The U.S. Food and Drug Administration has approved daraxonrasib, to be sold under the brand name Rasonque, for the treatment of adults with metastatic pancreatic adenocarcinoma who have received at least one prior systemic therapy or who are not candidates for multiagent systemic therapy. The approval follows results from an international phase 3 study co-led by UCLA that showed the targeted therapy significantly extended overall survival and reduced the risk of death by 60% compared with standard chemotherapy.
In the study, patients who received daraxonrasib, an oral RAS(ON) multi-selective inhibitor designed to block active RAS signaling, one of the primary drivers of pancreatic cancer, lived a median of 13.2 months compared with 6.7 months for those who received investigator’s choice chemotherapy.
The FDA approval provides a new treatment option for patients with metastatic pancreatic cancer, a disease that remains among the most lethal cancers and has historically had limited effective therapies.
The results were published in the New England Journal of Medicine and presented earlier this year at the annual meeting of the American Society of Clinical Oncology in Chicago.
“This FDA approval represents an important milestone for patients with metastatic pancreatic cancer, who have needed new and more effective treatment options,” said Dr. Zev Wainberg, professor of medicine and investigator at the UCLA Health Jonsson Comprehensive Cancer Center and co-first author of the study. “The results of this trial demonstrate that targeting RAS can meaningfully extend survival and improve disease control, and it is exciting to see these findings translated into an approved treatment for patients.”
More than 90% of tumors are driven by alterations in the RAS signaling pathway, particularly mutations in KRAS, a gene that helps regulate cell growth. When mutated, the gene can lock cells into a constant growth state, fueling tumor development. Despite decades of research, RAS proteins have proved notoriously difficult to target with drugs.
Unlike earlier targeted therapies that focused on a single mutation subtype, daraxonrasib is part of a new class of therapies designed to inhibit multiple RAS mutations, including G12, G13 and Q61 alterations that dominate pancreatic cancer.
The study involved 500 patients with metastatic pancreatic cancer whose disease had already progressed after one previous treatment from 60 clinical sites across six countries. Participants were randomly assigned to receive either daraxonrasib orally once daily (248 patients) or standard chemotherapy chosen by their doctor (252 patients). About 92% of patients had RAS G12 mutations.
In addition to improved overall survival, patients treated with daraxonrasib experienced significantly longer disease control. Median progression-free survival was 7.2 months compared with 3.6 months for chemotherapy, effectively doubling the time before cancer progression, in the overall study population.
Tumor shrinkage was also more frequent in the daraxonrasib group, with approximately 30% of patients achieving an objective response in the overall study population compared with about 11% in the chemotherapy group. Patients receiving the targeted therapy also experienced slower worsening of pain and better preservation of quality of life over time.
“While most patients had RAS G12 mutations, the benefit appeared generally consistent across different patient groups and mutation types,” said Wainberg, who is also the co-director of the UCLA GI Oncology Program. “These findings support the idea that blocking active RAS signaling will become an important treatment strategy for pancreatic cancer.”
The most common side effects of daraxonrasib include rash, diarrhea, stomatitis, nausea, fatigue, vomiting, abdominal pain, edema, decreased appetite and hemorrhage. The prescribing information also includes warnings and precautions for dermatologic and soft tissue toxicity, stomatitis and oral disorders, diarrhea, gastrointestinal perforation, interstitial lung disease or pneumonitis and embryo-fetal toxicity.
Rasonque is manufactured by Revolution Medicines.
