CHMP Recommends Approval of Daraxonrasib for Previously Treated Metastatic Pancreatic Cancer

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending marketing authorization for daraxonrasib (Rasonque) as monotherapy for the treatment of adult patients with metastatic pancreatic adenocarcinoma who have received at least 1 prior systemic therapy.¹

The European Commission will now consider the recommendation; if granted, the centralized authorization would apply across all European Union member states, as well as Iceland, Norway, and Liechtenstein.

The positive opinion is supported by data from the phase 3 RASolute 302 trial (NCT06625320), in which daraxonrasib (n = 248) produced a median overall survival (OS) of 13.2 months (95% CI, 10.0-not estimable) vs 6.7 months (95% CI, 5.8-8.0) with investigator's choice of chemotherapy (n = 252) in the overall population (HR, 0.40; 95% CI, 0.30-0.53; P = 4.6 × 10⁻¹¹).^2,3 Median progression-free survival (PFS) by blinded independent central review (BICR) was 7.2 months (95% CI, 5.7-7.5) vs 3.6 months (95% CI, 2.9-4.2), respectively (HR, 0.49; 95% CI, 0.38-0.64; P = 5.2 × 10⁻⁸).³

A subsequent ad hoc OS analysis showed a median OS of 12.4 months with daraxonrasib vs 6.7 months with chemotherapy (HR, 0.49; 95% CI, 0.39-0.62), which was generally consistent with the prespecified primary analysis.¹

The CHMP opinion follows the August 2026 FDA approval of daraxonrasib for the treatment of adult patients with metastatic pancreatic adenocarcinoma who have received at least 1 prior systemic therapy or are not candidates for multiagent systemic therapy, which was also based on RASolute 302 data.⁴ In the European Union, daraxonrasib holds orphan medicinal product designation for pancreatic cancer and received high-priority status under the EMA's Cancer Medicines Pathfinder project, which enabled an expedited, phased review.¹

“[The development of daraxonrasib] signals a new era in gastrointestinal [GI] oncology, where many cancers have different types of RAS mutations, and suggests that although there is toxicity, we can manage and directly affect the outcome of the cancer using RAS inhibitors, whereas 10 years ago, people would have said that RAS is basically an undruggable target,” Alok Khorana, MD, said in an interview with OncLive^® following the FDA approval. “Having said that, I want to be very careful because there's so much hype on this drug; this is not a magic bullet. It's not a cure. Nobody with advanced pancreatic cancer is cured by this drug, and we are actually already learning about the various resistance mechanisms via non[–KRAS] G12C pathways, for instance, or secondary RAS mutations that allow cancer cells to escape the effect of this RAS inhibitor. A second generation of RAS inhibitors is already on the way, [and] they appear to have less toxicity in early clinical trials, so the hope is that [daraxonrasib] is the first in a range of different RAS inhibitors that will have wide application across pancreatic cancers and many other cancers that carry RAS mutations.”

Khorana is a professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, the Sondra and Stephen Hardis Chair in Oncology Research, vice-chair for Clinical Services of the Taussig Cancer Institute, and director of the Gastrointestinal Malignancies Program at the Cleveland Clinic in Ohio.

What is the mechanism of action of daraxonrasib?

Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active, guanosine triphosphate–bound state of mutant and wild-type RAS, including variants harboring G12, G13, and Q61 mutations.^2,3 The agent binds intracellular cyclophilin A to form a binary complex that engages RAS(ON), sterically occluding effector binding and suppressing downstream signaling.³ Oncogenic RAS mutations are present in more than 90% of pancreatic ductal adenocarcinomas.²

How was the RASolute 302 trial designed?

The global, open-label, randomized phase 3 RASolute 302 trial enrolled adult patients with metastatic pancreatic ductal adenocarcinoma who had received 1 prior fluoropyrimidine- or gemcitabine-based regimen in the metastatic setting, had an ECOG performance status of 0 or 1, and had documented tumor RAS mutational status by local testing.³

Between October 16, 2024, and November 7, 2025, a total of 500 patients at 59 sites in 6 countries were randomly assigned 1:1 to receive daraxonrasib at 300 mg orally once daily (n = 248) or investigator's choice of gemcitabine plus nab-paclitaxel (Abraxane), modified FOLFIRINOX, liposomal irinotecan (Onivyde) plus fluorouracil and leucovorin, or FOLFOX (n = 252).^2,3 Randomization was stratified by performance status, metastatic disease at diagnosis, liver metastases at baseline, and tumor RAS mutational status.³

The dual primary end points were OS and PFS by BICR in the RAS G12 population. Key secondary end points included OS and PFS in the overall population, which comprised patients with RAS G12, G13, or Q61 mutations or no RAS mutation identified; objective response rate (ORR) in both populations; and time to deterioration in patient-reported pain and global health status/quality of life.^2,3

What additional efficacy data were reported?

In the RAS G12–mutant population, median OS was 13.2 months (95% CI, 10.0-not estimable) with daraxonrasib (n = 228) vs 6.6 months (95% CI, 5.4-8.2) with chemotherapy (n = 231; HR, 0.40; 95% CI, 0.30-0.54; P = 5.9 × 10⁻¹⁰); the 12-month OS rates were 53.3% and 18.7%, respectively.³ Median PFS in this population was 7.3 months (95% CI, 6.3-8.1) vs 3.5 months (95% CI, 2.9-3.8; HR, 0.45; 95% CI, 0.34-0.59; P = 3.2 × 10⁻⁹). In the overall population, 12-month OS rates were 53.2% with daraxonrasib vs 17.3% with chemotherapy. The OS benefit was observed across prespecified subgroups, including patients with RAS G13 or Q61 mutations or no RAS mutation identified (HR, 0.37; 95% CI, 0.15-0.93).

The confirmed ORR by BICR was 33.2% with daraxonrasib (n = 217) vs 11.8% with chemotherapy (n = 221) in the RAS G12 population and 31.6% (n = 237) vs 11.2% (n = 241) in the overall population (P < .0001 for both). Daraxonrasib also delayed time to deterioration in pain (median, 9.2 vs 3.8 months; HR, 0.51; 95% CI, 0.37-0.71; P < .0001) and in global health status/quality of life (median, 5.7 vs 2.6 months; HR, 0.60; 95% CI, 0.46-0.79; P = .0002) in the overall population.

What is the safety profile of daraxonrasib?

In the safety population, median time on treatment was 6.2 months (range, 0.03-14.1) with daraxonrasib (n = 241) and 1.5 to 3.2 months across chemotherapy regimens (n = 214). Treatment-related adverse effects (TRAEs) occurred in 97.9% of patients in the daraxonrasib arm vs 93.5% of those in the chemotherapy arm, and grade 3 or higher TRAEs occurred in 43.6% vs 57.5%, respectively. Serious TRAEs were reported in 10.8% vs 18.7% of patients. TRAEs led to dose reductions in 36.1% vs 57.5% of patients and to treatment discontinuation in 1.2% vs 11.2%. In the daraxonrasib arm, 1 patient (0.4%) died of treatment-related pneumonitis.

The most common TRAEs with daraxonrasib were rash (any grade, 85%; grade ≥3, 14%), diarrhea (58%; 5%), stomatitis (53%; 12%), nausea (46%; 2%), and vomiting (37%; <1%). Grade 3 or higher neutropenia occurred in 28% of patients in the chemotherapy arm vs 2% in the daraxonrasib arm.

What are the next steps for daraxonrasib?

Following the positive opinion, the European Commission will issue a final decision on marketing authorization.¹ Daraxonrasib is also being evaluated in the frontline setting; in September 2026, the FDA granted breakthrough therapy designation to daraxonrasib plus gemcitabine and nab-paclitaxel for patients with previously untreated metastatic pancreatic adenocarcinoma, and the phase 3 RASolute 303 trial (NCT07491445) is evaluating daraxonrasib monotherapy and daraxonrasib plus gemcitabine and nab-paclitaxel vs gemcitabine and nab-paclitaxel alone in this population, regardless of RAS genotype.⁵

“[The August 2026 FDA] approval was based on [superiority over] second-line chemotherapy. However, given the success rate in the second-line setting…there's no doubt that this will probably make its way to first-line therapy very soon, and then beyond that, looking at the high level of responses, it's very possible that this drug could be actually have even more utility in the preoperative setting where we are looking at responses to downstage tumors, so we can get people to do resection,” Khorana added. “I anticipate that some of these trials are already ongoing and will result out very soon, so we will likely, in the next 12 to 24 months, see an expansion of indications across pancreatic cancer and then also beyond pancreatic cancer.”

References

1. Revolution Medicines' Rasonque (daraxonrasib) receives positive CHMP opinion recommending marketing authorization in European Union for metastatic pancreatic cancer. News release. Revolution Medicines. October 15, 2026. Accessed October 15, 2026. https://www.revmed.com/media/news/13621/revolution-medicines-rasonque-tm-daraxonrasib-receives-positive-chmp-opinion-recommending-marketing-authorization-in-european-union-for-metastatic-pancreatic-cancer
2. O'Reilly EM, Wainberg ZA, Hendifar AE, et al; RASolute 302 Trial Investigators. Daraxonrasib or chemotherapy in previously treated metastatic pancreatic cancer. N Engl J Med. 2026;395(4):325-337. doi:10.1056/NEJMoa2605555
3. Wolpin BM, Wainberg ZA, Hendifar AE, et al. Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): primary and final analysis from the phase 3 RASolute 302 study. J Clin Oncol. 2026;44(suppl 17):LBA5. doi:10.1200/JCO.2026.44.17_suppl.LBA5
4. FDA approves first in class targeted therapy for metastatic pancreatic cancer. FDA. August 26, 2026. Accessed October 15, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-class-targeted-therapy-metastatic-pancreatic-cancer
5. 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 October 15, 2026. https://www.revmed.com/media/news/13431/revolution-medicines-announces-u-s-fda-breakthrough-therapy-designation-for-rasonquetm-daraxonrasib-in-combination-with-chemotherapy-for-first-line-metastatic-pancreatic-cancer