Adults with metastatic pancreatic adenocarcinoma who have undergone at least one prior systemic therapy or are unsuitable for multiagent systemic therapy are now eligible for daraxonrasib, an oral multi-selective RAS(ON) inhibitor, following its approval by the U.S. Food and Drug Administration, based on results from the phase 3 RASolute 302 trial, which was led by Brian Wolpin, MD, MPH, of Dana-Farber Cancer Institute.
Clinical Trial Results Show Significant Survival Benefit
The RASolute 302 study enrolled 500 patients across North America, Europe, and Asia, all previously treated with one line of chemotherapy for metastatic disease. Patients were randomized to receive either daraxonrasib or second-line chemotherapy. Those treated with daraxonrasib showed a 60% reduction in the risk of death, with a hazard ratio of 0.40. Median overall survival reached 13.2 months with the drug compared to 6.7 months with chemotherapy.
Objective response rates were notably higher with daraxonrasib at 31.6% versus 11.2% for chemotherapy. Among patients with RAS G12 mutations, 33.2% of those receiving daraxonrasib experienced substantial tumor shrinkage or disappearance, compared to 11.8% on chemotherapy. Progression-free survival also improved, with a median of 7.2 months versus 3.6 months for the chemotherapy group.
A First for RAS-Targeted Therapy in Pancreatic Cancer
Daraxonrasib represents the first approved targeted therapy specifically designed to inhibit RAS, a major cancer-driving pathway in pancreatic cancer. The drug functions as a molecular glue that binds cyclophilin A to block RAS signaling. Over 90% of pancreatic cancer patients harbor KRAS oncogene mutations.
Wolpin noted the historical challenge of targeting RAS, stating that successfully blocking RAS signaling had long been considered a potential transformation for pancreatic cancer treatment. The FDA approval, he said, marks a landmark advance, with the nearly doubling of median survival time representing meaningful progress for patients with limited treatment options.
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Safety Profile and Broader Cancer Treatment Context
No new safety signals emerged with daraxonrasib compared to earlier phase 1/2 trials, also led by Wolpin. Common side effects included rash, mouth inflammation, nausea, and diarrhea. The drug’s safety profile aligned with prior studies published in the New England Journal of Medicine.
Pancreatic ductal adenocarcinoma remains one of the deadliest cancers, with approximately 65,000 U.S. diagnoses annually and over 50,000 deaths. About 80% of cases are diagnosed at advanced stages, when the five-year relative survival rate hovers around 3%. The approval of daraxonrasib highlights the potential of sustained scientific investment in developing treatments for this challenging disease.
Benjamin L. Ebert, MD, PhD, CEO of Dana-Farber, called the approval a milestone for patients and a sign of the power of sustained research. He emphasized the institute’s role in preclinical and clinical work that enabled this advance and reaffirmed commitment to future therapies. The RASolute 302 trial investigators were identified as O’Reilly et al., with results published in the New England Journal of Medicine.
Wolpin described the approval as an unprecedented moment, signaling the start of a new era in pancreatic cancer treatment. He expressed optimism that further research by the Hale Family Center for Pancreatic Cancer Research and the broader field could lead to durable responses and more cures. The drug’s mechanism—targeting the RAS pathway, which drives most pancreatic cancers—opens avenues for future combinations and next-generation therapies.
