Systemic treatment of advanced pancreatic cancer: A Comprehensive Review.
IMPORTANCE: Pancreatic adenocarcinoma (PDAC) is an uncommon but potentially catastrophic diagnosis with historically poor prognosis. It is the tenth most prevalent cancer in the US & UK. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide, with a five-year survival rate of approximately 10%. Despite increasing understanding of its molecular biology, systemic treatment options for advanced disease remain limited, and survival outcomes have improved only modestly over the past decade. OBSERVATIONS: This narrative review traces the evolution of systemic therapy for advanced PDAC from gemcitabine monotherapy through the landmark FOLFIRINOX (PRODIGE trial) and gemcitabine/nab-paclitaxel (MPACT trial) combination regimens, which remain the standard of care. Second-line options including liposomal irinotecan plus 5-FU/LV (NAPOLI-1) and maintenance olaparib for germline BRCA1/2-mutated disease (POLO) are also reviewed. Emerging data on sequential treatment strategies (SEQUENCE trial), biomarker-driven treatment selection (PRIMUS-001, PASS-01), and precision medicine approaches targeting actionable molecular subgroups, including dMMR/MSI-H, NTRK fusions, and homologous recombination deficiency are discussed. Real-world evidence comparing FOLFIRINOX and gemcitabine/nab-paclitaxel is critically appraised, including the challenges of patient selection, tolerance, and applicability outside clinical trial settings. CONCLUSION AND RELEVANCE: Despite incremental progress, the treatment landscape of advanced PDAC remains challenging. Molecular stratification and biomarker-driven precision oncology represent the most promising path forward. This review serves as a clinical reference for physicians managing advanced pancreatic cancer, highlighting current evidence, evidence limitations, and future research priorities including prospective biomarker-driven trials and improved access to genomic testing.