MSI-H and TMB-H as Independent Predictors: Refining Immunotherapy Selection in Metastatic Castration-Resistant Prostate Cancer

Introduction: The Challenge of the ‘Cold’ Prostate Tumor

Metastatic castration-resistant prostate cancer (mCRPC) has historically been characterized as an immunologically ‘cold’ tumor. Unlike melanoma or non-small cell lung cancer, mCRPC typically exhibits a low mutational burden and a suppressive tumor microenvironment, leading to disappointing results for immune checkpoint inhibitors (ICIs) in unselected patient populations. Despite this, the FDA has granted tissue-agnostic approvals for ICIs like pembrolizumab for tumors exhibiting microsatellite instability-high (MSI-H) or high tumor mutational burden (TMB-H, defined as ≥10 mutations per megabase). However, the specific clinical utility of these biomarkers within the prostate cancer landscape—particularly the additive value of TMB in the absence of MSI-H—has remained an area of active investigation. A new study published in Clinical Cancer Research provides critical evidence on how these biomarkers should guide clinical decision-making.

Study Design and Methodology