Daraxonrasib's MOA: It is a sticky business | ASCO 2026

Daranoxrasib, the experimental pancreatic cancer drug, is making a big splash at this year’s annual meeting of the American Society of Clinical Oncology in Chicago, but the secret to the drug’s apparent success may be its sticktoitiveness.

The aberrant, cancer-producing protein that the experimental drug sticks is “like a shiny ball, you can’t stick anything to it — it just kind of slides off in a way,” Shubham Pant, M.D., M.B.B.S., a professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with Managed Healthcare Executive.

Daranoxrasib has been constructed to bind to a cellular chaperone called cyclophilin A that is “kind of like a molecular glue,” said Pant, explaining the drug’s mechanism of action (MOA). The result is a binary complex that adheres to the RAS protein, which, in turn, leads to tumor cell death.

“It’s a very unique mechanism of action of target drug that you’re not trying to find a groove inside the protein, but you're just trying to stick the protein for destruction,” Pant said.

Pant was one of the investigators of the open-label, phase 3 RASolute 302 study of daraxonrasib that showed the drug produced approximately double the overall survival and progression-free survival as standard chemotherapy in the second line of treatment of metastatic pancreatic cancer. Lead investigator Brian M. Wolpin, M.D., M.P.H., of the Dana-Farber Cancer Institute in Boston, shared data from the trial yesterday on an embargoed basis at a news conference that showed the overall survival among the patients randomly selected to be treated with daraxonrasib, a once-a-day pill, was 13.2 months compared with 6.6 months for those who were treated with one of four standard chemotherapy regimens.

Researchers have known for decades that proteins generated by the family of RAS oncogenes, one of which is KRAS, are culprits in the development of cancer, but they were seen as being “undruggable” because of their shape and other features. Pant explained that Krazati (adagrasib) and Lumakaras (sotorasib) are FDA-approved drugs for non-small cell lung cancer and colorectal cancer that inhibit KRAS proteins, but their target is quite specific. In contrast, daraxonrasib is a “pan-RAS inhibitor” that appears to be effective against tumor cells generated by many different kinds of RAS mutations.

Another important feature of daraxonrasib’s MOA is that it is effective against proteins generated by RAS genes stuck in an “on” position, while the other KRAS drugs affect proteins generated by alleles in the off position. Only a small percentage of pancreatic cancers are associated with those off-position alleles.