Dr Pant on the Mechanism of Action of Daraxonrasib in PDAC

“It’s a unique compound because it’s a RAS(ON) agent, which means it binds to RAS in the “on” state, and that’s where RAS is mostly active. Most other [RAS] inhibitors…have bound to KRAS in the “off” state.”

Shubham Pant, MD, MBBS, a professor in the Department of Gastrointestinal (GI) Medical Oncology and director of Clinical Research at The University of Texas MD Anderson Cancer Center, discussed why daraxonrasib’s mechanism of action is unique compared with prior RAS inhibitors and how this supports its use alongside chemotherapy in pancreatic cancer.

As an oral, potent, RAS(ON) multi-selective inhibitor, daraxonrasib targets KRAS mutations, which are present in approximately 90% of patients with pancreatic cancer. Pant emphasized that daraxonrasib is a first-of-its-kind RAS(ON) inhibitor, distinguishing it from earlier inhibitors—such as KRAS G12C–targeted agents—that typically bind to RAS in its inactive "off" state. Because RAS is primarily active in the "on" state in pancreatic cancer, binding directly to this configuration allows for more effective inhibition of the oncogenic driver.

As one of the first pan-RAS inhibitors to come into the clinic and demonstrate activity, the development of daraxonrasib represents a significant milestone in pancreatic cancer and supports the ongoing development of additional pan-RAS inhibitors for this disease, Pant asserted.

In clinical trials, daraxonrasib has been evaluated both as a monotherapy and in combination with standard chemotherapy, such as gemcitabine and nab-paclitaxel (Abraxane). Data from the phase 3 RASolute 302 trial (NCT06625320) and phase 1/2 studies (NCT05379985; NCT06445062) have demonstrated its potential in both the frontline and previously treated metastatic settings. Daraxonrasib is currently under investigation in the phase 3 RASolute-303 trial (NCT07491445), which will compare the agent in combination with chemotherapy vs chemotherapy alone in previously treated metastatic pancreatic ductal adenocarcinoma.

The agent previously received FDA breakthrough therapyand orphan drug designations for patients with previously treated metastatic PDAC harboring KRAS G12 mutations.Additionally, on May 1, 2026, the FDA issued a “safe to proceed” letter permitting the initiation of an expanded access treatment protocol (EAP) for daraxonrasib (RMC-6236) for patients with previously treated metastatic PDAC.