Treating Pancreatic Ductal Adenocarcinoma: The Targeted Revolution is Here

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is a rising cause of morbidity and mortality. An immunosuppressive, hostile tumor microenvironment, and KRAS -driven biology have contributed to poor outcomes in PDAC. Recent breakthroughs in targeting tumors with homologous repair deficiency, KRAS G12C mutations, rare gene fusions, and other molecular abnormalities have improved outcomes in subsets of patients. KRAS inhibitors, both allele specific and pan(K)RAS, claudin-targeting biologics, and PRMT5 inhibitors have demonstrated single agent activity in pretreated, biomarker selected PDAC. An improved understanding of the tumor immune microenvironment has facilitated the development of promising cancer vaccines and immunomodulating agents. This review summarizes the current state of PDAC therapeutics and describes drug development targets that will transform outcomes in PDAC in the proximate future.