Multinational phase 3 trial of daraxonrasib or chemotherapy in previously treated metastatic pancreatic cancer

Current therapies offer limited benefit for patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC). Aberrant activation of the RAS pathway is the key driver of PDAC, with oncogenic RAS mutations present in more than 90% of cases. Daraxonrasib is an oral RAS(ON) inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS. In the multinational phase 3 RASolute 302 trial, 500 patients with previously treated mPDAC (91.8% with RAS G12 mutations) were randomized to receive daraxonrasib (n=248) or investigator’s choice of chemotherapy (n=252). Dual primary endpoints were overall survival and progression-free survival in the RAS G12 population. The median overall survival in this population was 13.2 months with daraxonrasib and 6.6 months with chemotherapy; the median overall survival in the overall population was 13.2 months and 6.7 months, respectively; the HR was 0.40 in both populations (p<0.001). The median progression-free survival in the RAS G12 population was 7.3 months with daraxonrasib and 3.5 months with chemotherapy, and that in the overall population was 7.2 months and 3.6 months, respectively; HRs were 0.45 and 0.49, respectively (p<0.001 for both comparisons. Adverse events were reported in all patients in the daraxonrasib group and 97.7% of those in the chemotherapy group; the incidence of adverse events of grade 3 or higher was 61.8% and 69.9%, respectively. Treatment-related adverse events that led to treatment discontinuation occurred in 1.2% of the patients in the daraxonrasib group and 11.2% of patients in the chemotherapy group. The authors conclude that among patients with previously treated mPDAC, treatment with daraxonrasib led to significantly longer overall survival and progression-free survival than chemotherapy.