Actionable mutations in pancreatic cancer: where targeted therapies are making a difference

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumours, with 5-year survival consistently below 10% and only modest gains from conventional chemotherapy after first-line failure. Although oncogenic KRAS mutations dominate the genomic landscape, recent large-scale sequencing has revealed a series of less frequent but therapeutically actionable alterations. This review synthesises evidence from phase I-II trials published through April 2025. It demonstrates that targeting these lesions can yield outcomes that meet or exceed the benchmarks set by the NAPOLI-1 trial (liposomal irinotecan plus 5-fluorouracil and leucovorin), with a median overall survival of 6.2 months and progression-free survival of 3.1 months. Objective response rates reach 33% with adagrasib in KRAS G12C PDAC, 22% with olaparib maintenance in germline BRCA1/2 cancers, and over 50% with RET or NTRK inhibitors with fusion alterations; pembrolizumab produces durable benefit in the 1-3% of tumours that are MSI-H/dMMR. Emerging data highlight NRG1 fusions (overall response rate 42% with zenocutuzumab), HER2 amplification, MTAP deletion with PRMT5 dependency and variant-specific (MRTX1133) or pan-RAS (daraxonrasib) inhibitors as the next frontier. Toxicity profiles of targeted agents are generally favourable and often allow prolonged administration compared with cytotoxic regimens. Taken together, these advances represent a substantive therapeutic progress in PDAC over the past decades, even though they currently apply to a minority of patients. These findings underscore the necessity of comprehensive next-generation sequencing for every patient with advanced disease, enabling identification of rare, yet clinically meaningful, targets and moving PDAC management towards a precision-oncology paradigm.