FDA Approves Daraxonrasib for Metastatic Pancreatic Cancer

The FDA has approved daraxonrasib for patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC).¹

The approval is supported by results from the phase 3 RASolute 302 trial (NCT06625320), in which daraxonrasib reduced the risk of death by 60% compared with investigator's choice of chemotherapy in this disease setting.^2,3 In the primary analysis population (patients with RAS G12 mutations), the median OS was 13.2 months (95% CI, 10.0-not estimable) with the oral RAS(ON) multiselective inhibitor daraxonrasib vs 6.6 months (95% CI, 5.4-8.2) with chemotherapy, representing a 60% reduction in the risk of death (HR, 0.40; 95% CI, 0.30-0.54; P = 5.9 × 10⁻¹⁰). At 12 months, 53.3% of patients in the daraxonrasib arm remained alive compared with 18.7% in the chemotherapy arm.

The OS benefit was confirmed across the overall population, which included patients with and without an identified tumor RAS mutation (n = 248 daraxonrasib; n = 252 chemotherapy). Median OS was 13.2 months (95% CI, 10.0-not estimable) vs 6.7 months (95% CI, 5.8-8.0) with an identical HR of 0.40 (95% CI, 0.30-0.53; P = 4.6 × 10⁻¹¹). The 12-month OS rate in the overall population was 53.2% with daraxonrasib vs 17.3% with chemotherapy.

Daraxonrasib also significantly improved PFS by blinded independent central review (BICR). In the RAS G12 population, median PFS was 7.3 months (95% CI, 6.3-8.1) with daraxonrasib compared with 3.5 months (95% CI, 2.9-3.8) with chemotherapy (HR, 0.45; 95% CI, 0.34-0.59; P = 3.2 × 10⁻⁹). In the overall population, median PFS 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). The 6-month PFS rates were 58.7% vs 31.7% in the RAS G12 population and 56.0% vs 32.9% in the overall population.

The confirmed ORR by BICR was 33.2% with daraxonrasib vs 11.8% with chemotherapy in the RAS G12 population (P < .0001), and 31.6% vs 11.2% in the overall population (P < .0001), with both comparisons including complete and partial responses.

“Today’s approval provides a critical new option for patients facing an extraordinarily difficult and historically hard-to-treat cancer. It is our fundamental duty to deliver more cures and meaningful treatments to patients as quickly as possible,” Acting FDA Commissioner Kyle Diamantas, JD, stated in a news release.¹ “I am immensely proud of the dedicated FDA scientists whose fast, thorough review and relentless commitment made this groundbreaking milestone a reality.”

Based on the findings, the FDA previously authorized an expanded access treatment protocol for daraxonrasib in this patient population.⁴

Patient-Reported Outcomes

Daraxonrasib also demonstrated significant benefits in patient-reported outcomes. Using EORTC QLQ-PAN26 and EORTC QLQ-C30 questionnaires administered on day 1 of each cycle and at end of treatment, daraxonrasib significantly 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) compared with chemotherapy in the overall population.

Safety

The safety profile of daraxonrasib was generally more favorable than that of chemotherapy, with notably lower rates of dose reduction, discontinuation, and serious treatment-related adverse events (TRAEs). Median time on treatment was 6.2 months (range, 0.03-14.1) with daraxonrasib vs 1.5 to 3.2 months (range, 0.03-12.9) across chemotherapy regimens. Median dose intensity was 93.1% with daraxonrasib and 65.3% to 95.0% across chemotherapy regimens.

Any TRAEs occurred in 97.9% of patients receiving daraxonrasib (n = 236 of 241) and 93.5% of patients receiving chemotherapy (n = 200 of 214). Grade ≥3 TRAEs were reported in 43.6% of daraxonrasib patients vs 57.5% of those receiving chemotherapy. Serious TRAEs were less frequent with daraxonrasib (10.8%) vs chemotherapy (18.7%). TRAEs leading to dose reduction occurred in 36.1% of daraxonrasib patients vs 57.5% of chemotherapy patients. TRAEs leading to treatment discontinuation were markedly lower with daraxonrasib at 1.2% vs 11.2% with chemotherapy.

The most common TRAEs leading to dose reduction with daraxonrasib were rash (17.4%) and stomatitis (6.6%), while those most commonly driving dose reduction with chemotherapy included neutropenia (16.8%), thrombocytopenia (13.6%), fatigue (12.6%), diarrhea (10.3%), and peripheral neuropathy (7.9%). One patient in the daraxonrasib arm died from treatment-related pneumonitis; no treatment-related deaths occurred in the chemotherapy arm.

Study Design and Patient Characteristics

RASolute 302 (NCT06625320) is a global, randomized, 1:1, open-label, phase 3 trial conducted across 59 sites in 6 countries.1 Eligible patients were adults with mPDAC who had received one prior fluoropyrimidine- or gemcitabine-based regimen in the metastatic setting, ECOG performance status of 0-1, and documented tumor RAS mutational status by local testing, including patients with RAS G12, G13, or Q61 mutations and those with no RAS mutation identified. Patients were randomized to daraxonrasib 300 mg orally once daily or investigator's choice of one of four chemotherapy regimens: gemcitabine plus nab-paclitaxel, modified FOLFIRINOX, nanoliposomal irinotecan plus 5-fluorouracil/leucovorin, or FOLFOX.

The dual primary end points were OS and PFS in the RAS G12 population. Key secondary endpoints included OS and PFS in the overall population, ORR in both populations, and time to deterioration in patient-reported outcomes. Randomization was stratified by ECOG performance status (0 vs 1), metastatic disease at diagnosis (yes vs no), liver metastases at baseline (yes vs no), and tumor RAS mutational status (RAS G12D/V vs other RAS G12 vs RAS G13 or Q61 mutation or no RAS mutation identified). The data cutoff for this primary and final analysis was February 10, 2026, with a median follow-up of 8.5 months (range, 3.2-15.9 months).

Daraxonrasib previously received FDA breakthrough therapy and orphan drug designations.

“This drug showed unprecedented results in an area of high unmet need,” Angelo de Claro, MD, director of the FDA’s Oncology Center of Excellence, stated in the news release. “The approval was granted 6.5 months before the user fee deadline, demonstrating the FDA’s commitment to accelerating the approval of new cancer treatments for patients with serious and life-threatening conditions.”

REFERENCES

1. FDA Approves First in Class Targeted Therapy for Metastatic Pancreatic Cancer. Published online and accessed August 26, 2026. https://tinyurl.com/457vwtek

2. 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 44, 2026 (suppl 17; abstr LBA5)

3. American Society of Clinical Oncology. Multi-selective RAS inhibitor nearly doubles survival in pancreatic cancer. ASCO Press Center. Published May 31, 2026. Accessed May 31, 2026. https://tinyurl.com/yeachuvv

4. FDA permits expanded access for investigational pancreatic cancer drug daraxonrasib [press release]. Silver Spring, MD: US Food and Drug Administration; May 1, 2026. Accessed May 30, 2026. https://tinyurl.com/6pmzfjn5