The investigational multiselective RAS(ON) inhibitor daraxonrasib may represent a new standard second-line treatment option for patients with metastatic pancreatic ductal adenocarcinoma, according to results from the phase III RASolute 302 trial. In the study, presented by Brian Wolpin, MD, MPH, of Dana-Farber Cancer Institute, at the 2026 ASCO Annual Meeting, daraxonrasib nearly doubled both overall survival and progression-free survival compared with standard chemotherapy while producing fewer serious adverse events (Abstract LBA5).
Background and Study Details
Pancreatic cancer remains one of the deadliest malignancies, with more than half of cases diagnosed after metastasis has occurred and a 5-year relative survival rate of approximately 3% for metastatic disease. Current second-line chemotherapy regimens provide only modest benefit, with a median progression-free survival of 3 to 4 months and a median overall survival of 6 to 7 months.
Daraxonrasib is a novel multiselective RAS(ON) inhibitor designed to target activated KRAS signaling across multiple RAS variants. Unlike earlier KRAS inhibitors that are specific to individual mutations, daraxonrasib can inhibit KRAS activity regardless of the specific variant present, and it demonstrated activity in both RAS-mutant and RAS–wild-type tumors.
The international trial enrolled 500 patients with previously treated metastatic pancreatic ductal adenocarcinoma from North America, Europe, and Asia. Participants had an ECOG performance status of 0 or 1 and were randomly assigned to receive either daraxonrasib (n = 248) or chemotherapy (n = 252). Most patients in both groups had tumors harboring a RAS G12 mutation.
Key Takeaways
At a median follow-up of 8.5 months, median overall survival reached 13.2 months among patients treated with daraxonrasib, compared with 6.6 months among those with RAS G12–mutant disease receiving chemotherapy and 6.7 months in the overall chemotherapy population. Median progression-free survival was 7.3 months in patients with RAS G12 variants and 7.2 months overall in the daraxonrasib arm, compared with 3.5 and 3.6 months, respectively, in the chemotherapy arm.
Objective response rates also favored daraxonrasib. Among patients with RAS G12–mutant tumors, the objective response rate was 33.2% with daraxonrasib vs 11.8% with chemotherapy. Across the overall study population, response rates were 31.6% and 11.2%, respectively.
The investigational agent also demonstrated a favorable safety profile. Grade 3 or higher adverse events occurred in 43.6% of patients receiving daraxonrasib compared with 57.5% of those receiving chemotherapy. Treatment discontinuation due to adverse events was substantially less common with daraxonrasib (1.2% vs 11.2%).
“These results are landscape-changing for metastatic pancreatic cancer patients with a KRAS mutation,” said Rachna Shroff, MD, MS, FASCO, Chief of the Division of Hematology/Oncology at the University of Arizona Cancer Center and an ASCO Expert in gastrointestinal cancers. “We are seeing unprecedented survival and efficacy in second-line treatment with an expected safety profile. The RAS revolution is here, and this study is proof of principle that targeting KRAS in pancreatic cancer is feasible and effective.”
DISCLOSURE: For full disclosures of the study authors, visit coi.asco.org.
