Overcoming Resistance to the RAS Inhibitor Daraxonrasib in Pancreatic Cancer

Circulating tumor DNA analyses in 44 patients with pancreatic cancer, alongside preclinical translational modeling approaches, have identified specific mechanisms of acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib, according to findings published in Nature Medicine on August 11, 2026. The research evaluates how tumors adapt during monotherapy and provides data to inform potential combination treatment strategies.

Clinical Trial Background and Patient Cohort

According to a scientific poster presentation detailed in supplemental records from Revolution Medicines, the findings stem from investigations involving 44 patients with pancreatic ductal adenocarcinoma, or PDAC. These patients received daraxonrasib—also known as RMC-6236—as part of a phase 1/2 clinical trial registered under the identifier NCT05379985. Pancreatic ductal adenocarcinoma is recognized as an aggressive malignancy driven by oncogenic RAS mutations in over 90 percent of cases. Previous data from the investigational study showed an encouraging efficacy profile with acceptable safety and tolerability, yielding a median progression-free survival of 8.5 months at a 300-milligram dose.

Genomic Alterations Identified in Circulating Tumor DNA

Researchers tracked disease progression by analyzing circulating tumor DNA, or ctDNA, collected from the trial participants. An acquired alteration was defined as an oncogenic or likely oncogenic variant annotated by OncoKB that was not detected in pre-treatment ctDNA samples. The analysis revealed distinct genomic shifts as patients developed resistance to the monotherapy. These resistance mechanisms identified in pancreatic cancer patients may be distinct from those previously documented in acquired resistance to KRAS G12C(OFF) inhibitors, where secondary oncogenic KRAS mutations have been observed.

Preclinical Modeling and Next-Stage Evaluation

To validate the clinical observations, the study team utilized preclinical translational modeling approaches. These models help map how cancer cells bypass the inhibitory effects of daraxonrasib. By pairing the ctDNA findings from the phase 1/2 trial with laboratory models, investigators mapped pathways that could mitigate resistance. Based on the broader clinical development program for the drug, a randomized Phase 3 trial designated as RASolute 302 and tracked under identifier NCT06625320 is currently underway to compare daraxonrasib against chemotherapy.