Daraxonrasib: The first-in-class RAS(ON) multi-selective inhibitor approved for treatment of metastatic pancreatic adenocarcinoma.

Abstract

Advanced pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with limited benefits from conventional chemotherapy. Daraxonrasib is an oral, noncovalent RAS(ON) multi-selective inhibitor that forms a ternary complex with cyclophilin A and GTP-bound RAS, blocking downstream signaling across multiple mutant and wild-type RAS proteins. On August 26, 2026, the US Food and Drug Administration approved daraxonrasib for adults with metastatic pancreatic adenocarcinoma previously treated with systemic therapy or ineligible for multiagent systemic therapy, without a mutation-specific restriction. In the randomized phase III RASolute 302 trial involving 500 previously treated patients with a good performance status, daraxonrasib improved median overall survival from 6.7 to 13.2 months (hazard ratio, 0.40) and progression-free survival from 3.6 to 7.2 months in the overall randomized population. Grade 3 or higher treatment-related adverse events were less frequent with daraxonrasib than chemotherapy (43.6% versus 57.5%), although one treatment-related death from pneumonitis occurred. Common toxicities included rash, diarrhea, and stomatitis. Limited follow-up and small non-G12 subgroups warrant caution regarding the generalizability of that trial's results. Acquired resistance, frequently involving RAS pathway reactivation, remains an important challenge. Ongoing studies are evaluating earlier treatment settings and combination strategies, while long-term safety and outcomes in patients with a poorer performance status require further investigation.