A new study shows that tumor-intrinsic DNA repair gene alterations modulate response to combination chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC). Investigators analyzed treatment outcomes across cohorts stratified by homologous recombination and other DNA-repair pathway defects, finding differential sensitivity patterns that could guide regimen selection. The results point to DNA-repair profiling as a potential predictive biomarker to personalize cytotoxic strategies in PDAC. Sponsors and clinical investigators should consider incorporating targeted sequencing panels into trial designs and exploring synthetic-lethality combinations where DNA-repair deficiencies exist.