Systemic Therapy for Advanced Pancreatic Cancer in 2025: Current Standard-of-Care and Emerging Therapeutic Strategies.

Advanced pancreatic cancer remains a leading cause of cancer death in developed countries and has seen limited progress in systemic therapy over the past decade. This review highlights recent first-line standard of care treatment options and explores biomarker-driven strategies, particularly homologous recombination deficiency for personalized treatment selection. We emphasize how the adoption of tumor next-generation sequencing is shaping precision therapy, including tumor-agnostic targets such as NRG1 fusions and BRAF alterations in KRAS wild-type tumors. Advances in KRAS inhibitors, PROTACs, tumor treating fields, and PRMT5 inhibitors for MTAP-deleted tumors are rapidly expanding potential treatment options for patients. Emerging immunotherapies targeting Claudin18.2 and CXCR4 offer hope to overcome tumor resistance. Together, these strategies underscore the promise of molecular stratification, synthetic lethality, and novel targets to improve pancreatic cancer survival.