Introduction: The Challenge of Immunotherapy in Prostate Cancer
Metastatic castration-resistant prostate cancer (mCRPC) represents a significant clinical challenge, characterized by a complex genomic landscape and a historically ‘cold’ tumor immune microenvironment. While immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various solid tumors, their efficacy in unselected mCRPC patients has been modest. Large-scale Phase 3 trials, such as KEYNOTE-199 and KEYNOTE-921, failed to demonstrate a broad survival benefit for pembrolizumab in the general mCRPC population. However, these results masked the profound benefits observed in small, molecularly defined subsets of patients.
Currently, the FDA has granted tissue-agnostic approvals for ICIs in patients with microsatellite instability-high (MSI-H) or high tumor mutational burden (TMB-H, typically defined as ≥10 mutations per megabase). Despite these approvals, several clinical questions persist in the context of prostate cancer. Specifically, the independent utility of TMB-H in the absence of MSI-H remains debated, and the reliability of blood-based MSI (bMSI) testing as a surrogate for tissue-based testing in patients with limited biopsy material has not been fully elucidated. A recent study published in Clinical Cancer Research by Sayegh and colleagues provides critical evidence to address these gaps.
