Phase 3 zoldonrasib (RMC-9805) KRAS G12D RAS(ON) inhibitor + daraxonrasib (RMC-6236) RAS(ON) multi-selective inhibitor

Revolution Medicines’ RASolute 309 is a Phase 3, randomized, open-label study testing whether dual RAS(ON) blockade improves outcomes versus standard chemotherapy in first-line metastatic pancreatic adenocarcinoma with a KRAS G12D mutation. Patients are randomized to zoldonrasib, a KRAS G12D-selective RAS(ON) inhibitor designed to bind active GTP-bound KRAS G12D, plus daraxonrasib, a RAS(ON) multi-selective inhibitor, versus gemcitabine + nab-paclitaxel. The primary goal is to improve progression-free and/or overall survival compared with chemotherapy. The key angle is moving daraxonrasib—now FDA-approved for previously treated metastatic pancreatic adenocarcinoma and for certain patients unable to receive multiagent systemic therapy—into the first-line setting and pairing it with the investigational G12D-selective zoldonrasib. KRAS mutations occur in the great majority of pancreatic adenocarcinomas, with G12D the most common allele, making this a large biomarker-defined subgroup. Current first-line treatment remains systemic chemotherapy, commonly modified FOLFIRINOX or gemcitabine + nab-paclitaxel, so this is a registrational test of whether precision RAS therapy can replace chemotherapy up front for eligible patients.