Metastatic Castration-Resistant Prostate Cancer, Immune Checkpoint Inhibitors, and Beyond

Abstract

The therapeutic landscape of several genitourinary malignancies has been revolutionized by the development of immune checkpoint inhibitors (ICIs); however, the utility of immunotherapies in prostate cancer has been limited, partly due to the immunologically “cold” tumor terrain of prostate cancer. As of today, pembrolizumab is the only immune checkpoint inhibitor approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) in a select group of patients with high microsatellite instability (MSI-H), deficient mismatch repair (dMMR), or high tumor mutational burden (TMB). Looking ahead, several combinatorial approaches with ICIs involving radioligands, radiotherapy, PARP inhibitors, interleukin inhibitors, and cancer vaccines are exploring a potential synergistic effect. Furthermore, B7-H3 is an alternative checkpoint that may hold promise in adding to the treatment landscape of mCRPC. This review aims to summarize previous monotherapy and combination therapy trials of ICIs as well as novel immunotherapy combination therapeutic strategies and treatment targets in mCRPC.

A landscape of checkpoint blockade resistance in cancer: underlying mechanisms and current strategies to overcome resistance

“… 49 , 50 As of today, the only ICI FDA-approved treatment for prostate cancer patients is pembrolizumab (anti-PD-1), but only for metastatic castration-resistant prostate cancer (mCRPC) patients with high tumor mutational burden (TMB-H), high microsatellite instability (MSI-H), or mismatch repair deficiency (MMR-D). 63 However, several clinical trials continue to show the limited response of mCRPC patients to single-agent ICI therapy, including pembrolizumab and other ICIs such as atezolizumab (anti-PD-L1) and ipilimumab (anti-CTLA-4). 63 Besides poor infiltration in “cold tumors,” these tumors rarely express PD-L1 (immunologically ignorant) and show low expression of neoantigens and immunosuppressive TME, all contributing factors to their unresponsiveness to checkpoint blockade.…”

“… 63 However, several clinical trials continue to show the limited response of mCRPC patients to single-agent ICI therapy, including pembrolizumab and other ICIs such as atezolizumab (anti-PD-L1) and ipilimumab (anti-CTLA-4). 63 Besides poor infiltration in “cold tumors,” these tumors rarely express PD-L1 (immunologically ignorant) and show low expression of neoantigens and immunosuppressive TME, all contributing factors to their unresponsiveness to checkpoint blockade. 49 …”

Molecular Mechanisms of Prostate Cancer Development in the Precision Medicine Era: A Comprehensive Review

“…Favorable responses to ICIs such as pembrolizumab have been reported in MMR-deficient, MMR-mutated, MSI-high, or high-tumor-mutational-burden mCRPC [327][328][329][330][331][332][333]. However, prospective trials comparing ICIs to standard systemic therapy in MMR-deficient PCa are currently lacking [334,335].…”

Tumor-associated antigen targets for novel immune-based strategies in prostate cancer

“…B7-H3 is a surface membrane protein that is a newly identified member of the B7 immunomodulator protein family. More well-known member proteins include PD-L1, PD-1, and CTLA-4 [123][124][125] . While originally hypothesized to promote costimulatory immune activation, recent data suggest a dual role, with both costimulatory and, more predominantly, coinhibitory role for the antigen [125][126][127][128][129] .…”