Daraxonrasib For Pancreatic Cancer: What To Know

  • Daraxonrasib delivered the first phase 3 survival advantage ever seen for RAS‑mutated metastatic PDAC, earning a plenary slot at ASCO and signaling a potential shift in second‑line treatment for a population historically marked by single‑digit response rates and rapid progression.
  • Daraxonrasib cut the risk of death by 60% compared to chemotherapy in previously treated metastatic pancreatic cancer. Median overall survival was 13.2 months versus 6.6 months (HR 0.40; p<0.001), with more than half of patients on daraxonrasib still alive at 12 months.
  • The drug was better tolerated than chemotherapy on the metrics that matter most: fewer grade ≥3 adverse events (43.6% vs. 57.5%), far less neutropenia, peripheral neuropathy, and thrombocytopenia, and a treatment discontinuation rate of just 1.2% versus 11.2% with chemotherapy.
  • The emergence of an active RAS‑targeted therapy makes comprehensive molecular profiling non‑negotiable in PDAC, reinforces the importance of using daraxonrasib earlier rather than later, and marks the beginning of a broader wave of RAS‑directed agents now advancing through clinical development.

When the American Society of Clinical Oncology gives a drug the spotlight at its Annual Meeting plenary session, the message is usually clear enough: pay attention.

On May 31, Dr. Brian Wolpin of Dana-Farber Cancer Institute, presented the primary results of RASolute 302, the global phase 3 randomized trial comparing daraxonrasib to standard second-line chemotherapy in patients with metastatic RAS-mutated pancreatic ductal adenocarcinoma. The results, published simultaneously in the New England Journal of Medicine, were met with audible reaction from the audience.

In both the RAS G12 population and the overall population, daraxonrasib reduced the risk of death by 60% compared to chemotherapy: hazard ratio 0.40, p<0.001. Median overall survival was 13.2 months with daraxonrasib versus 6.6 months with chemotherapy in the RAS G12 population. At 12 months, 53% of patients on daraxonrasib were alive, compared to 18.7% on chemotherapy.

For a disease where second-line options have barely moved the needle in two decades, the numbers landed with weight.

SurvivorNet was on the ground at ASCO and spoke with Dr. Diane Simeone, director of the Moores Cancer Center at UC San Diego Health, about the breakthrough.

“We now can double the length of their lives. And this is step one, a big breakthrough, because we really haven’t been able to find things that are effective beyond standard chemotherapy, except in rare instances,” Dr. Simeone explains.

ASCO 2026: The Latest Results

The RASolute 302 trial enrolled 500 patients at 59 sites across six countries between October 2024 and November 2025. Patients had histologically confirmed mPDAC with progression after one prior fluoropyrimidine- or gemcitabine-based therapy for metastatic disease. ECOG 0–1 was required. Of the 500 patients enrolled, 459 (91.8%) had RAS G12 mutations, consistent with the expected real-world PDAC mutation distribution.

Randomization was 1:1 to daraxonrasib 300 mg once daily or investigator’s choice of chemotherapy: gemcitabine plus nab-paclitaxel (56.5%), liposomal irinotecan plus 5-FU/leucovorin (32.7%), modified FOLFIRINOX (5.6%), or FOLFOX (5.1%). The chemotherapy control arm reflects contemporary clinical practice. Crossover was not permitted.

The dual primary endpoints were overall survival and progression-free survival in the RAS G12 population.

Overall Survival

  • In the RAS G12 population, median OS was 13.2 months (95% CI, 10.0–not reached) with daraxonrasib versus 6.6 months (95% CI, 5.4–8.2) with chemotherapy (HR 0.40; 95% CI, 0.30–0.54; p<0.001).
  • In the overall population, median OS was 13.2 months versus 6.7 months (HR 0.40; 95% CI, 0.30–0.53; p<0.001).
  • Twelve-month OS was 53.3% with daraxonrasib versus 18.7% with chemotherapy in the RAS G12 population.

Progression-Free Survival

  • Median PFS in the RAS G12 population was 7.3 months (95% CI, 6.3–8.1) with daraxonrasib versus 3.5 months (95% CI, 2.9–3.8) with chemotherapy (HR 0.45; 95% CI, 0.34–0.59; p<0.001).
  • In the overall population: 7.2 months versus 3.6 months (HR 0.49; 95% CI, 0.38–0.64; p<0.001).
  • Six-month PFS was 58.7% versus 31.7% in the RAS G12 population.

Objective Response

  • ORR in the RAS G12 population was 33.2% (95% CI, 27.0–39.9) with daraxonrasib versus 11.8% (95% CI, 7.8–16.8) with chemotherapy.
  • Median time to response was 1.9 months in both arms.

Patient-Reported Outcomes

  • Time to deterioration in pain was 9.0 months with daraxonrasib versus 3.7 months with chemotherapy in the RAS G12 population (HR 0.51; p<0.001).
  • Time to deterioration in global health status–quality of life was 5.6 months versus 2.4 months (HR 0.60; p<0.001).

In a disease defined by pain, biliary obstruction, and functional decline, these patient-reported endpoints reflect the clinical reality of what this drug does for patients day to day.

Safety: Better Tolerated Than Chemotherapy

The safety profile of daraxonrasib in RASolute 302 was consistent with the phase 1/2 experience. The most common treatment-related adverse events were rash (85.5%), diarrhea (58.1%), stomatitis (53.1%), nausea (46.5%), and vomiting (36.9%).

“There are side effects that come with these drugs — pretty significant rash, and there can be GI side effects, nausea, which can be debilitating for some patients,” Dr. Simeone notes. She adds that she expects second- and third-generation agents in this class to carry an improved profile as the field matures.

The key comparisons with chemotherapy are worth reviewing carefully:

  • Grade ≥3 treatment-related adverse events: 43.6% with daraxonrasib vs. 57.5% with chemotherapy
  • Serious treatment-related adverse events: 10.8% vs. 18.7%
  • Treatment discontinuation due to adverse events: 1.2% vs. 11.2%
  • Dose reductions due to adverse events: 36.1% vs. 57.5%

Daraxonrasib caused substantially less neutropenia (7.5% vs. 38.3% grade ≥3: 1.7% vs. 27.6%), thrombocytopenia (10.0% vs. 33.2%), anemia (18.3% vs. 39.7%), peripheral neuropathy (1.7% vs. 25.2%), and alopecia (3.3% vs. 15.0%) than chemotherapy. The median duration of treatment was 6.2 months in the daraxonrasib group versus 1.5 to 3.2 months across the chemotherapy regimens, meaning patients stayed on it longer and tolerated it better.

One grade 5 treatment-related event occurred in the daraxonrasib group: pneumonitis in one patient. That should be noted and monitored for in clinical practice.

The practical takeaway for prescribers is rash and stomatitis are the adverse events most likely to require dose modification. In the trial, these were managed with topical and systemic antibiotics, sun protection measures, and dose adjustments as needed. Most patients who required dose modifications were able to continue treatment.

Clinical Implications

Even before RASolute 302 data are fully digested, several practice-relevant points emerge.

First, biomarker testing is no longer optional in PDAC. It was already a standard-of-care recommendation; the arrival of an active agent targeting the most prevalent RAS mutations in pancreatic cancer makes comprehensive molecular profiling (including next-generation sequencing to identify specific KRAS alleles) genuinely consequential for treatment decisions. Patients who have not undergone tumor NGS should be tested now, not at the time of progression.

“All patients with pancreas cancer should have tumor sequencing and germline testing — these are now built into the NCCN guidelines. But it’s not being done in the community setting as much as it should be. And 70% of all pancreatic cancer patients are seen in the community setting,” Dr. Simeone notes.

Additionally, the argument for using daraxonrasib at first progression, rather than reserving it for later lines, is now backed by a positive phase 3 OS readout. The differential activity signals across lines of therapy in the phase 1/2 data. ORR 35% second-line versus 21% third-line or later reinforce what the phase 3 trial was designed to confirm.

The OS and PFS benefit of daraxonrasib over chemotherapy was broadly consistent across prespecified subgroups including ECOG PS, stage at initial diagnosis, presence of liver metastases, and RAS mutational status. That said, fewer than 10% of patients had non-RAS G12 mutations, and findings in those smaller subgroups should be interpreted descriptively. The authors note that additional studies may be warranted to better characterize outcomes in rare RAS subtypes.

Finally, daraxonrasib is the first but almost certainly not the last. Multiple other RAS-targeting agents are now entering or advancing through clinical trials in PDAC. The field that spent three decades stalled on “undruggable RAS” is now moving with unusual speed. For patients who have historically had almost nothing to offer in second line, this shift represents a genuine change in trajectory.

Fast Facts: RASolute 302

  • Drug: Daraxonrasib 300 mg QD vs. investigator’s choice chemotherapy (gem/nab-pac, nal-IRI, mFOLFIRINOX, FOLFOX)
  • Population: Previously treated mPDAC (1 prior line for metastatic disease); 91.8% RAS G12 mutations
  • Trial size: 500 patients, 59 sites, 6 countries
  • Primary endpoints: OS and PFS in RAS G12 population
  • Median OS (RAS G12): 13.2 vs. 6.6 months (HR 0.40; 95% CI, 0.30–0.54; p<0.001)
  • Median OS (overall): 13.2 vs. 6.7 months (HR 0.40; 95% CI, 0.30–0.53; p<0.001)
  • Median PFS (RAS G12): 7.3 vs. 3.5 months (HR 0.45; p<0.001)
  • ORR (RAS G12): 33.2% vs. 11.8%
  • Grade ≥3 TRAEs: 43.6% (daraxonrasib) vs. 57.5% (chemotherapy)
  • Treatment discontinuation due to AEs: 1.2% vs. 11.2%
  • Median treatment duration: 6.2 months (daraxonrasib) vs. 1.5–3.2 months (chemotherapy)

Dr. Rodrigo C. Leão Edelmuth is a board certified digestive surgeon at Hospital Israelita Albert Einstein in São Paulo, Brazil. He holds his General Surgery and Digestive Surgery degree from São Paulo University Medical School.

He underwent a postgraduate course on Surgical Leadership at Harvard Medical School and a Research Fellowship in the Department of Surgery at Weill Cornell Medicine in New York. Dr. Edelmuth is member of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and of the Society for Surgery of the Alimentary Tract (SSAT). In 2022 he received the SAGES Career Development Award.

Read More