NAPOLI-3 began recruiting 770 patients with metastatic pancreatic ductal adenocarcinoma at the start of the COVID-19 pandemic. Until the disease progressed, there was unacceptable toxicity, or the patient withdrew from the study, the patients were randomly randomized to receive the combination of liposomal irinotecan with 5-fluorouracil/leucovorin and oxaliplatin (NALIRIFOX) or nab-paclitaxel plus gemcitabine therapy. OS served as the study’s primary endpoint, whereas progression-free survival (PFS) and the objective response rate (ORR) served as secondary objectives. The main goal of the study—prolonged overall survival—was achieved with NALIRIFOX. The survival curves split at around 3 months, and this divergence was maintained for the duration of the investigation. NALIRIFOX also increased the median PFS. Moreover, NALIRIFOX therapy was preferred in all previously identified categories in terms of both OS and PFS. The ORR with NALIRIFOX was 41.8%, and the ORR with nab-paclitaxel/gemcitabine was 36.2%, virtually entirely made up of incomplete responses.