Emerging precision therapeutics for pancreatic ductal adenocarcinoma: KRAS and beyond

Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related death with a rising incidence in younger individuals and no standard early detection exam. Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated gene of the RAS family, and KRAS mutations are found in approximately 85%-90% of PDAC. Long considered undruggable due to its molecular structure, the advent of sotorasib and adagrasib has ushered in multiple novel therapeutics targeting the RAS pathway, including mutation-selective, pan-KRAS, and pan-RAS inhibitors. Combination strategies using chemotherapy and directed against EGFR, SOS1, SHP2, and immune pathways, among others, aim to overcome resistance to RAS inhibitor monotherapy and enhance the depth and duration of clinical benefit. The minority of PDAC tumors that are KRAS-wildtype are enriched for rare, actionable alterations, including Neuregulin-1, HER2, and BRAF amenable to targeted treatments. For patients with metastatic disease carrying a germline BRCA1/2 or PALB2 pathogenic variant, PARP inhibitors remain an option as maintenance treatment after achieving at least stable disease with platinum-based chemotherapy. Importantly, ongoing and future clinical trials are shifting the use of targeted therapies from the refractory setting to earlier lines and the perioperative setting with promising results. Here, we detail the different areas of investigation targeting KRAS and other precision-based therapies in PDAC, as well as the potential emerging roles of local interventions (radiation, surgery) for select patients with oligometastatic disease. Composite predictive biomarkers using genomic, proteomic, and radiographic factors are needed to refine and individualize treatment selection and ultimately improve patient outcomes.