Additive Clinical Utility of Microsatellite Instability and Tumor Mutational Burden to Predict Immune Checkpoint...

Area of Science:

• Oncology
• Immunotherapy
• Genomics

Background:

• Immune checkpoint inhibitors (ICIs) demonstrate limited efficacy in unselected metastatic castration-resistant prostate cancer (mCRPC) patients.
• Current approvals for ICIs in mCRPC are restricted to biomarker-defined subsets, specifically microsatellite instability-high (MSI-H) and/or high tumor mutational burden (TMB-H).
• The efficacy of ICIs in TMB-H but not MSI-H disease, and outcomes associated with blood-based MSI (bMSI) in mCRPC, remain incompletely understood.

Purpose of the Study:

• To evaluate the efficacy of ICIs in mCRPC based on tissue-assessed MSI (tMSI) and TMB (tTMB) status.
• To assess ICI outcomes in relation to blood-based MSI (bMSI) status.
• To compare ICI efficacy with taxane treatment in patients with tTMB ≥ 10.

Main Methods:

• Utilized the US-based deidentified Flatiron Health-Foundation Medicine prostate cancer Clinico-Genomic Database (FH-FMI CGDB).
• Included patients with tMSI and tTMB status treated with single-agent ICI, or ICI or taxane for bMSI assessment.
• Analyzed time to treatment failure (TTNT) and overall survival (OS) based on biomarker status.

Main Results:

• Among 2,965 mCRPC patients, tMSI-H (3.2%) frequently overlapped with tTMB ≥ 10 mut/Mb (4.7%).
• In 84 ICI-treated patients, tMSI-H and tTMB ≥ 10 (without tMSI-H) were associated with significantly more favorable TTNT and OS compared to tTMB < 10.
• Blood-based MSI-H detection correlated with improved TTNT and OS on ICI when tumor fraction was ≥ 1%.

Conclusions:

• Tissue-assessed TMB and MSI are valuable biomarkers for predicting ICI monotherapy benefit in mCRPC.
• Blood-based MSI testing offers a viable alternative for predicting ICI response when tissue is unavailable.
• These findings support expanded use of genomic biomarkers to guide ICI treatment selection in mCRPC.