BACKGROUND: In NAPOLI 3 (NCT04083235), first-line (1L) liposomal irinotecan plus 5-fluorouracil/leucovorin plus oxaliplatin (NALIRIFOX) demonstrated statistically significant improvements in overall survival and progression-free survival compared with gemcitabine plus nab-paclitaxel (Gem + NabP) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). In this exploratory analysis, health-related quality of life (HRQoL) and performance status (PS) outcomes from NAPOLI 3 were evaluated. MATERIALS AND METHODS: HRQoL was assessed at baseline, day 1 of each treatment cycle, and at end of treatment (EoT) using the European Organisation for Research and Treatment of Cancer Quality of Life core questionnaire (EORTC QLQ-C30). Analyses included patients who provided baseline and at least one subsequent assessment. A mixed model for repeated measures was used to describe score evolution over time between treatment arms. Eastern Cooperative Oncology Group (ECOG) PS was recorded in the intention-to-treat (ITT) population at baseline, days 1, 8, and 15 of each treatment cycle, and EoT. Time to deterioration (TTD) in EORTC QLQ-C30 and ECOG PS scores was estimated using the Kaplan-Meier methodology. RESULTS: Overall, 245 patients in the NALIRIFOX arm (ITT population, n = 383) and 232 patients in the Gem + NabP arm (n = 387) provided baseline and at least one subsequent EORTC QLQ-C30 assessment. There was an initial decline in global health status (GHS) from baseline to week 12 across both treatment arms [least-squares mean -2.4, 95% confidence interval (CI) -5.9 to 1.1; Gem + NabP: -0.7 (-4.2 to 2.9)], with no further deterioration from week 16 onwards. TTD in GHS (hazard ratio 0.74, 95% CI 0.53-1.04, nominal P = 0.08) and ECOG PS score (hazard ratio 0.72, 95% CI 0.55-0.92, nominal P = 0.009) was longer with NALIRIFOX than with Gem + NabP. CONCLUSIONS: These data suggest that 1L NALIRIFOX provides efficacy benefits for patients with mPDAC without compromising HRQoL or PS compared with Gem + NabP.