Additive clinical utility of tissue biomarkers of microsatellite instability (MSI) status and tumor mutational burden (TMB) to predict immune checkpoint inhibitor (ICI) effectiveness for real-world patients with metastatic castration-resistant prosta

5064 Background: FoundationOneCDx (F1CDx) supports two FDA-approved biomarkers to guide treatment decisions for ICI for patients with mCRPC: MSI status and TMB. MSI-H and TMB-H (10+ mut/MB) have strongly overlapping prevalence. We sought to better characterize ICI outcome associations of TMB-H / non-MSI-H population and relative effectiveness of taxanes & ICI among patients who received these agents in sequence. Methods: Following a prespecified analysis plan, this study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine mCRPC clinico-genomic database (FH-FMI CGDB), with data originating from ~280 US cancer clinics (~800 sites of care). Inclusion criteria included patients with mCRPC treated with single-agent anti-PD(L)1 therapy in the FH network between 1/1/2011 - 3/30/2024. This study used the MSI and TMB algorithms from the tissue based F1CDx. Time to next treatment (TTNT) and OS were assessed with Kaplan-Meier plots and in multivariable Cox models adjusted for ECOG performance score, socioeconomic status, prior treatment history, and baseline PSA. Among patients who received taxanes in a prior line of therapy, the effectiveness (TTNT1 vs. TTNT2) of taxane and ICI were compared. Results: Among 2995 prostate cancer tissue specimens in the database, 95 (3.1%) were MSI-H and 142 (4.7%) were TMB-H. 94 (3.1%) were MSI-H & TMB-H, 1 was MSI-H & TMB-L, and 48 (1.6%) were TMB-H & not MSI-H. Among these, 84 patients with mCRPC were treated with ICI and met inclusion criteria, including MSI-H & TMB-H (n = 30), non-MSI-H & TMB-H (n = 8), and non-MSI-H and TMB-L (n = 46). The respective median TTNT on ICI was 8.0 vs. 9.6 vs. 3 months. The respective median OS from initiation of ICI was 10.9 vs. not reached vs. 4.4 months. In multivariable models evaluating ICI only, compared to non-MSI-H & TMB-L, the MSI-H & TMB-H group had more favorable TTNT (HR: 0.20, 95%CI: 0.10 – 0.41, p < 0.001) and OS (HR: 0.33, 95%CI: 0.16 – 0.70, p = 0.004), and the non-MSI-H & TMB-H group also had more favorable TTNT (HR: 0.13, 95%CI: 0.04 – 0.45, p = 0.002) and OS (HR: 0.20, 95%CI: 0.05 – 0.75, p = 0.017). 50 of the 84 (60%) patients treated with ICI had prior mCRPC taxane treatment. Better TTNT2 on subsequent ICI vs. prior taxane was observed for MSI-H (HR: 0.49, 95%CI: 0.23 – 1.01, p = 0.051) and TMB-H (0.54, 95%CI: 0.30 – 0.98, p = 0.044), but the opposite was true for non-MSI-H and TMB-L subgroups, with significant treatment interactions for each (p = 0.0018, p = 0.00052). Conclusions: TMB-H (4.7%) is more prevalent than MSI-H (3.1%) by F1CDx in mCRPC. Non-MSI-H / TMB-H (1.6%) in the routine practice cohort have similar outcome associations on ICI to MSI-H. Both MSI-H and TMB-H by F1CDx are predictive of differential benefit for ICI vs. taxanes in later mCRPC treatment lines.