DNA damage response inhibitors in pancreatic cancer: progress and challenges

Pancreatic cancer is one of the most lethal malignancies, with very limited treatment options beyond standard chemotherapy. The discovery of homologous recombination repair (HRR) deficiencies-such as BRCA1/2 and PALB2 mutations-has revealed a targetable vulnerability through the DNA damage response (DDR) pathway. This review systematically summarizes the application and current clinical landscape of DDR-targeted therapies in pancreatic cancer. We first discuss how DDR inhibitors have successfully translated from research into clinical practice as a targeted treatment option for pancreatic cancer patients. However, single-agent DDR inhibitors face major limitations, including a narrow beneficiary population, primary and acquired resistance, and dose-limiting toxicities. The central theme of this review is the paradigm shift from monotherapy to rational combination strategies. We therefore focus on emerging combination approaches, such as the PAD/PAD_tal triple regimen, dual-target inhibitors, sequential scheduling, combinations with immunotherapy, combinations with KRAS inhibitors, and novel targets (PRMT5, PARG, HuR). These strategies aim to overcome resistance, extend benefits beyond BRCA-mutant patients, and remodel the tumor immune microenvironment. Finally, we summarize current challenges-including limited accessibility, resistance mechanisms, and toxicities-and outline future directions, such as novel biomarkers, liquid biopsy for real-time resistance monitoring, and innovative adaptive trial designs. This review highlights the evolution of DDR-targeted therapy in pancreatic cancer toward personalized, combination-based precision medicine.