Phase 3 Trial of Daraxonrasib Plus Zoldonrasib Begins in RAS G12D PDAC

Patients have begun receiving treatment in the phase 3 RASolute 309 trial (NCT07805954) evaluating daraxonrasib (Rasonque) plus zoldonrasib as a first-line treatment for adults with metastatic RAS G12D pancreatic adenocarcinoma (PDAC).¹

RASolute 309 is a global, randomized, open-label trial comparing daraxonrasib, a RAS(ON) multi-selective inhibitor, plus zoldonrasib, an investigational RAS(ON) G12D-selective inhibitor, against gemcitabine and nab-paclitaxel (GnP) in adult patients with metastatic RAS G12D PDAC.

“RAS G12D is the most common RAS variant in PDAC,” Alan Sandler, MD, chief development officer of Revolution Medicines, stated in a news release. “In preclinical studies, the combination of RAS(ON) multi-selective and G12D-selective inhibitors achieved deeper and more sustained suppression of RAS signaling than either agent alone, accompanied by greater tumor control. Likewise, initial clinical data showed that [daraxonrasib] plus zoldonrasib delivered compelling antitumor activity in patients with previously treated metastatic PDAC, with a manageable safety and tolerability profile.”

Background on Daraxonrasib and Zoldonrasib

Daraxonrasib is an oral, RAS(ON) multi-selective, noncovalent, tri-complex inhibitor that received accelerated FDA approval for adult patients with metastatic PDAC who have received at least 1 prior systemic therapy or who are not candidates for multiagent systemic therapy based on the phase 3 RASolute 302 trial (NCT06625320). The agent is being investigated through a global phase 3 registrational program spanning PDAC and metastatic RAS-mutant non–small cell lung cancer (NSCLC), and received breakthrough designation for treatment-naive PDAC based on findings from the phase 1/2 RMC-GI-102 trial (NCT06445062).

Zoldonrasib is an investigational, oral, RAS(ON) G12D-selective, covalent tri-complex inhibitor that binds cyclophilin A, forming a binary complex that binds to and inhibits the active, oncogenic RAS(ON) G12D mutation, according to the news release. RAS G12D is the most prevalent RAS mutation overall, accounting for 29% of all RAS-driven cancers, with an estimated 61,000 new patients with RAS G12D cancers diagnosed annually in the US across tumor types; no targeted therapy is currently approved for this broader population.^1,2 Zoldonrasib is being evaluated as monotherapy and in combination with daraxonrasib and standard-of-care regimens in lung and gastrointestinal cancers.

Supporting Evidence for the Combination and Phase 3 Trial Design

In its approved PDAC indication, serious adverse events occurred in 30% of patients treated with daraxonrasib, with those occurring in at least 2% of patients including diarrhea (3.7%), pyrexia (3.3%), sepsis (2.9%), fatigue (2.1%), and hemorrhage (2.1%). The most common adverse events were rash, diarrhea, stomatitis, nausea, fatigue, vomiting, abdominal pain, edema, decreased appetite, and hemorrhage.³

In phase 1/2 data from the RMC-9805-001 trial (NCT06040541) in 60 patients with second-line or third-line and beyond RAS G12D-mutated PDAC, zoldonrasib plus daraxonrasib demonstrated a manageable safety profile consistent with that of single-agent daraxonrasib; grade 3 or higher treatment-related adverse events were reported in 35%. The overall response rate (ORR) was 50% and the disease control rate (DCR) was 97% in the second-line cohort; ORR and DCR were 47% and 90%, respectively, in the third-line and beyond cohort.⁴ The median progression-free survival (PFS) was 9.6 months in the second line and 7.6 months in the third line and beyond; the median overall survival (OS) was not estimable in the second-line cohort and 10.5 months in the third-line and beyond cohort.

The phase 3 trial will randomly assign an estimated 400 patients with documented RAS G12D mutations who had no previous treatment in the locally advanced unresectable or metastatic settings to receive zoldonrasib plus daraxonrasib or GnP.⁵ It has dual primary end points of PFS and OS, with key secondary end points including PFS, ORR, duration of response, safety and tolerability, pharmacokinetics, and patient-reported outcomes.

“RASolute 309 is the first phase 3 study evaluating a RAS(ON) inhibitor doublet approach and it marks an important milestone in our efforts to advance a range of potential treatment options for patients with RAS-driven cancers across tumor types and treatment settings,” Sandler stated in the news release.¹

REFERENCES

1. 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. News release. Revolution Medicines, Inc. October 5, 2026. Accessed October 5, 2026. https://tinyurl.com/43rsyhhf

2. Lee JK, Sivakumar S, Schrock AB, et al. Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors. NPJ Precis Oncol. 2022;6(1):91. Published 2022 Dec 9. doi:10.1038/s41698-022-00334-z

3. Wolpin BM, Wainberg ZA, Hendifar AE, et al. Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): primary and final analysis from the phase 3 RASolute 302 study. J Clin Oncol. 2026;44(suppl 17):LBA5. doi:10.1200/JCO.2026.44.17_suppl.LBA5

4. Revolution Medicines presents phase 1/2 clinical data for zoldonrasib combination regimens in patients with RAS G12D metastatic pancreatic cancer at ESMO Gastrointestinal Cancers Congress 2026. News release. Revolution Medicines. July 2, 2026. Accessed October 5, 2026. https://tinyurl.com/23jkz3dk

5. A study of daraxonrasib plus zoldonrasib versus gemcitabine and nab-paclitaxel in metastatic RAS G12D pancreatic adenocarcinoma (RASolute 309). ClinicalTrials.gov. Updated September 8, 2026. Accessed October 5, 2026. https://clinicaltrials.gov/study/NCT07805954