PURPOSE Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX/mFFX) is the standard adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC), offering survival benefits over gemcitabine (GEM). However, the contribution of molecular biomarkers to treatment selection remains unclear. Here, we characterize the molecular landscape of tumors from the PRODIGE-24/CCTG PA6 trial and assess the clinical impact of genomic alterations and molecular subtypes. PATIENTS AND METHODS Tumor DNA sequencing was successfully performed in 317/350 tumors (168 mFFX; 149 GEM), complemented by transcriptomic subtyping using the PurIST classifier. Mutational status of four key PDAC driver genes and 24 homologous recombination repair (HRR)–associated genes was analyzed, alongside single-base substitution (SBS) mutational signatures. Primary and secondary end points were disease-free survival (DFS) and cancer-specific survival (CSS), respectively. RESULTS In the mFFX group, the PurIST subtype was prognostic, with classical tumors showing superior DFS compared with basal-like tumors (stratified hazard ratio sHR, 0.48 95% CI, 0.31 to 0.77). Among KRAS- mutated patients, mFFX significantly improved DFS compared with GEM (sHR, 0.60 95% CI, 0.45 to 0.79; P < .001), while no benefit was observed in KRAS wild-type tumors (interaction test, P int. = 0.010). HRR and BRCA status were not predictive ( P int. = .568 and P int. = .785, respectively). The benefit of mFFX was consistent across SBS-positive and SBS-negative subgroups. CONCLUSION Overall, these results do not support a change in current adjuvant treatment strategies. mFFX remains the standard adjuvant regimen in PDAC, and the observed lack of benefit in KRAS wild-type tumors should be considered hypothesis-generating and warrants further investigation.
Witz et al. (2026) studied this question.