Phase 3 zoldonrasib (RMC-9805) KRAS G12D-selective RAS(ON) inhibitor plus chemo in 1L metastatic PDAC.

This registrational, randomized, double-blind, placebo-controlled Phase 3 study (RASolute 305) tests whether adding zoldonrasib (RMC-9805)—Revolution Medicines’ oral KRAS G12D-selective “RAS(ON)” inhibitor that targets the active, GTP-bound KRAS state—improves outcomes versus placebo when combined with investigator’s choice chemotherapy in first-line metastatic pancreatic adenocarcinoma with a KRAS G12D mutation. Patients receive either modified FOLFIRINOX (oxaliplatin DNA crosslinker + irinotecan topoisomerase I inhibitor + 5-FU thymidylate synthase inhibitor + leucovorin) or gemcitabine + nab-paclitaxel (DNA synthesis inhibition + microtubule inhibition) with zoldonrasib or matched placebo. The scientific/commercial angle is a direct, mutation-selective KRAS G12D backbone moving into front-line PDAC—an attempt to outperform today’s care, which is multi-agent chemo (mFOLFIRINOX or gemcitabine/nab-paclitaxel) with subsequent lines often limited by rapid resistance and cumulative toxicity rather than targeted options for most patients.