Additive Clinical Utility of Microsatellite Instability and Tumor Mutational Burden to Predict Immune Checkpoint Inhibitor Effectiveness in Metastatic Castration-Resistant Prostate Cancer

Abstract Background: Immune checkpoint inhibitors (ICIs) have shown limited efficacy in unselected patients with metastatic castration-resistant prostate cancer (mCRPC). However, ICIs are approved for biomarker-defined subsets: microsatellite instability-high (MSI-H) and/or high tumor mutational burden (TMB-H). However, the efficacy of ICIs in TMB-H but not MSI-H disease remains unclear, and limited data exists evaluating ICI outcomes associated with blood-based MSI (bMSI) in mCRPC. Methods: This study used the US-based deidentified Flatiron Health-Foundation Medicine prostate cancer Clinico-Genomic Database (FH-FMI CGDB). Patients with tissue-assessed MSI (tMSI) and TMB (tTMB) status by an algorithm supporting an FDA-approved CDx for pembrolizumab were included if treated with single-agent ICI. Separately, outcomes on ICI associated with or bMSI were assessed. included if treated with single-agent ICI or taxane. Results: Among 2,965 patients with mCRPC, tMSI-H (3.2%) was nearly always also tTMB≥10 mut/Mb (4.7%). In 84 ICI-treated patients, TTNT and OS were more favorable in tMSI-H with any TMB (TTNT HR: 0.18, 95%CI: 0.09–0.37 and OS HR: 0.32, 95%CI: 0.15–0.66) and tTMB≥10 without tMSI-H (TTNT HR: 0.18, 95%CI: 0.04–0.48 and OS HR: 0.20, 95%CI: 0.05–0.77) compared to tTMB < 10 without tMSI-H group. In intra-patient assessments, patients with tTMB≥10 had more favorable TTNT with subsequent ICI vs. prior taxane. Detection of bMSI-H was associated with more favorable TTNT on ICI (HR: 0.34, 95%CI: 0.14–0.83) and OS (HR: 0.21, 95%CI: 0.06–0.75) when tumor fraction ≥1%. Conclusion: These findings add support for tTMB and tMSI in predicting ICI monotherapy benefit in mCRPC and provide evidence supporting bMSI testing when tissue is unavailable.