Standing ovation at ASCO 2026: Daraxonrasib Shines in Pancreatic Cancer Breakthrough
USA: A phase 3 international clinical trial has found that daraxonrasib, a novel oral RAS-targeting therapy, significantly improved survival outcomes compared with standard chemotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC). The findings, published in The New England Journal of Medicine, offer encouraging evidence for a disease that has historically had limited treatment options and a poor prognosis after initial therapy failure.
The study was led by Eileen M. O’Reilly and colleagues. Pancreatic ductal adenocarcinoma is largely driven by abnormalities in the RAS signaling pathway, with more than 90% of tumors harboring oncogenic RAS mutations. Daraxonrasib is designed to inhibit the active form of both mutant and wild-type RAS proteins, thereby disrupting a key mechanism that promotes tumor growth and progression.
Researchers conducted an international, open-label, randomized phase 3 trial involving patients with metastatic pancreatic cancer whose disease had progressed despite prior treatment. Participants were assigned to receive either daraxonrasib or the investigator’s choice of chemotherapy. The study primarily evaluated overall survival and progression-free survival among patients carrying RAS G12 mutations, the most common RAS alteration in pancreatic cancer. Secondary analyses examined outcomes in the broader study population, which included patients with other RAS mutations or no detectable RAS mutation.
A total of 500 patients were enrolled in the trial, with approximately 92% carrying RAS G12 mutations. Of these, 248 patients received daraxonrasib and 252 received chemotherapy.
The following were the key findings:
- Median overall survival in patients with RAS G12 mutations was 13.2 months with daraxonrasib versus 6.6 months with chemotherapy.
- Median overall survival in the overall population was 13.2 months with daraxonrasib and 6.7 months with chemotherapy.
- Median progression-free survival in the RAS G12 subgroup was 7.3 months with daraxonrasib compared with 3.5 months with chemotherapy.
- Median progression-free survival in the overall population was 7.2 months versus 3.6 months, respectively.
- Adverse events were reported in 100% of patients receiving daraxonrasib and 97.7% receiving chemotherapy.
- Grade 3 or higher adverse events occurred in 61.8% of the daraxonrasib group and 69.6% of the chemotherapy group.
- Treatment discontinuation due to treatment-related adverse events occurred in 1.2% of patients on daraxonrasib compared with 11.2% on chemotherapy.
- Daraxonrasib significantly improved survival outcomes and showed a lower rate of severe adverse events than chemotherapy.
Based on these findings, the investigators concluded that daraxonrasib provides a significant survival benefit over chemotherapy in previously treated metastatic pancreatic cancer. The results suggest that targeting the RAS pathway with a multiselective inhibitor may represent a promising new therapeutic strategy for patients with this aggressive malignancy.
Reference:
DOI: 10.1056/NEJMoa2605555
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