Daraxonrasib Treatment in RAS-Mutated Pancreatic Cancer: Mechanisms, Clinical Evidence and Future Perspectives

Abstract

Pancreatic ductal adenocarcinoma (PDAC) ranks among the deadliest malignancies worldwide, with its poor prognosis stemming from aggressive progression, delayed detection, and limited treatment responses. While KRAS has attracted substantial interest as a therapeutic target, its molecular architecture long defied direct pharmacological intervention. The recent introduction of daraxonrasib (RMC-6236)—a multiselective RAS(ON) inhibitor capable of engaging multiple active RAS variants—marks a notable shift in this landscape. By targeting a broader range of mutations rather than a single subtype, this agent holds promise for treating a wider patient population. Preclinical investigations have demonstrated robust suppression of RAS signalling and notable tumour regression, while clinical studies have yielded encouraging patient outcomes. The Phase III RASolute 302 trial, in particular, reported substantial gains in overall survival, progression-free survival, and objective response rates relative to standard second-line chemotherapy. This review explores the pathogenic role of KRAS mutations in pancreatic cancer, traces the development and mechanism of daraxonrasib, evaluates supporting clinical data, and discusses its strengths, limitations, and future positioning in managing RAS-mutated PDAC.