Background. Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a 5-year overall survival below 12%. Oncogenic KRAS mutations are the dominant driver event, present in over 90% of cases. For decades KRAS was considered undruggable. The recent clinical validation of RAS(ON) inhibitors has fundamentally altered the therapeutic landscape. Methods. Narrative review of published clinical data, phase I-III trial results, and genomic landscape studies through June 2026, with a focus on RAS inhibitor development and the relationship between KRAS and BRCA alterations. Results. RAS(ON) multi-selective inhibition with daraxonrasib (RMC-6236) has demonstrated a doubling of overall survival in previously treated metastatic PDAC (OS 13.2 vs 6.7 months; HR 0.40; p<0.0001) in the phase 3 RASolute 302 trial, representing the most significant advance in second-line PDAC treatment in over a decade. G12D-selective inhibition (zoldonrasib, MRTX1133) and KRAS degradation (setidegrasib) are emerging as complementary strategies. BRCA1/2 alterations are largely enriched in the KRAS wild-type PDAC subset (~10% of all PDAC), creating a clinically relevant molecular dichotomy: KRAS-mutant tumors are the target of RAS inhibitors, while KRAS wild-type tumors require extended NGS profiling to identify BRCA, BRAF fusions, FGFR2, and other actionable targets. Conclusions. The integration of RAS inhibitor strategies and biomarker-driven patient selection — based on KRAS mutational status, allele subtype, and co-occurring alterations including BRCA/HRD — is redefining the precision oncology framework for PDAC. Routine comprehensive NGS profiling is now a clinical imperative.
Mauro Iannopollo (Wed,) studied this question.