ESMO Recommends Daraxonrasib After Chemotherapy for RAS G12–Mutant Metastatic Pancreatic Cancer

Clinical Summary: 

• Design/Population: The ESMO Clinical Practice Guideline Express Update revised recommendations for molecular profiling and second-line treatment of metastatic pancreatic ductal adenocarcinoma based primarily on results from the phase 3 RASolute 302 trial of daraxonrasib vs investigator’s choice of chemotherapy in previously treated metastatic disease.
• Key Outcomes: In patients with RAS G12–mutant tumors, daraxonrasib improved median overall survival to 13.2 months vs 6.6 months with chemotherapy and median progression-free survival to 7.3 months vs 3.5 months. Objective response rates were 33.2% and 11.8%, respectively, and deterioration in pain and global health status/quality of life was also delayed with daraxonrasib.
• Clinical Relevance: ESMO now recommends daraxonrasib after chemotherapy for patients with RAS G12–mutant metastatic pancreatic cancer and ECOG performance status 0 to 1, establishing a molecularly selected second-line option in a disease historically dominated by cytotoxic chemotherapy. Evidence remains insufficient to support the same recommendation for RAS wild-type, RAS G13–mutant, or RAS G61–mutant disease.

An ESMO Clinical Practice Guideline Express Update has added daraxonrasib monotherapy as a recommended treatment after chemotherapy for patients with previously treated RAS G12-mutant metastatic pancreatic ductal adenocarcinoma and an ECOG performance status of 0 to 1.

The update also recommends tumor molecular profiling at diagnosis for all patients with unresectable pancreatic ductal adenocarcinoma to identify actionable alterations, including RAS G12 mutations. The revised guidance reflects the growing clinical relevance of direct RAS inhibition in a disease in which KRAS alterations occur in the large majority of tumors.

Daraxonrasib is an oral pan-RAS(ON) multi-selective inhibitor that targets the active form of mutated and wild-type KRAS, HRAS, and NRAS. The updated recommendation was informed by phase 1/2 findings and results from the randomized phase 3 RASolute 302 trial.

RASolute 302 enrolled 500 patients with previously treated metastatic pancreatic ductal adenocarcinoma and randomized them 1:1 to receive 300 mg of oral daraxonrasib once daily or investigator’s choice of chemotherapy with gemcitabine plus nab-paclitaxel, modified FOLFIRINOX, FOLFOX, or liposomal irinotecan plus 5-fluorouracil and leucovorin. Most patients RAS G12–mutant tumors (91.8%). 

In the RAS G12–mutant population, median overall survival (OS) was 13.2 months with daraxonrasib compared with 6.6 months with chemotherapy, corresponding to a 60% reduction in the risk of death (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.30 to 0.54; P < .001). Similar results were observed in the overall study population, with median OS of 13.2 months and 6.7 months, respectively.

Daraxonrasib also significantly improved progression-free survival (PFS). Among patients with RAS G12-mutant tumors, median PFS was 7.3 months with daraxonrasib compared with 3.5 months with chemotherapy (HR, 0.45; 95% CI, 0.34 to 0.59; P < .001). In the overall population, median PFS was 7.2 month and 3.6 months, respectively.

Objective response rates (ORR) also favored daraxonrasib. In the RAS G12-mutant population, the investigator-assessed ORR was 33.2% with daraxonrasib compared with 11.8% with chemotherapy. Corresponding rates in the overall population were 31.6% and 11.2%.

Patient-reported outcomes further supported the efficacy findings. Median time to worsening of pain was 9 months with daraxonrasib and 3.7 months with chemotherapy in patients with RAS G12–mutant tumors. Median time to deterioration in global health status/quality of life was 5.6 month and 2.4 months, respectively.

The adverse-event profiles differed between treatment groups. The most common treatment-related adverse events with daraxonrasib were rash, diarrhea, stomatitis, nausea, and vomiting. Grade ≥3 rash occurred in 13.7% of patients and grade ≥3 stomatitis occurred in 12% of patients. Chemotherapy was associated with higher rates of severe hematologic toxicity, including grade ≥3 neutropenia (27.6%) and anemia (16.4%). Serious treatment-related adverse events occurred in 10.8% of patients receiving daraxonrasib and 18.7% receiving chemotherapy.

The evidence was less definitive outside the RAS G12-mutant population. In the small subgroup with RAS G13, RAS G61, or RAS wild-type tumors, the PFS analysis did not demonstrate a benefit with daraxonrasib. ESMO therefore noted that additional data are needed before its efficacy and tolerability can be established in these less common molecular subsets.

Based on the available evidence, ESMO recommends daraxonrasib monotherapy after chemotherapy for patients with RAS G12–mutant metastatic pancreatic ductal adenocarcinoma and ECOG performance status 0 to 1, with a level I, grade A recommendation. At the time of the update, daraxonrasib was not approved by either the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA).

Source: 

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