Revolution Medicines has begun enrolling patients in RASolute 303 (NCT07491445), a Phase III trial testing daraxonrasib (RMC-6236) as a first-line treatment for metastatic pancreatic ductal adenocarcinoma. The announcement marks the drug's entry into the treatment-naive setting, a departure from the later-line contexts in which RAS-targeted agents have previously been evaluated. The trial is enrolling patients with metastatic PDAC harboring any RAS mutation, reflecting daraxonrasib’s multi-selective RAS(ON) profile rather than a mutation-specific approach.
RASolute 303 is a global, randomized, open-label study with three arms: daraxonrasib monotherapy, daraxonrasib combined with gemcitabine and nab-paclitaxel, and gemcitabine plus nab-paclitaxel alone as the comparator. Primary endpoints are progression-free survival and overall survival, with secondary endpoints covering antitumor activity, safety, and patient-reported outcomes. The trial is the third of three Phase III registrational studies Revolution Medicines is running in PDAC, with a fourth evaluating daraxonrasib in non-small cell lung cancer.
Research context
The rationale for targeting RAS in PDAC is grounded in the genetics of the disease. More than 90% of PDAC tumors carry oncogenic RAS mutations, making it the most RAS-driven of all common cancers. Daraxonrasib operates by blocking the interaction between active, GTP-bound RAS — the so-called RAS(ON) state — and its downstream effectors, suppressing signaling through the MAPK pathway and related cascades. This mechanism differs from the first generation of approved KRAS inhibitors, which lock the protein in its inactive GDP-bound conformation and are restricted to the G12C variant. Because daraxonrasib acts on the active state and covers multiple oncogenic variants simultaneously, it can in principle be deployed across the full spectrum of RAS-mutant PDAC rather than the minority of patients carrying any single substitution.
The decision to enroll patients irrespective of RAS genotype in RASolute 303 follows directly from this pharmacology. In a disease where genotype-agnostic eligibility captures nearly the entire patient population, this design avoids the enrollment bottlenecks that have historically slowed mutation-stratified PDAC trials and allows the drug to be tested against the broadest possible clinical need.
First-line treatment for metastatic PDAC has for years rested on two cytotoxic backbones: FOLFIRINOX and gemcitabine plus nab-paclitaxel. In February 2024, the FDA approved NALIRIFOX — irinotecan liposome combined with oxaliplatin, fluorouracil, and leucovorin — based on the NAPOLI-3 trial, providing a third chemotherapy option for the first-line setting. Beyond chemotherapy, approved targeted agents exist only for rare molecular subsets: olaparib for BRCA1/2-mutated disease, pembrolizumab for the roughly 1–2% of patients with MSI-H tumors, and zenocutuzumab-zbco for NRG1 fusion-positive PDAC following its accelerated approval in December 2024. None of these address the dominant RAS-mutant population.