N Engl J Med
ASCO 2026: Breakthrough RAS therapy may redefine second-line care in metastatic pancreatic cancer
Clinical Takeaway: In previously treated metastatic pancreatic cancer, once-daily oral daraxonrasib significantly improved overall survival, progression-free survival, response rates, and patient-reported outcomes versus standard chemotherapy, with fewer treatment discontinuations due to adverse events.
Metastatic pancreatic cancer has long lacked effective second-line options, with median survival typically measured in months. These results suggest a targeted oral RAS(ON) inhibitor could become a new standard of care for a broad population of patients.
In the international phase 3 RASolute 302 trial, investigators randomized 500 patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC) to receive daraxonrasib, an oral multiselective RAS(ON) inhibitor, or investigator’s-choice chemotherapy. More than 90% of enrolled patients had RAS G12-mutated tumors.
Daraxonrasib reduced the risk of death by 60% compared with chemotherapy (HR, 0.40; P<0.001), extending median overall survival to 13.2 months versus 6.7 months. Progression-free survival was also nearly doubled at 7.2 months versus 3.6 months (HR, 0.49; P<0.001). Benefits were consistent in the primary RAS G12 population and were generally observed regardless of RAS mutation status.
Objective response rates were substantially higher with daraxonrasib than with chemotherapy in the overall study population (31.6% vs. 11.2%), while among patients with RAS G12 mutations, response rates reached 33.2% versus 11.8%, respectively. Daraxonrasib also delayed deterioration in pain and quality of life compared with chemotherapy.
Safety findings were consistent with earlier studies. Grade 3 or higher adverse events occurred in 61.8% of patients receiving daraxonrasib versus 69.6% receiving chemotherapy, and treatment discontinuation due to treatment-related adverse events was markedly lower (1.2% vs. 11.2%). Common adverse effects included rash, diarrhea, stomatitis, nausea, and vomiting.
“This is the first RAS inhibitor evaluated in a large, randomized trial for patients with pancreatic cancer, and it demonstrates how important an impact these novel medicines are likely to have on the treatment of the disease,” said lead investigator Brian Wolpin, MD, MPH, of Dana-Farber Cancer Institute. “It is exciting to see that we may soon be able to help patients with metastatic pancreatic cancer in ways we haven’t been able to before, improving both survival and quality of life.”
Source: O’Reilly EM, et al; RASolute 302 Trial Investigators. (2026, May 31). N Engl J Med. Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer