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) multiselective, tri-complex inhibitor of the active guanosine triphosphate–bound state of mutant and wild-type RAS.
In this phase 3, international, open-label, randomized trial, we randomly assigned patients with previously treated mPDAC to receive daraxonrasib or chemotherapy of the investigator’s choice. The dual primary end points were overall survival and progression-free survival in the subpopulation of patients with RAS G12 mutations (the RAS G12 population). Key secondary end points included overall survival and progression-free survival in the overall population (which included patients with RAS G12, G13, or Q61 mutations or with no RAS mutation identified) and objective response and patient-reported quality of life in the RAS G12 and overall populations. Safety was also assessed. Research Summary Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer
A total of 500 patients, including 91.8% with RAS G12 mutations, were randomly assigned to receive daraxonrasib (248 patients) or chemotherapy (252 patients). 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; the hazard ratio was 0.40 in both populations (P
Among patients with previously treated mPDAC, treatment with daraxonrasib led to significantly longer overall survival and progression-free survival than chemotherapy. (Funded by Revolution Medicines; RASolute 302 ClinicalTrials.gov number, NCT06625320.) Quick Take Daraxonrasib in Metastatic Pancreatic Cancer 2m 18s
45 patients with Non–Small-Cell Lung Cancer (NSCLC) who received the 600-mg dose, 36% had a partial response, the median progression-free survival (PFS) was 8.3 months, estimated 12-month overall survival was 59% 21 patients with metastatic pancreatic ductal adenocarcinoma 24% had a response, the median PFS was 3.0 months and the median overall survival was 10.3 months.
In this Korean retrospective review of >6MM patients, heavy ethanol consumption in patients between 20-39 years of age was associated with associated with about a 20% increased risk of pancreatic cancer. This should be taken with a grain of salt (not on your margarita) but does suggest a dose dependent effect of ethanol use and pancreatic cancer risk.
Interesting study that quantifies the risk of Venous Thromboembolism (VTE) in patients undergoing neo(adjuvant) treatment. Risk was about 9% overall, underscoring the need to be aware and potentially provide prophylaxis where appropriate.
PAXG (capecitabine 1250 mg/m² total daily dose administered as 625 mg/m² twice daily, plus intravenous cisplatin 30 mg/m², nab-paclitaxel 150 mg/m², and gemcitabine 800 mg/m² every 14 days) significantly improved event-free survival (EFS) compared with modified FOLFIRINOX (mFOLFIRINOX) in patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC) (16.0 months vs 10.2 months).
The GENERATE/JCOG1611 trial in Japanese patients with metastatic or recurrent PDAC found that neither mFOLFIRINOX nor S-IROX improved overall survival (OS) versus nab-paclitaxel/gemcitabine (median OS 14.0 vs 13.6 vs 17.0 months; hazard ratio (HR) ≈1.29), and the study was stopped early for futility. Progression-free survival (PFS) was similar across arms (≈5.8–6.7 months) but nab-paclitaxel/gemcitabine had fewer grade 3–4 GI toxicities and less febrile neutropenia, supporting its continued use in this population. The OS difference likely reflects more effective second-line sequencing after nab-paclitaxel/gemcitabine, including liposomal irinotecan, rather than intrinsic superiority. In Western studies, NALIRIFOX outperformed Nab-P/Gem, but in the Japanese trial, Nab-P/Gem remained at least as effective as triplet regimens, likely due to differences in patient population, sequencing, and access to second-line therapies.