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Ref Type Journal Article
PMID (42223072)
Authors O'Reilly EM, Wainberg ZA, Hendifar AE, Borad MJ, Pietrantonio F, Pant S, Hammel P, Cremolini C, Manji GA, Oberstein PE, Garrido-Laguna I, Springfeld C, Azad NS, Ueno M, Chui SY, Zhang Y, Patel H, Lee Y, Salman Z, Wolpin BM, RASolute 302 Trial Investigators
Title Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer.
Journal Vol Issue Date Pages Journal Short Title
The New England journal of medicine 2026 May 31 N Engl J Med
URL
Abstract Text Current therapies offer limited benefit for patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC). Aberrant activation of the RAS pathway is the key driver of PDAC, with oncogenic RAS mutations present in more than 90% of cases. Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS.In this phase 3, international, open-label, randomized trial, we randomly assigned patients with previously treated mPDAC to receive daraxonrasib or chemotherapy of the investigator's choice. The dual primary end points were overall survival and progression-free survival in the subpopulation of patients with RAS G12 mutations (the RAS G12 population). Key secondary end points included overall survival and progression-free survival in the overall population (which included patients with RAS G12, G13, or Q61 mutations or with no RAS mutation identified) and objective response and patient-reported quality of life in the RAS G12 and overall populations. Safety was also assessed.A total of 500 patients, including 91.8% with RAS G12 mutations, were randomly assigned to receive daraxonrasib (248 patients) or chemotherapy (252 patients). The median overall survival in the RAS G12 population was 13.2 months with daraxonrasib and 6.6 months with chemotherapy, and the median overall survival in the overall population was 13.2 months and 6.7 months, respectively; the hazard ratio was 0.40 in both populations (P<0.001). The median progression-free survival in the RAS G12 population was 7.3 months with daraxonrasib and 3.5 months with chemotherapy, and that in the overall population was 7.2 months and 3.6 months, respectively; the hazard ratios were 0.45 and 0.49, respectively (P<0.001 for both comparisons). Adverse events that occurred after the start of treatment were reported in all the patients in the daraxonrasib group and in 97.7% of those in the chemotherapy group; the incidence of adverse events of grade 3 or higher was 61.8% and 69.6%, respectively. Treatment-related adverse events that led to treatment discontinuation occurred in 1.2% of the patients in the daraxonrasib group and in 11.2% of those in the chemotherapy group.Among patients with previously treated mPDAC, treatment with daraxonrasib led to significantly longer overall survival and progression-free survival than chemotherapy. (Funded by Revolution Medicines; RASolute 302 ClinicalTrials.gov number, NCT06625320.).

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
HRAS G12X pancreatic ductal adenocarcinoma sensitive Daraxonrasib Phase III Actionable In a Phase III trial (RASolute 302), treatment with Daraxonrasib (RMB-6236) in patients with metastatic pancreatic ductal adenocarcinoma significantly improved median overall survival (mOS, 13.2 vs 6.6 months, HR=0.40, p<0.001) and median progression-free survival (mPFS, 7.3 vs 3.5 months, HR=0.45, p<0.001) compared to chemotherapy in patients harboring RAS G12X, and mOS (13.2 vs 6.7 months, HR=0.40, p<0.001) and mPFS (7.2 vs 3.6 months, HR=0.49, p<0.001) in the overall cohort (PMID: 42223072; NCT06625320). 42223072
NRAS G12X pancreatic ductal adenocarcinoma sensitive Daraxonrasib Phase III Actionable In a Phase III trial (RASolute 302), treatment with Daraxonrasib (RMB-6236) in patients with metastatic pancreatic ductal adenocarcinoma significantly improved median overall survival (mOS, 13.2 vs 6.6 months, HR=0.40, p<0.001) and median progression-free survival (mPFS, 7.3 vs 3.5 months, HR=0.45, p<0.001) compared to chemotherapy in patients harboring RAS G12X, and mOS (13.2 vs 6.7 months, HR=0.40, p<0.001) and mPFS (7.2 vs 3.6 months, HR=0.49, p<0.001) in the overall cohort (PMID: 42223072; NCT06625320). 42223072