In the Phase 3 randomized RASolute 302 trial of previously treated metastatic pancreatic ductal adenocarcinoma (PDAC), the oral RAS(ON) inhibitor daraxonrasib demonstrated a significant overall survival (OS) benefit compared with standard-of-care (SOC) chemotherapy, nearly doubling median OS (13.2 months vs. 6.7 months). The treatment also improved progression-free survival (PFS) with a favorable and manageable safety profile, with no new safety signals identified. These results support daraxonrasib as a potential new SOC option and validate direct inhibition of active RAS as a clinically meaningful therapeutic strategy in RAS-driven cancers.

Daraxonrasib (RMC-6236)

  • Name: Daraxonrasib (RMC-6236)
  • Manufacturer: Revolution Medicines
  • Drug Class: Targeted, multi-selective, non-covalent small-molecule inhibitor
  • Method of Administration: Oral
  • Mechanism of Action: First-in-class RAS(ON) inhibitor targeting the active (GTP-bound) RAS protein:
    • Multi-selective across RAS isoforms and mutations (including KRAS variants common in PDAC)
    • Uses a tri-complex mechanism
      • Binds cyclophilin A → engages active RAS → blocks downstream signaling
Figure 1: A cyclophilin A–mediated tri-complex engaging KRAS(ON).

RASolute 302 Study Design (NCT06625320)

  • Study design: Ongoing, Phase 3, randomized, controlled, multicenter, open-label clinical trial
  • Study Objective: Evaluate efficacy and safety of daraxonrasib vs. standard-of-care (SOC) chemotherapy
  • Hypothesis: Daraxonrasib improves PFS and OS compared with SOC in previously treated metastatic PDAC
  • Participants: 501 patients with PDAC previously treated with 1 prior line of therapy
    • Daraxonrasib Arm (Arm A): 250 patients
      • 300 mg orally, once daily
    • SOC chemotherapy Arm (Arm B): 251 patients
      • Gemcitabine ± nab-paclitaxel, FOLFIRINOX / modified FOLFIRINOX, Liposomal irinotecan + 5-FU/leucovorin, or FOLFOX (based on prior first-line therapy)

Enrolled patients harbored a range of RAS variants, including RAS G12 mutations (e.g., G12D, G12V, and G12R), and patients lacking an identified tumor RAS mutation (wild type).

Primary Outcomes

  • OS and PFS:
    • Median OS: 13.2 months with daraxonrasib vs. 6.7 months with SOC chemotherapy (Hazard Ratio: 0.40, p < 0.0001)
    • PFS: Statistically significant improvement with daraxonrasib vs. SOC chemotherapy, consistent with OS findings (exact median values not specified)

Daraxonrasib was generally well tolerated, with a manageable safety profile and no new safety signals. These results confirm a disease-control advantage in addition to a survival benefit.

Clinical Implications

  • ✔ Practice-changing overall survival benefit in metastatic PDAC: Daraxonrasib nearly doubled median overall survival versus standard chemotherapy (13.2 vs 6.7 months), establishing a magnitude of benefit that strongly supports potential replacement of current second-line SOC chemotherapy in this setting.
  • ✔ First validated, broadly active RAS(ON)-targeted therapy in pancreatic cancer: The drug’s activity across a wide spectrum of RAS variants (and even tumors without identifiable mutations) signals a clinically meaningful advance in overcoming the historically “undruggable” RAS biology that drives >90% of PDAC cases.
  • ✔ Potential new standard of care in previously treated metastatic PDAC: Given the large survival delta and manageable toxicity profile, daraxonrasib is positioned to displace cytotoxic chemotherapy in the post-first-line setting, where therapeutic options have historically been limited and minimally impactful.
  • ✔ Class validation for RAS(ON) inhibition strategy across solid tumors: The clinical success provides proof-of-concept that direct, multi-selective RAS inhibition can translate into meaningful survival gains, potentially expanding development across other RAS-driven malignancies such as NSCLC and colorectal cancer.

    • Sources:

    1. “Daraxonrasib Demonstrates Unprecedented Overall Survival Benefit in Pivotal Phase 3 RASolute 302 Clinical Trial in Patients with Metastatic Pancreatic Cancer | Revolution Medicines.” Revolution Medicines, 2026, ir.revmed.com/news-releases/news-release-details/daraxonrasib-demonstrates-unprecedented-overall-survival-benefit. Accessed 13 Apr. 2026.
    2. “Revolution Medicines.” Revolution Medicines, 14 May 2025, www.revmed.com/science/. Accessed 13 Apr. 2026.