Abstract 2448: Somatic DDR mutations as potential predictive biomarkers of platinum benefit in metastatic pancreatic cancer

Abstract Background: Next-generation sequencing (NGS) has faciliated widespread identification of genetic alterations in pancreatic ductal adenocarcinoma (PDAC). Germline DNA damage repair (DDR) mutations, including BRCA1/2, PALB2, and ATM, predict sensitivity to first-line platinum-based chemotherapy (CTX). However, the predictive role of somatic DDR mutations remains undefined. Methods: We retrospectively identified patients with metastatic PDAC (mPDAC) harboring a somatic DDR mutation (sDDR) who were treated at the Dan L Duncan Comprehensive Cancer Center (Houston, TX) between January 2018 and June 2025. Patients with germline DDR mutations or MSI-high tumors and those who 2 cycles of CTX were excluded. Best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) were assessed. OS was defined as the interval between CTX initiation and death, hospice enrollment, or last follow-up. Outcomes for sDDR patients receiving first-line platinum vs non-platinum CTX within our cohort were compared using Fisher’s exact test. Outcomes for sDDR patients receiving first-line platinum CTX were compared with unselected PRODIGE controls using a one-sample binomial test (ORR) and a one-sample χ2 test under exponential survival assumptions (PFS, OS). Results: Eighteen patients met inclusion criteria; 14 (77.8%) had de novo mPDAC and 4 (22.2%) had recurrences post-resection. sDDR mutations included ATM (11, 61.1%), BRCA2 (5, 27.8%), BRCA1 (1, 5.6%), and PALB2 (1, 5.6%). Twelve patients received first-line FOLFIRINOX (5-fluorouracil, irinotecan, and oxaliplatin): 4 (33.3%) had partial response, 4 (33.3%) had stable disease, and 4 (33.3%) had progressive disease, yielding an overall response rate (ORR) of 33.3% and disease control rate (DCR) of 66.6%. The remaining 6 patients received non-platinum CTX (n=6): 5 (83.3%) had stable disease and 1 (16.7%) had progressive disease, yielding an ORR of 0% and DCR of 83.3%. Median PFS was 13 months in the platinum group versus 16 months in the non-platinum group (p=0.5), and median OS was 27 vs 31 months (p=0.6). Compared to the unselected population who received FOLFIRINOX in PRODIGE, sDDR patients who received platinum CTX in our cohort demonstrated a comparable ORR (33.3% vs 31.6%, p=1.0), but longer PFS (13 vs 6.4 months, χ2 =70.6, p 0.001) and OS (27 vs 11.1 months, χ2 =87.5, p 0.001). Conclusion: In this exploratory single-institution cohort, PFS and OS were longer in sDDR-mutated mPDAC patients treated with FOLFIRINOX compared to unselected patients treated with FOLFIRINOX in PRODIGE. Within our small sDDR cohort, outcomes were not statistically superior with platinum versus non-platinum CTX. These hypothesis-generating findings are limited by small sample size, retrospective design, and selection bias toward patients completing ≥2 CTX cycles. Larger studies are needed to clarify whether sDDR mutations predict mPDAC outcomes. Citation Format: Ethan L. Low, Aakash Shah, Eunji Jo, Aliya Lackan, Susan Hilsenbeck, Benjamin L. Musher. Somatic DDR mutations as potential predictive biomarkers of platinum benefit in metastatic pancreatic cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2448.