Therapeutic options for metastatic pancreatic ductal adenocarcinoma (PDAC) remain limited, with second-line treatments typically yielding modest benefit. Activation of the RAS pathway, most commonly driven by KRAS mutations, occurs in the vast majority of PDAC cases and represents a critical oncogenic dependency. Daraxonrasib, an oral, multi-selective RAS(ON) inhibitor targeting the active, GTP-bound state of RAS, is being evaluated as a novel strategy to address this unmet need.
In the global phase III RASolute-302 trial (NCT06625320), patients with previously treated metastatic PDAC were randomized to receive daraxonrasib 300 mg once daily (n=248) or investigator’s choice of chemotherapy (n=252).
At data cutoff on February 10, 2026, daraxonrasib demonstrated statistically significant and clinically meaningful improvements in median overall survival (OS; daraxonrasib, 13.2 months vs chemotherapy, 6.6 months; hazard ratio [HR], 0.40) and progression-free survival (7.2 vs 3.6 months, respectively) in patients with the KRAS G12 mutation, with consistent benefit observed across the overall study population.
Objective response rates were also improved with daraxonrasib (31.6% vs 11.2%), further supporting the antitumor activity of RAS pathway inhibition in this population.
These findings represent one of the first demonstrations of meaningful OS improvement with a RAS-directed therapy in PDAC.
Patients with metastatic PDAC have historically faced limited treatment options after disease progression, making improvements in survival outcomes especially meaningful in this setting.
In addition to improving survival outcomes, daraxonrasib delayed deterioration in patient-reported quality of life and pain compared with chemotherapy.
The safety profile was manageable and generally favorable relative to chemotherapy, with fewer grade 3 or higher treatment-related adverse events (AEs) and substantially lower rates of treatment discontinuation. Common toxicities with daraxonrasib included rash and stomatitis, while cytopenias such as neutropenia and anemia were more frequent with chemotherapy. Treatment discontinuation due to AEs was low with daraxonrasib (1.2%) compared with chemotherapy (11.2%).
As an oral targeted therapy, daraxonrasib may also introduce new considerations for multidisciplinary care teams, including patient education, adherence monitoring, toxicity management, and coordination of supportive care services.
These results support daraxonrasib as a potential new treatment option for patients with previously treated metastatic PDAC and may influence future treatment standards in this setting.
Source: Wolpin BM, Wainberg ZA, Hendifar A, 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. Presented at: ASCO Annual Meeting. May 29-June 2, 2026; Chicago, IL. Abstract LBA5.
