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

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.

Duke Scholars

Author Tian Zhang Medicine, Medical Oncology