What it is
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 this cancer, with oncogenic RAS mutations present in more than 90% of cases. Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active, GTP-bound state of both mutant and wild-type RAS. In RASolute 302, a phase 3, international, open-label, randomized trial, 500 patients with previously treated mPDAC, 91.8% of them with RAS G12 mutations, were randomly assigned to daraxonrasib (248 patients) or to chemotherapy of the investigator's choice (252 patients). The dual primary end points were overall survival and progression-free survival in patients with RAS G12 mutations. Median overall survival in that population was 13.2 months with daraxonrasib and 6.6 months with chemotherapy, and in the overall population, which also included patients with G13 or Q61 mutations or no RAS mutation identified, 13.2 and 6.7 months; the hazard ratio was 0.40 in both populations. Median progression-free survival was 7.3 versus 3.5 months in the RAS G12 population and 7.2 versus 3.6 months overall, with hazard ratios of 0.45 and 0.49. Adverse events after the start of treatment were reported in every patient given daraxonrasib and in 97.7% of those given chemotherapy, and events of grade 3 or higher in 61.8% and 69.6% respectively; treatment-related adverse events led to discontinuation in 1.2% and 11.2%. The authors conclude that daraxonrasib led to significantly longer overall and progression-free survival than chemotherapy in previously treated mPDAC. The trial was funded by Revolution Medicines.
Why it matters
In a phase 3 trial in previously treated metastatic pancreatic cancer, oral RAS inhibitor daraxonrasib gave median overall survival of 13.2 months versus 6.7 on chemotherapy. Current therapies offer limited benefit once this cancer has been treated, and oncogenic RAS mutations are present in more than 90% of cases. Daraxonrasib inhibits the active form of both mutant and normal RAS. Of the 500 patients, 91.8% had RAS G12 mutations; in that population, where the primary end points were measured, median overall survival was 13.2 versus 6.6 months and median progression-free survival 7.3 versus 3.5 months. Fewer patients stopped treatment because of treatment-related adverse events (1.2% versus 11.2%).
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Filed underPancreatic and Hepatic Oncology Research, Colorectal Cancer Treatments and Studies, Pancreatitis Pathology and Treatment
