Daraxonrasib (RMC-6236) demonstrated statistically significant and clinically meaningful improvements in overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and patient-reported quality of life (QOL) compared with investigator's choice of chemotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC) regardless of RAS mutation status, according to primary and final results from the phase 3 RASolute 302 trial (NCT06625320).1 These data were presented at the 2026 ASCO Annual Meeting.
In the dual primary analysis population of patients with RAS G12 mutations, daraxonrasib (n = 228) reduced the risk of death by 60% vs chemotherapy (n = 231; HR, 0.40; 95% CI, 0.30-0.54; P = 5.9 × 10⁻¹⁰). At a median follow-up of 8.5 months (range, 3.2-15.9), the median OS was 13.2 months (95% CI, 10.0-not estimable [NE]) compared with 6.6 months (95% CI, 5.4-8.2), respectively. The 12-month OS rate was 53.3% with daraxonrasib vs 18.7% with chemotherapy. The median PFS was 7.3 months (95% CI, 6.3-8.1) with daraxonrasib (n = 228) vs 3.5 months (95% CI, 2.9-3.8) with chemotherapy (HR, 0.45; 95% CI, 0.34-0.59; P = 3.2 × 10⁻⁹). The 6-month PFS rates were 58.7% and 31.7%, respectively. The respective ORRs were 33.2% with daraxonrasib (n = 217) vs 11.8% with chemotherapy (n = 221; P < .0001).
These results were consistent across the overall population, which included patients with less common RAS mutations and those with no identified RAS mutations. Daraxonrasib (n = 248) produced a median OS of 13.2 months (95% CI, 10.0-NE) vs 6.7 months (95% CI, 5.8-8.0) with chemotherapy (n = 252; HR, 0.40; 95% CI, 0.30-0.53; P = 4.6 × 10⁻¹¹). The median PFS was 7.2 months (95% CI, 5.7-7.5) vs 3.6 months (95% CI, 2.9-4.2), respectively (HR, 0.49; 95% CI, 0.38-0.64; P = 5.2×10⁻⁸). The respective 6-month PFS rates were 56.0% vs 32.9%. The ORR was 31.6% with daraxonrasib (n = 237) vs 11.2% with chemotherapy (n = 241; P < .0001).
“Daraxonrasib met all primary and key secondary end points…in previously treated metastatic pancreatic cancer. These results support daraxonrasib as a new SOC [in this setting].” - Brian M. Wolpin, MD, MPH, stated in his presentation of the data.
Wolpin serves as director of the Gastrointestinal Cancer Center and Hale Family Center for Pancreatic Cancer Research and is the Robert T. and Judith B. Hale Chair in Pancreatic Cancer. He is also a physician at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School in Boston, Massachusetts.
What data have previously read out for daraxonrasib in pretreated PDAC?
Findings from the phase 1/2 RMC-6236-001 trial (NCT05379985), which were recently published in the New England Journal of Medicine, showed antitumor activity and a manageable safety profile with daraxonrasib monotherapy across RAS mutation status and multiple dose levels in previously treated PDAC.2 These data served as a proof-of-concept for RASolute 302.1,2
The ORR was 35% (95% CI, 17%-56%), the median duration of response (DOR) was 8.2 months (95% CI, 3.8-NE), and the median PFS and OS were 8.5 months (95% CI, 6.7-10.5) and 13.1 months (95% CI, 10.9-NE), respectively.2 Moreover, among patients with any RAS mutation (G12, G13, or Q61) treated with 300 mg in the second line (n = 38), the ORR was 29% (95% CI, 15%-46%), the disease control rate (DCR) was 95% (95% CI, 82%-99%), the median PFS was 8.1 months (95% CI, 5.9-10.1), and the median OS was 15.6 months (95% CI, 10.9-NE).
The Path to Potential Approval: Key Regulatory Milestones for Daraxonrasib in PDAC
- On April 13, 2026, the developer of daraxonrasib, Revolution Medicines, announced its intent to submit a new drug application for daraxonrasib under the FDA's Commissioner's National Priority Voucher pilot program—a designation the agent had received from the FDA in October 2025.
- The FDA also issued a "safe to proceed" letter on May 1, 2026, permitting the initiation of an expanded access treatment protocol for daraxonrasib in previously treated metastatic PDAC with RAS mutations.
- The agent holds FDA breakthrough therapy and orphan drug designations for patients with previously treated metastatic PDAC harboring KRAS G12 mutations.
How was RASolute 302 designed?
This global, randomized, open-label, phase 3 trial enrolled adult patients with mPDAC who had received 1 prior fluoropyrimidine- or gemcitabine-based regimen in the metastatic setting, had an ECOG performance status (PS) of 0 or 1, and had documented tumor RAS mutational status by local testing.1 Importantly, all patients were eligible for enrollment regardless of whether their tumors harbored a RAS mutation. The trial was conducted across 59 sites in 6 countries.
Eligible patients were randomly assigned 1:1 to receive either 300 mg of daraxonrasib orally once daily or investigator's choice of the following standard chemotherapy regimens: gemcitabine plus nab-paclitaxel, modified FOLFIRINOX, nanoliposomal irinotecan plus 5-fluorouracil (5-FU) and leucovorin, or FOLFOX.
The dual primary end points were OS and PFS by blinded independent central review per RECIST 1.1 criteria in the RAS G12–mutant population, which represents the predominant mutation type in PDAC. Secondary end points included OS and PFS in the overall population, ORR by BICR in both the RAS G12–mutant and overall populations, and time to deterioration (TTD) in patient-reported outcomes (PROs). The data cutoff was February 10, 2026.
What should be known about daraxonrasib’s safety profile?
In the safety population, the median time on treatment was 6.2 months (range, 0.03-14.1) with daraxonrasib (n = 241) vs 1.5 to 3.2 months (range, 0.03-2.9) across the 4 chemotherapy regimens (n = 214). The median dose intensity was 93.1% with daraxonrasib and 65.3% to 95.0% across chemotherapy regimens.
Any-grade treatment-emergent adverse effects (TEAEs) occurred in all patients receiving daraxonrasib and 97.7% receiving chemotherapy. Any-grade treatment-related AEs (TRAEs) were reported in 97.9% and 93.5% of patients, respectively. Key distinctions in tolerability between arms were as follows:
- TRAEs leading to dose reduction: 36.1% with daraxonrasib vs 57.5% with chemotherapy
- TRAEs leading to dose interruption: 56.0% vs 55.1%
- TRAEs leading to treatment discontinuation: 1.2% vs 11.2%
- Grade ≥3 TRAEs: 43.6% vs 57.5%
- Serious TRAEs: 10.8% vs 18.7%
- Grade 5 TRAEs: 0.4% with daraxonrasib (1 patient died from treatment-related pneumonitis) vs 0% with chemotherapy
The most common TRAEs leading to dose reduction with daraxonrasib were rash (17.4%) and stomatitis (6.6%). With chemotherapy, the most common causes of dose reduction were neutropenia (16.8%), thrombocytopenia (13.6%), fatigue (12.6%), diarrhea (10.3%), and peripheral neuropathy (7.9%). Notably, 3 patients discontinued daraxonrasib due to TRAEs, including 2 with grade 3 maculo-papular rash and 1 with grade 3 ALT and grade 4 AST elevation.
"While there have been questions around the safety profile of daraxonrasib and targeting RAS specifically, the other important takeaway is that [its] safety profile is relatively predictable and did not lead to a significant amount of discontinuation," said Rachna T. Shroff, MD, MS, chief of the Division of Hematology/Oncology at the University of Arizona Cancer Center in Tucson, who provided expert commentary during the press briefing. "We see that in how patients stayed on this treatment because it was providing durable and meaningful benefit to them."
What did the PRO analysis show?
PROs were assessed using the EORTC QLQ-PAN26 and EORTC QLQ-C30 questionnaires, administered on day 1 of each treatment cycle and at the end-of-treatment visit in the overall population. Daraxonrasib significantly delayed time to deterioration in both measured domains compared with chemotherapy.
- Pain (EORTC QLQ-PAN26): median time to deterioration (TTD) of 9.2 months with daraxonrasib vs 3.8 months with chemotherapy (HR, 0.51; 95% CI, 0.37-0.71; P < .0001)
- Global health status/quality of life (EORTC QLQ-C30): median TTD of 5.7 months with daraxonrasib vs 2.6 months with chemotherapy (HR, 0.60; 95% CI, 0.46-0.79; P = .0002).
What is the broader significance of these results?
In her commentary, Shroff framed the magnitude of the benefit in terms rarely applied to pancreatic cancer outcomes. "To me, this study is a proof of principle that targeting the RAS signaling pathway is critical in the treatment of pancreatic cancer," she said. "It literally checks all of the boxes when we think about relevant, important, and meaningful clinical outcomes. We have honestly never seen [outcomes like this] in previously treated pancreatic cancer, with a doubling of survival and a reduced risk of death by 60% in patients who have already progressed on chemotherapy."
Wolpin also highlighted the broad applicability of the findings during his presentation, noting that, "we saw very similar results…in patients that have less common RAS mutations than G12 and also those that did not have an identified RAS mutation," he said.
The benefit also extended beyond survival, Shroff noted. "A tripling of ORR in terms of shrinking of tumor can then subsequently lead to improved clinical benefit with things like pain, improvement in pain and QOL, which is incredibly meaningful to these patients," she concluded.
Beyond RASolute 302, daraxonrasib is being evaluated in RASolute 303 (NCT07491445), a global, 3-arm, randomized, open-label study evaluating daraxonrasib with or without chemotherapy vs chemotherapy alone as first-line treatment in metastatic PDAC.⁵
References
- 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):LBA4005. doi:10.1200/JCO.2026.44.17_suppl.LBA4005.
- Wolpin B, Park W, Garrido-Laguna I, et al. Daraxonrasib in previously treated advanced RAS-mutated pancreatic cancer. N Engl J Med. 2026;394(18):1790-1802. doi:10.1056/NEJMoa2505783
- Revolution Medicines announces daraxonrasib demonstrates unprecedented overall survival benefit in pivotal phase 3 RASolute 302 clinical trial in patients with metastatic pancreatic cancer. News release. Revolution Medicines. April 13, 2026. Accessed May 30, 2026. https://ir.revmed.com/news-releases/news-release-details/daraxonrasib-demonstrates-unprecedented-overall-survival-benefit
- FDA permits expanded access for investigational pancreatic cancer drug. FDA. May 1, 2026. Accessed May 30, 2026. https://www.fda.gov/news-events/press-announcements/fda-permits-expanded-access-investigational-pancreatic-cancer-drug
- Study of daraxonrasib and daraxonrasib + GnP as first-line treatment in patients with metastatic pancreatic adenocarcinoma (RASolute 303). ClinicalTrials.gov. Updated April 4, 2026. Accessed May 30, 2026. https://clinicaltrials.gov/study/NCT07491445
