Daraxonrasib vs Chemotherapy in Previously Treated Metastatic Pancreatic Cancer

Key Takeaways

• Daraxonrasib was associated with longer overall survival and progression-free survival than investigator's choice chemotherapy in the prespecified RAS G12 population.
• Benefit was also reported in the overall population, and 91.8% of enrolled patients had RAS G12 mutations.
• Adverse events were common in both groups, and grade 3 or higher events and treatment-related discontinuations were less frequent with daraxonrasib.

In the phase 3 RASolute 302 trial, patients with previously treated metastatic pancreatic ductal adenocarcinoma in the RAS G12 population lived a median of 13.2 months with daraxonrasib and 6.6 months with investigator's choice chemotherapy.

Investigators randomly assigned 500 patients in an international, open-label study to daraxonrasib or investigator's choice chemotherapy, with 248 and 252 patients in each group. Daraxonrasib was an oral RAS(ON) multiselective, tri-complex inhibitor, and 91.8% of enrolled patients had RAS G12 mutations. The overall population included patients with RAS G12, G13, or Q61 mutations or no RAS mutation identified. Dual primary end points were overall survival and progression-free survival in the RAS G12 population, while key secondary end points covered those measures in the overall population plus objective response and patient-reported quality of life in both populations.

Results were consistent in the prespecified and overall populations. In the RAS G12 population, the overall survival comparison carried a hazard ratio of 0.40, with a P value below 0.001, and median progression-free survival was 7.3 months with daraxonrasib and 3.5 months with chemotherapy. In the overall population, median overall survival was 13.2 months with daraxonrasib and 6.7 months with chemotherapy, with a hazard ratio of 0.40 and P<0.001. Median progression-free survival in the overall population was 7.2 months and 3.6 months, respectively, with a hazard ratio of 0.49, while the RAS G12 progression-free survival hazard ratio was 0.45, and both comparisons had P<0.001.

Adverse events after treatment started occurred in all patients who received daraxonrasib and in 97.7% of those who received chemotherapy. Grade 3 or higher adverse events occurred in 61.8% of the daraxonrasib group and 69.6% of the chemotherapy group, and treatment-related adverse events leading to discontinuation occurred in 1.2% and 11.2%, respectively.