A Pill Targeting Pancreatic Cancer’s Main Driver Nearly Doubled Median Survival

Pancreatic cancer has a molecular engine found in almost every tumor: RAS. For decades, the protein was considered exceptionally difficult to drug. Its surface offered few pockets where a conventional drug molecule could bind.

Daraxonrasib takes a different approach. Instead of searching for a natural pocket on RAS, it helps create one.

In an international phase 3 trial, daraxonrasib was compared with standard chemotherapy in 500 patients with metastatic pancreatic ductal adenocarcinoma whose cancer had progressed after one previous line of treatment. Half received the oral drug once daily; the others received one of several accepted chemotherapy regimens.

Median overall survival was 13.2 months with daraxonrasib and 6.7 months with chemotherapy. This does not mean that every patient lived twice as long. The median is the point at which half the participants have died and half remain alive. Still, the separation between the groups was substantial: the hazard ratio for death was 0.40, corresponding to an approximately 60% lower risk of death during follow-up.

Median progression-free survival was 7.2 months with daraxonrasib and 3.6 months with chemotherapy. Tumors shrank substantially in roughly one third of patients receiving the drug, compared with about 12% of those receiving chemotherapy. Pain also took longer to worsen: a median of 9.2 months versus 3.8 months.

The drug works like a molecular clamp. Daraxonrasib first binds to an intracellular protein called cyclophilin A. Together they form a new binding surface that captures active, GTP-bound RAS — the state known as RAS(ON). This three-part complex prevents RAS from interacting with downstream signaling proteins that drive tumor-cell growth.

That mechanism is particularly relevant in pancreatic cancer. More than 90% of pancreatic tumors carry activating RAS mutations, most often in KRAS. Earlier RAS inhibitors were designed for specific mutations that are uncommon in this disease. Daraxonrasib is multiselective: it can inhibit several mutant forms as well as active wild-type RAS.

Adverse events were common in both groups. Grade 3 or higher events occurred in 61.8% of patients receiving daraxonrasib and 69.6% of those receiving chemotherapy. Rash, diarrhea, and inflammation of the mouth were among the most frequent problems associated with the new drug. Treatment-related adverse events led to discontinuation in 1.2% of patients on daraxonrasib and 11.2% on chemotherapy.

The result has important boundaries. The trial was open-label, so both patients and clinicians knew which treatment had been assigned. Median follow-up was only 8.5 months. The findings apply specifically to previously treated metastatic disease and cannot be extended to newly diagnosed or operable pancreatic cancer. The study was funded by the drug’s manufacturer, Revolution Medicines.

Daraxonrasib remains investigational and has not received standard marketing approval. The FDA has permitted expanded access for some eligible patients in the United States, but expanded access is not the same as regulatory approval.

The drug does not make metastatic pancreatic cancer curable. Its deeper significance is methodological: a protein once considered almost impossible to target can become druggable when chemistry changes the way the target is approached.