Associations of DNA damage repair (DDR) pathway class and allelic configuration with survival in metastatic renal cell carcinoma.

455 Background: Alterations in DNA damage repair (DDR) pathways occur in a subset of metastatic renal cell carcinoma (mRCC) and may influence therapeutic response and outcomes. While DDR mutations are increasingly detected on tumor genomic profiling, the combined effect of DDR pathway class and allelic configuration on survival in mRCC remains poorly characterized. Methods: We retrospectively identified 17 patients with pathogenic DDR mutations treated for mRCC between 2016–2025 at a comprehensive cancer center. DDR genes were categorized by pathway: homologous recombination repair (HRR: BRCA2, FANCA, RAD51C ), mismatch repair (MMR: MLH1, MSH6 ), base excision repair (BER: MUTYH ), and non-homologous end joining (NHEJ: ATM, RAD50 ). Allelic configuration (mono- vs. biallelic) was determined from review of aggregate genomic data. Overall survival (OS) was measured from first systemic therapy to death or last follow-up. Kaplan–Meier estimates and log-rank tests compared OS across DDR classes and allelic groups. Results: Median age was 70 years (IQR 63–78); 88% male. Histology included clear cell (76%) with sarcomatoid features present in 18% of these, and non-clear cell (24%). By IMDC criteria, 35% were poor-risk and 65% intermediate-risk. Common DDR alteration were BRCA2 (18%), ATM (12%), RAD50 (12%), and MUTYH (12%); 29% had biallelic loss. Median OS for the cohort was 19.1 months (range 4.7–74.9). Patients with HRR alterations (n = 4) had significantly longer OS than those with non-HRR DDR mutations (n = 13) (χ²(1) = 6.86, p = 0.0088). OS differed across pathway classes (χ²(3) = 8.30, p = 0.04). Monoallelic cases trended toward longer OS (31.7 vs. 11.9 months; p = 0.13). HRR-mutated tumors had only one observed death versus nine in non-HRR, indicating a favorable prognosis. Conclusions: In this single-institution cohort, DDR pathway class and allelic configuration were associated with survival in mRCC. HRR mutations conferred markedly improved OS, whereas biallelic DDR loss was linked to poorer outcomes. These findings highlight the potential prognostic and therapeutic relevance of DDR biology in mRCC and support integration of DDR pathway and allelic status into biomarker-driven trial design.