daraxonrasib in the treatment of pancreatic cancer

Daraxonrasib in the treatment of pancreatic cancer

• is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS

Aberrant activation of the RAS pathway is the key driver of pancreatic ductal adenocarcinoma (PDAC), with oncogenic RAS mutations present in more than 90% of cases (1).

RAS (Rat Sarcoma Virus)

• is a superfamily of genes encoding small GTPase proteins that function as binary molecular switches
  • cycle between an active, GTP-bound state ("ON") and an inactive, GDP-bound state ("OFF")
    • active RAS stimulates downstream pathways which govern cell proliferation, differentiation, and survival
• the three primary human RAS oncogenes are KRAS, NRAS, and HRAS

O’Reilly et al undertook and open-label, randomized trial, where they randomly assigned patients with previously treated metastatic PDAC (mPDAC) to receive daraxonrasib or chemotherapy of the investigator’s choice (1):

• total of 500 patients, including 91.8% with RAS G12 mutations, were randomly assigned to receive daraxonrasib (248 patients) or chemotherapy (252 patients)
• dual primary end points were overall survival and progression-free survival in the subpopulation of patients with RAS G12 mutations (the RAS G12 population)
• the median overall survival in the RAS G12 population was 13.2 months with daraxonrasib and 6.6 months with chemotherapy, and the median overall survival in the overall population was 13.2 months and 6.7 months, respectively
• 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
• treatment-related adverse events that led to treatment discontinuation occurred in 1.2% of the patients in the daraxonrasib group and in 11.2% of those in the chemotherapy group

The study authors concluded that “..Among patients with previously treated mPDAC, treatment with daraxonrasib led to significantly longer overall survival and progression-free survival than chemotherapy..”

Reference:

1. O’Reilly EM et al; RASolute 302 Trial Investigators. Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer. N Engl J Med. 2026 May 31.