Revolution Medicines starts Phase 3 RAS G12D PDAC doublet trial
Revolution Medicines has begun treating patients in RASolute 309, a global, randomised Phase 3 trial evaluating the combination of its approved RAS(ON) multi-selective inhibitor RASONQUE (daraxonrasib) and the investigational agent zoldonrasib as a first-line treatment for metastatic RAS G12D pancreatic adenocarcinoma (PDAC). The Redwood City-based company described the initiation as the first Phase 3 study to evaluate a RAS(ON) inhibitor doublet approach in any tumour type.
The trial compares the oral doublet regimen against gemcitabine plus nab-paclitaxel, the most widely used first-line chemotherapy backbone in metastatic PDAC. Dual primary endpoints are progression-free survival and overall survival, with secondary endpoints including objective response rate, duration of response, pharmacokinetics and patient-reported outcomes.
Why this mutation, why now
RAS G12D is the predominant RAS variant in PDAC, present in approximately 40% of patients, and accounts for roughly 29% of all RAS-driven cancers across tumour types. Despite the mutation's prevalence, no targeted therapy has been approved for RAS G12D across any indication. The company estimates that around 61,000 patients are diagnosed with RAS G12D cancers in the United States each year.
Alan Sandler, chief development officer at Revolution Medicines, said preclinical work showed the doublet "achieved deeper and more sustained suppression of RAS signalling than either agent alone, accompanied by greater tumour control." Early clinical data in previously treated metastatic PDAC also supported what the company characterised as compelling antitumour activity with a manageable tolerability profile, providing the biological rationale for advancing the combination into the first-line setting.
RASONQUE itself received FDA approval in August 2026 for adult patients with metastatic PDAC who have received at least one prior systemic therapy or who are not candidates for multiagent treatment. RASolute 309 therefore represents a move to expand the label into earlier lines of therapy, a strategy familiar in oncology drug development where second-line approvals frequently serve as the bridgehead for first-line studies.
Competitive and regulatory context
Pancreatic adenocarcinoma remains one of the most intractable solid tumours, with a five-year relative survival rate of around 3% for metastatic disease and approximately 50,000 deaths in the United States annually. The poor prognosis reflects both late diagnosis, with roughly 80% of patients presenting after the disease has spread, and the limited efficacy of existing therapies.
The RAS inhibitor field has accelerated sharply since the approval of sotorasib and adagrasib for KRAS G12C non-small cell lung cancer opened the door to direct RAS targeting. G12D has proved a harder problem mechanistically, and Revolution Medicines' cyclophilin A-dependent tri-complex approach for zoldonrasib represents a differentiated strategy relative to competing programmes in academic centres and smaller biotechs. Investors and oncologists will be watching readout timelines closely: a Phase 3 overall survival result in first-line PDAC, if positive, would represent a meaningful shift in standard of care and a substantial commercial opportunity in a disease area with few approved targeted options. The company has not disclosed an expected primary completion date for RASolute 309.