Daraxonrasib Demonstrates Consistent Survival Benefit Across Subgroups in Pretreated mPDAC

At the 2026 European Society for Medical Oncology (ESMO) Congress, subgroup analyses from the phase 3 RASolute 302 trial (NCT06625320) demonstrated that overall survival (OS) favored daraxonrasib (Rasonque) over chemotherapy across key patient subgroups, including in every RAS genotype subgroup, among patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC).¹

How did daraxonrasib perform across RAS genotype subgroups?

Among enrolled patients, RAS G12D was the most common alteration (43.2%), followed by G12V (35.6%), G12R (12.2%), Q61 (4.4%), and G13 (0.6%). No RAS mutation was identified in 3.2%. “This is one of the largest prospective studies done to collect RAS genotype information in real time in the enrollment of a clinical trial,” presenting study author Zev A. Wainberg, MD, MSc, said. “Most of the literature has been based on retrospective and real-world prevalence, and…[this study] mimics very carefully what was demonstrated in the older retrospective reviews.” Wainberg is a professor of medicine at the University of California, Los Angeles (UCLA), and co-director of the UCLA Gastrointestinal Oncology Program in Los Angeles, California.

Overall, the OS HR was 0.42 (95% CI, 0.32-0.55) in favor of daraxonrasib vs chemotherapy. By genotype, the OS HRs were 0.49 for G12D (95% CI, 0.33-0.74), 0.32 for G12V (95% CI, 0.19-0.54), 0.61 for G12R (95% CI, 0.29-1.30), 0.29 for other RAS mutations (95% CI, 0.08-1.06), and 0.43 for no RAS mutation identified (95% CI, 0.09-1.98). Objective response rate by BICR was 32% with daraxonrasib vs 11% with chemotherapy overall, including 50% vs 15% in the G12V subgroup and 24% vs 9% in the G12D subgroup.

Progression-free survival (PFS) by blinded independent central review (BICR) also favored daraxonrasib overall (HR, 0.55; 95% CI, 0.43-0.70). Across subgroups, the HR was 0.48 (95% CI, 0.33-0.69) in the G12D group, 0.54 (95% CI, 0.33-0.87) in the G12V subgroup, and 0.80 (95% CI, 0.41-1.56) in the G12R subgroup.

Did daraxonrasib’s benefit hold across chemotherapy regimens and prior treatment settings?

OS favored daraxonrasib against each preselected regimen: gemcitabine plus nab-paclitaxel (GnP; HR, 0.45; 95% CI, 0.32-0.65), leucovorin, fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX) or leucovorin, fluorouracil, and oxaliplatin (FOLFOX; HR, 0.46; 95% CI, 0.23-0.95), and liposomal irinotecan (NAL-IRI) with fluorouracil and leucovorin (HR, 0.32; 95% CI, 0.18-0.58). Wainberg said the Kaplan-Meier curves “separated early and stayed separated throughout the duration of the curves.”

In 76 patients diagnosed with metastatic disease within 6 months of neoadjuvant or adjuvant therapy, the OS HR was 0.36 (95% CI, 0.17-0.75), compared with 0.43 (95% CI, 0.32-0.58) among 424 patients who had received 1 prior line of therapy for metastatic disease.

What is the design and regulatory status of RASolute 302?

The trial randomly assigned 500 patients 1:1 to oral daraxonrasib at 300 mg once daily (n = 248) or investigator’s choice of chemotherapy (n = 252): GnP, mFOLFIRINOX, NAL-IRI with fluorouracil and leucovorin, or FOLFOX. Patients had received 1 prior fluoropyrimidine- or gemcitabine-based regimen in the metastatic setting and had documented tumor RAS status by local testing. The dual primary end points were OS and PFS per BICR in the RAS G12 population.

In the primary analysis, median OS was 13.2 vs 6.7 months in the overall population (HR, 0.40; 95% CI, 0.30-0.53).² The FDA approved daraxonrasib on August 26, 2026, for the treatment of patients with metastatic PDAC who have received at least 1 prior systemic therapy or who are not candidates for multiagent systemic therapy.³ The subgroup analyses used a Feb 10, 2026, data cutoff.

What did the investigators conclude?

The investigators concluded that OS improvement was observed across all RAS genotype subgroups, regardless of tumor RAS status, as expected from the drug’s mechanism of action. “These improvements across the board reinforce daraxonrasib as a new standard of care for all patients with previously treated metastatic pancreatic cancer,” Wainberg said.

Disclosures: Wainberg reported consultancy for Amgen, Arcus Bioscience, Astellas, AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, EMD Serono, Genentech, Gilead, Ipsen, Merck, Novartis, Revolution Medicines, Taiho, and Takeda; and reported participating in a data and safety monitoring board for AngioDynamics Inc., AstraZeneca, Daiichi Sankyo, and Pfizer.

References

1. Wainberg ZA, Wolpin BM, Hendifar AE, et al. Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): additional subgroup analyses from the phase 3 RASolute 302 study. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA82.
2. O'Reilly EM, Wainberg ZA, Hendifar AE, et al; RASolute 302 Trial Investigators. Daraxonrasib or chemotherapy in previously treated metastatic pancreatic cancer. N Engl J Med. 2026;395(4):325-337. doi:10.1056/NEJMoa2605555
3. FDA approves first in class targeted therapy for metastatic pancreatic cancer. News release. FDA. August 26, 2026. Accessed October 23, 2026. https://tinyurl.com/4dt6cwnv