Revolution Medicines Begins Phase 3 RASolute 309 Trial of Daraxonrasib and Zoldonrasib

Revolution Medicines has begun treating patients in the global Phase 3 RASolute 309 trial, evaluating RASONQUE™ (daraxonrasib) in combination with zoldonrasib as a first-line treatment for adults with metastatic RAS G12D pancreatic ductal adenocarcinoma (PDAC). The randomized study is comparing the investigational RAS(ON) inhibitor doublet with gemcitabine plus nab-paclitaxel, a commonly used chemotherapy regimen for metastatic PDAC.

The study represents the company’s move to evaluate dual RAS(ON) inhibition in previously untreated metastatic disease. RAS G12D is the most prevalent RAS mutation subtype in PDAC, occurring in approximately 40% of patients, while metastatic pancreatic cancer remains associated with poor outcomes and limited treatment options.

RASolute 309 Evaluates a RAS(ON) Doublet

RASolute 309 (NCT07805954) is a global, randomized, open-label Phase 3 study evaluating whether combining daraxonrasib with zoldonrasib can improve outcomes compared with gemcitabine plus nab-paclitaxel.

The trial is enrolling adults with metastatic RAS G12D PDAC who have not previously received systemic therapy for metastatic disease. Its dual primary endpoints are progression-free survival (PFS) and overall survival (OS).

Secondary endpoints include objective response rate, duration of response, safety and tolerability, pharmacokinetics and patient-reported outcomes. The study is designed to provide a direct comparison between targeted RAS inhibition and chemotherapy in the first-line setting.

According to Revolution Medicines, RASolute 309 is the first Phase 3 study evaluating a RAS(ON) inhibitor doublet approach, making it an important clinical test of whether complementary RAS inhibition can translate into improved outcomes.

Combining multi-selective and G12D-Selective RAS Inhibition

Daraxonrasib is an oral, noncovalent RAS(ON) multi-selective tri-complex inhibitor designed to target the active state of multiple RAS proteins. RASONQUE is approved in the United States for certain adults with metastatic PDAC who have received at least one prior systemic therapy or who are not candidates for multiagent systemic therapy.

Zoldonrasib is an investigational oral, covalent RAS(ON) G12D-selective tri-complex inhibitor. It binds to cyclophilin A to form a complex capable of binding and inhibiting active oncogenic RAS G12D.

The combination is based on the rationale that inhibiting RAS signaling through complementary mechanisms could produce deeper and more sustained pathway suppression than either inhibitor alone. In preclinical studies, Revolution Medicines reported greater tumor control with the combination than with either treatment individually.

Phase 3 Development Builds on Earlier Clinical Data

The RASolute 309 program builds on earlier clinical evaluation of the two agents in metastatic PDAC. In a Phase 1/2 program involving previously treated patients with RAS G12D metastatic PDAC, the daraxonrasib and zoldonrasib combination demonstrated antitumor activity.

In the reported second-line cohort, the combination produced an objective response rate of 50% and a disease control rate of 97%. Among patients treated in the third-line or later setting, the objective response rate was 47% and the disease control rate was 90%. These findings provided clinical support for advancing the combination into a Phase 3 study, although the earlier data were generated in previously treated patients and cannot establish the efficacy of the regimen in first-line disease.

The company is also evaluating its RAS(ON) inhibitors individually and in combination with chemotherapy across additional pancreatic cancer treatment settings.

RAS-Driven Pancreatic Cancer Remains a Major Challenge

PDAC is the most common form of pancreatic cancer and is frequently diagnosed after the disease has already spread. Approximately 80% of patients are diagnosed with advanced disease, when curative treatment is generally no longer possible. In the United States, the five-year relative survival rate for metastatic pancreatic cancer remains approximately 3%.

RAS alterations are central drivers of PDAC biology, making RAS inhibition an important area of drug development. RAS G12D has historically been a difficult therapeutic target, creating a need for effective targeted approaches.

With treatment now underway in RASolute 309, Revolution Medicines is testing whether simultaneous inhibition of broader RAS signaling and the G12D subtype can improve first-line outcomes in metastatic PDAC. The Phase 3 study will determine whether the targeted doublet can provide clinically meaningful improvements in disease control and survival compared with chemotherapy.

Results from RASolute 309 will ultimately establish whether the complementary RAS(ON) inhibition strategy can translate the activity observed in earlier clinical development into a meaningful treatment benefit for patients with first-line metastatic RAS G12D PDAC.

Reference

Revolution Medicines Begins Treating Patients in Phase 3 RASolute 309 Trial Evaluating RASONQUE™ (daraxonrasib) Plus Zoldonrasib as First-Line Treatment for Metastatic RAS G12D Pancreatic Cancer, Revolution Medicine, 05 October 2026

Study of Zoldonrasib (RMC-9805) Plus Daraxonrasib (RMC-6236) Versus Gemcitabine and Nab-Paclitaxel as First-Line Treatment in Metastatic KRAS G12D-Mutated Pancreatic Adenocarcinoma (RASolute 309), ClinicalTrials.gov ID NCT07805954