VJToday

RASolute 302: daraxonrasib improves survival in RAS-mutant PDAC at ASCO 2026

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors, with most patients presenting with metastatic disease and a notoriously low 5-year survival rate.  More than 90% of PDAC tumors harbor activating RAS pathway alterations, most commonly KRAS mutations, making oncogenic RAS an attractive therapeutic target. However, direct targeting of RAS-driven cancers has historically proven challenging, creating a major unmet need for effective biomarker-directed therapies in metastatic PDAC. 1,2

The Phase III RASolute 302 trial (NCT06625320), presented at the 2026 American Society of Clinical Oncology (ASCO) Meeting, evaluated daraxonrasib, a RAS(ON) inhibitor, in patients with second-line metastatic PDAC. 500 patients were randomized 1:1 to receive daraxonrasib or investigator’s choice of standard chemotherapy. The dual primary endpoint was overall survival (OS) and progression-free survival (PFS) in patients with RAS G12 mutations, and secondary endpoints included OS and PFS in the general population, as well as objective response rate (ORR) and safety in all patients.3

The trial met the primary endpoints, where median OS was 13.2 months and 6.7 months in patients with RAS G12 mutations receiving daraxonrasib and chemotherapy respectively (HR 0.40, 95% CI: 0.30-0.54), marking a significant survival benefit. PFS was 7.3 versus 3.5 months respectively (HR 0.45, 95% CI: 0.34-0.59). The safety profile was manageable and consistent with previous studies, with gastrointestinal adverse events, fatigue, and rash among the most frequently reported toxicities. Treatment discontinuation rates remained relatively low despite the advanced disease setting.3

Yelena Janjigian, MD, Memorial Sloan Kettering Cancer Center, New York, NY, comments on the game-changing nature of the trial:

“I think all of the space now is reinvigorated and very hopeful because, of course, we are successfully targeting and overcame treatment barriers in pancreatic cancer, which is for RAS mutant tumors. And so we’re interested in looking for RAS targeting across tumor types, including gastric, of course, colorectal cancer, where it’s very promising.”

The results of RASolute 302 represent a landmark achievement in pancreatic cancer, validating oncogenic RAS as a therapeutic target and establishing a new treatment paradigm for patients with RAS-mutated metastatic PDAC in the second-line setting. As one of the first biomarker-driven therapies to demonstrate an overall survival advantage in this disease, daraxonrasib has the potential to become a new standard of care and may pave the way for future RAS-targeted combination strategies in pancreatic cancer.

References:

  1. Nagaraju GP, Nellipudi H, Ganji C, Kuppala V, Ganji SP, Kumari S, Farran B, Srilatha M, Guenter R, El-Rayes BF. Pancreatic ductal adenocarcinoma: Integrating molecular insights for targeted interventions. Signal Transduction and Targeted Therapy, 2026; 11(1). https://doi.org/10.1038/s41392-026-02705-5
  2. Alanazi FE, Alatawi Y, Alattar A, Alshaman R, Kotb AA, Hetta HF. Broad-spectrum ras inhibition in pancreatic ductal adenocarcinoma: Mechanistic advances and therapeutic promise. Pharmaceuticals. 2025 Nov 24;18(12):1788. doi:10.3390/ph18121788
  3. Wolpin BM, Wainberg ZA, Hendifar A, 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):Abstr LBA5.