Revolution Medicines Begins Phase 3 Trial for Daraxonrasib in First-Line Pancreatic Cancer

Revolution Medicines has begun treating patients in a global Phase 3 clinical trial evaluating its investigational drug daraxonrasib as a first-line treatment for metastatic pancreatic cancer. The RASolute 303 trial will test daraxonrasib as monotherapy and in combination with chemotherapy versus standard-of-care chemotherapy in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC), enrolling patients irrespective of tumor RAS genotype.

The company expects top-line data from its separate Phase III RASolute 302 trial in second-line PDAC in the first half of 2026. That trial is designed as an overall survival event-driven program, with the readout triggered by a prespecified number of deaths based on company modeling. While the trial has dual primary endpoints of progression-free survival and overall survival, the FDA has made it clear publicly that it is seeking overall survival as the primary driver.

RASolute 303 is a global, randomized, open-label Phase 3 trial evaluating daraxonrasib as monotherapy or in combination with gemcitabine and nab-paclitaxel versus standard-of-care gemcitabine and nab-paclitaxel in patients with previously untreated metastatic PDAC. The primary endpoints are progression-free survival and overall survival, with key secondary endpoints including additional measures of antitumor activity, safety and tolerability, and patient reported outcomes.

The company's CEO described three potential outcomes at the interim analysis for RASolute 302: failing to meet statistical significance on both endpoints, succeeding on both, or achieving statistical significance on progression-free survival but not yet on overall survival. In the latter case, the trial would remain an interim analysis rather than a final analysis.

For the chemotherapy control arm in second-line PDAC, the CEO pointed to multiple historic Phase III trials showing fairly consistent outcomes in previously treated pancreatic cancer, citing progression-free survival of roughly three to four months and overall survival in the six to seven month range. He said he sees no reason to expect a sudden change in that backdrop by 2026.

The company has implemented a nested trial design in which the core analysis focuses on patients with G12 mutations, which represent about 85% of pancreatic cancer and constitute the subset with the most supporting data. Patients with other mutations (G13, Q61) or no detectable mutation are included in a broader population analyzed as secondary.

Pancreatic cancer is one of the most lethal malignancies, characterized by its typically late-stage diagnosis, resistance to standard chemotherapy, and high mortality rate. In the U.S., recent estimates indicate that approximately 60,000 people are diagnosed annually with pancreatic cancer, and about 50,000 people will die from this aggressive disease. Due to the lack of early symptoms and detection methods, approximately 80% of patients are diagnosed with PDAC at an advanced or metastatic stage.

Daraxonrasib is an oral, direct RAS(ON) multi-selective inhibitor with the potential to help address a broad range of cancers driven by oncogenic RAS, including PDAC, non-small cell lung cancer and colorectal cancer. The drug suppresses RAS signaling by blocking the interaction of wild-type and mutant RAS(ON) with its downstream effectors. Daraxonrasib is currently being evaluated in four global Phase 3 registrational trials, including three trials in patients with PDAC and one in patients with non-small cell lung cancer.