only 12% (6). These findings confirm robust and durable benefit in dMMR/MSI-H tumors, while activity in TMB-high and CDK12 subsets appeared inconsistent.

Importantly, exploratory analyses showed that responding patients exhibited higher stromal infiltration of CD8/CD4 T cells, B lymphocytes, and M1 macrophages, suggesting the tumor microenvironment may predict benefit beyond genomic alterations.

PERSEUS1 reinforces a simple, practice-changing message: all patients with mCRPC should undergo MSI/dMMR testing. Though rare (~3% prevalence), the potential for transformative benefit with pembrolizumab justifies universal screening. Other biomarkers—TMB-high and CDK12 loss—remain exploratory and should guide enrollment in clinical trials rather than routine care.

The study was limited by small sample size and early closure due to slow accrual, reflecting the rarity of eligible patients. Broader implementation of next-generation sequencing (NGS) testing is needed to facilitate timely identification of these molecular subsets. Barriers also remain around cost and access to both molecular testing and IO, which limit equity of care.

However, we emphasize that mismatch repair status can be assessed by immunohistochemistry (IHC) through the evaluation of the MLH1, MSH2, MSH6, and PMS2 genes. IHC is a widely available and low-cost method already integrated into routine pathology; therefore, the use of this approach can reduce barriers to testing implementation (4).

In addition to biomarkers predictive of response to IO, the evaluation of genes associated with homologous recombination deficiency, such as BRCA1, BRCA2, ATM, and PALB2, should also be part of the standard of care in metastatic prostate cancer. This should be done since the proven efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors in this subgroup has already been established (7).

The identification of pathogenic variants in homologous recombination genes, and especially BRCA1 or BRCA2, has implications that go beyond the issue of therapeutic selection. Therefore, in these cases, referral for genetic counseling should be carried out. Testing, including of at-risk family members, enables screening, prevention, and early diagnosis strategies, expanding the clinical and public health impact of precision oncology (8).

The next step is randomized trials in biomarker-selected mCRPC, particularly MSI-H/dMMR disease, to establish the magnitude of IO benefit relative to standard therapies. Efforts should also focus on rational combinations—IO with PARP inhibitors, androgen receptor (AR)-targeted therapies, or radioligands—to expand benefit beyond rare subgroups (2,9). Finally, the field must advance biomarker discovery beyond genomics, including immune microenvironment signatures, PD-L1 expression, and transcriptomic profiles (9,10).

In conclusion, IO in prostate cancer should not be applied indiscriminately. For most mCRPC patients, checkpoint inhibitors provide little benefit. Yet, for the rare few with MSI-H/dMMR, responses can be profound and long-lasting. The challenge now is twofold: to ensure universal testing so these patients are not missed, and to continue research aimed at broadening the reach of IO in this disease.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-729/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-729/coif). P.C.B. reports personal fees from Astellas, AstraZeneca, AVEO Oncology, Bayer, BMS, Dendreon, Eisai, EMD Serono, ESSA Pharma, Guardant Health, Ipsen, Caris Life Sciences, Exelixis, Janssen, Merck, Merus, MJH, Myovant, Novartis, Pfizer, Seattle Genetics, Syncromune, and UroToday. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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