Daraxonrasib Receives FDA Breakthrough Therapy Status in 1L Metastatic PDAC

The FDA has granted breakthrough therapy designation to daraxonrasib (Rasonque), an oral RAS(ON) multi-selective inhibitor, in combination with gemcitabine and nab-paclitaxel (GnP) for the management of treatment-naive metastatic pancreatic adenocarcinoma (PDAC), according to a news release from the developer, Revolution Medicines.¹ The designation marks the company's third breakthrough designation for daraxonrasib.

What data supported the breakthrough therapy designation?

Supporting data for the FDA’s decision come from the phase 1/2 RMC-GI-102 trial (NCT06445062), which evaluated daraxonrasib-based combinations across multiple subprotocols in patients with RAS mutant gastrointestinal tumors.² Within this trial, the treatment-naive metastatic PDAC cohort received daraxonrasib at 200 mg orally once daily in 28-day cycles combined with GnP administered on a day 1 and day 15 schedule. As of a December 1, 2025, data cutoff, 40 patients with previously untreated RAS mutant metastatic PDAC had been treated in this cohort. The combination showed encouraging preliminary antitumor activity and a manageable safety profile consistent with the known profiles previously observed for both daraxonrasib and GnP individually.

“This breakthrough therapy designation underscores the significant unmet need among patients with previously untreated metastatic [PDAC] and recognizes the importance of advancing new treatment options earlier in their treatment journey,” stated Alan Sandler, MD, chief development officer of Revolution Medicines, in the press release.¹ “Data from the RMC-GI-102 study have now shown the therapeutic potential of [daraxonrasib] in combination with GnP, a commonly used multiagent systemic therapy, in treatment-naive patients. Together with our other ongoing studies, these findings reflect our deep commitment to advancing a broad RAS(ON) approach for patients with some of the most difficult-to-treat cancers.”

What is daraxonrasib's full regulatory history in pancreatic cancer?

Daraxonrasib monotherapy was previously approved by the FDA on August 26, 2026, for patients with metastatic PDAC who have received at least 1 prior systemic therapy or who are not candidates for multiagent systemic therapy based on findings from the phase 3 RASolute 302 trial (NCT06625320).³ That approval was reviewed under the FDA Commissioner's National Priority Voucher pilot program and granted 6.5 months ahead of the standard user fee deadline.

Prior to the full approval, the FDA permitted an expanded access program for daraxonrasib in previously treated metastatic PDAC in May 2026.⁴ In July 2026, the European Medicines Agency's Committee for Medicinal Products for Human Use began a phased review of daraxonrasib, an accelerated assessment pathway for medicines addressing unmet medical needs.⁵ The following month, the European Society for Medical Oncology issued a Clinical Practice Guideline Express Update recommending daraxonrasib monotherapy after chemotherapy progression in patients with RAS G12–mutated metastatic PDAC and an ECOG performance status of 0 or 1.⁶

What is the RASolute 303 trial evaluating?

In the phase 3 RASolute 303 trial (NCT07491445), which began treating patients in April 2026, daraxonrasib was evaluated as monotherapy or in combination with GnP against standard-of-care GnP alone as first-line treatment for patients with previously untreated metastatic PDAC, who were enrolled irrespective of tumor RAS genotype.⁷ The trial is designed to enroll approximately 900 patients, randomly assigned 1:1:1 to daraxonrasib once daily as monotherapy, daraxonrasib once daily plus GnP, or GnP alone.⁸ Eligible patients must have confirmed metastatic PDAC with no prior systemic treatment in the metastatic setting, an ECOG performance status of 0 or 1, and documented tumor RAS mutational status, whether mutant or wild type.

The dual primary end points are overall survival and progression-free survival. Key secondary end points include objective response rate, duration of response, safety and tolerability, pharmacokinetics, and quality of life.

What is daraxonrasib and how does it work?

Daraxonrasib is an oral, noncovalent tri-complex inhibitor that suppresses RAS signaling by blocking the interaction between wild-type and mutant RAS(ON) proteins and their downstream effectors. It binds intracellular cyclophilin A to engage GTP-bound RAS mutations, including G12, G13, and Q61 variants, as well as RAS wild-type.

References

1. Revolution Medicines announces US FDA breakthrough therapy designation for RASONQUE (daraxonrasib) in combination with chemotherapy for first line metastatic pancreatic cancer. News release. Revolution Medicines, Inc. September 14, 2026. Accessed September 15, 2026. https://tinyurl.com/3bzemsdw
2. Revolution Medicines to present updated phase 1/2 clinical data for daraxonrasib in first line metastatic pancreatic cancer across monotherapy and combination cohorts at the 2026 AACR Annual Meeting. News release. Revolution Medicines, Inc. Accessed September 15, 2026. https://tinyurl.com/ytrxs7ph
3. FDA approves first in class targeted therapy for metastatic pancreatic cancer. News release. FDA. August 26, 2026. Accessed August 26, 2026. https://tinyurl.com/4dt6cwnv
4. FDA permits expanded access for investigational pancreatic cancer drug. News release. FDA. May 1, 2026. Accessed September 15, 2026. https://tinyurl.com/4xbhx3pd
5. European Medicines Agency expedites assessment of Revolution Medicines' daraxonrasib under phased review process. News release. Revolution Medicines, Inc. July 7, 2026. Accessed September 15, 2026. https://tinyurl.com/4c6cmxcu
6. Conroy T, Ducreux M; on behalf of the ESMO Guidelines Committee. ESMO Clinical Practice Guideline Express Update on daraxonrasib in the treatment of metastatic pancreatic cancer. Ann Oncol. Published online August 19, 2026. doi:10.1016/j.annonc.2026.08.003
7. Revolution Medicines begins treating patients in phase 3 RASolute 303 trial evaluating daraxonrasib as first line treatment for patients with metastatic pancreatic cancer. News release. Revolution Medicines, Inc. April 2, 2026. Accessed September 15, 2026. https://tinyurl.com/mtx9875c
8. Study of daraxonrasib and daraxonrasib + GnP as first-line treatment in patients with metastatic pancreatic adenocarcinoma (RASolute 303). ClinicalTrials.gov. Updated September 14, 2026. Accessed September 15, 2026. https://tinyurl.com/2zmb3my5