Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for mPDAC following progression with gemcitabine-based therapy. A phase 1/2 study (Wainberg et al. Eur J Cancer 2021;151:14–24; NCT02551991) demonstrated promising anti-tumor activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m² + 5-FU 2400 mg/m² + LV 400 mg/m² + oxaliplatin 60 mg/m² (NALIRIFOX). Herein, we present results from NAPOLI-3 (NCT04083235), a randomized, open-label, phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel + gemcitabine as first-line therapy in patients with mPDAC. Methods: Eligible patients with histopathologically/cytologically confirmed untreated metastatic PDAC were randomized (1:1) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m² + gemcitabine 1000 mg/m² (Gem+NabP) on days 1, 8 and 15 of a 28-day cycle. Randomization was stratified by ECOG performance status, geographic region and presence or absence of liver metastases. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. OS was evaluated when ≥ 543 events were observed using a stratified log-rank test with an overall 1-sided significance level of 0.025. Results: Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Baseline characteristics were well balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. The median OS was 11.1 months in the NALIFIROX arm as compared with 9.2 months in the Gem+NabP arm (HR 0.84 [95% CI 0.71–0.99]; p = 0.04); PFS was also significantly improved (7.4 months vs 5.6 months; HR 0.70 [0.59–0.84]; p = 0.0001). Grade 3/4 treatment-emergent adverse events (TEAEs) with ≥ 10% frequency in patients receiving NALIRIFOX versus Gem+NabP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%). Conclusions: First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in treatment-naïve patients with mPDAC. The safety profile of NALIRIFOX was manageable and consistent with the profiles of the treatment components. Funding: Funded by Ipsen. Clinical trial information: NCT04083235.