LAUSR

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.