Emerging Role of Targeted Therapy in Metastatic Pancreatic Adenocarcinoma

SIMPLE SUMMARY: Metastatic pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that has limited treatment options. Standard of care treatment involves systemic chemotherapy, although all tumors invariably develop resistance to these cytotoxic therapies. With the advent of genomic sequencing and identification of therapeutically actionable alterations, there are subsets of patients with PDAC who may benefit from targeted therapies matched to their molecular profile. As more molecularly matched therapies are developed, precision medicine has great potential in patients with PDAC. ABSTRACT: The aggressive biology of pancreatic ductal adenocarcinoma (PDAC), along with its limited sensitivity to many systemic therapies, presents a major challenge in the management of patients with metastatic PDAC. Over the past decade, the incorporation of combinatorial cytotoxic chemotherapy regimens has improved patient outcomes. Despite these advances, resistance to cytotoxic chemotherapy inevitably occurs, and there is a great need for effective therapies. A major focus of research has been to identify molecularly defined subpopulations of patients with PDAC who may benefit from targeted therapies that are matched to their molecular profile. Recent successes include the demonstration of the efficacy of maintenance PARP inhibition in PDAC tumors harboring deleterious BRCA1, BRCA2, and PALB2 alterations. In addition, while therapeutic targeting of KRAS was long thought to be infeasible, emerging data on the efficacy of KRAS G12C inhibitors have increased optimism about next-generation KRAS-directed therapies in PDAC. Meanwhile, KRAS wild-type PDAC encompasses a unique molecular subpopulation of PDAC that is enriched for targetable genetic alterations, such as oncogenic BRAF alterations, mismatch repair deficiency, and FGFR2, ALK, NTRK, ROS1, NRG1, and RET rearrangements. As more molecularly targeted therapies are developed, precision medicine has the potential to revolutionize the treatment of patients with metastatic PDAC.