Background: The optimal first-line regimen in the treatment of mPDAC remains unknown. Recent data demonstrated superiority of 5-FU/liposomal irinotecan/oxaliplatin (NALIRIFOX) over gemcitabine/nab-paclitaxel. However, the question remains open if both irinotecan and oxaliplatin are required in first-line treatment and whether these agents can be given sequentially. Methods: Eligible patients with histologically confirmed diagnosis of mPDAC were randomized 1:1:1 to receive in Arm A standard treatment (gemcitabine 1000 mg/m² + nab-paclitaxel 125 mg/m²) or investigational therapy applying in Arm B the NAPOLI regimen (liposomal irinotecan 80 mg/m² + folinic acid 400 mg/m² + 5-FU 2400 mg/m²) or in Arm C a sequence of NAPOLI and mFOLFOX6 (oxaliplatin 85mg/m² + folinic acid 400mg/m² + 5-FU 2400 mg/m²). Overall, 274 patients were enrolled at 48 sites in Germany. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate, disease control rate, duration of study treatment and safety. Results: In the full analysis set (n=265), neither treatment with NAPOLI (3.1 months, HR 1.224, p= 0.2123) nor the sequence of NAPOLI and mFOLFOX6 (6.0 months, HR 0.864 p= 0.0720) lead to a statistically significant improvement of PFS over gemcitabine/nab-paclitaxel (4.3 months). Median duration of treatment was 3.5 months in Arm A, 2.0 months in Arm B and 3.7 months in Arm C, respectively. In a first analysis of overall survival, OS in Arm A was 8.7 months (95% CI, 7.1-11.9 months) versus 7.9 months in Arm B (95% CI, 6.6-12.3 months; HR 1.178, P= 0.348) and 11.0 months in Arm C (95% CI, 8.4-13.6 months; HR 0.879, P=0.154). Overall, safety was comparable with published data, with higher rates of neutropenia and peripheral neuropathy in Arm A, while diarrhea was more frequent in Arms B and C. Conclusions: The study did not show superiority of either NAPOLI or the sequence of NAPOLI/mFOLFOX6 over standard therapy with gemcitabine/nab-paclitaxel. In view of the published evidence, the present data supports the hypothesis that sequential NAPOLI/mFOLFOX6 may be equally effective with regard to OS, but less toxic, compared to mFOLFIRINOX. Clinical trial information: NCT03487016.