Association of <i>MUTYH</i> mutations with clinical outcomes in metastatic prostate cancer.

Abstract

83 Background: Identification of novel biomarkers that can better predict treatment outcome and prognosis in metastatic hormone sensitive prostate cancer (mHSPC) is needed. An independent study of 34 mHSPC patients treated at the University of Miami from 11/1/21 to 12/31/24 who underwent tumor sequencing via liquid biopsy revealed a significant association between mutant MUTYH and both shorter overall survival (OS) and time to castration resistance (TTCR). MUTYH is a DNA repair gene involved in base-excision repair of oxidative DNA damage. Based on the results of this discovery cohort, we hypothesized that mHSPC patients with mutant MUTYH will have shorter OS and TTCR compared to patients with wild-type MUTYH . Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine prostate cancer clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (~800 sites of care). Patients with advanced prostate cancer treated with ARPI (Androgen Receptor Pathway Inhibitor) or taxanes chemotherapy in the mHSPC setting and genomic profiling, by tissue or liquid NGS testing (minimum 1% ctDNA tumor fraction), were included. Differences among genomically-defined patient groups were evaluated with Cox PH models and visualized with Kaplan-Meier plots. Results: Of 6101 patients with mHSPC with longitudinal clinical data and NGS testing in the database, 4285 were excluded for not having treatment with either ARPI or taxane chemotherapy in the mHSPC setting and 414 for having tumor fraction &lt; 1%. In the remaining 1402 patients included, 851 were treated with single-agent ARPI and 551 were treated with taxane chemotherapy without ARPI. Results of the univariate and multivariate Cox PH models are shown in the table. The multivariate models controlled for pre-treatment prognostic features including PSA, ECOG performance status, and socioeconomic status. Conclusions: The association between MUTYH mutation status and TTCR and OS in mHSPC observed in the University of Miami cohort was not validated in FH-FMI CGDB cohort in either the ARPI group or the taxane group. Additionally, no significant association was uncovered when accounting for potential confounding variables. Further investigation is ongoing to identify genomic signatures of prognostic value in mHSPC. Hazard Ratio (95% CI) p-value TTCR on ARPI 1.39 (0.72, 2.7) 0.331 TTCR on taxanes 1.46 (0.65, 3.27) 0.36 OS on ARPI 1.1 (0.49, 2.48) 0.814 OS on taxanes 1.56 (0.7, 3.52) 0.279 TTCR on ARPI (multivariate analysis) 1.55 (0.79, 3.04) 0.207 OS on ARPI (multivariate analysis) 1.32 (0.58, 2.98) 0.506