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4022 Background: Sequential treatment with nab-paclitaxel, gemcitabine followed by oxaliplatin, leucovorin and 5-fluorouracil ( nab-P/Gem-mFOLFOX) have shown a good safety profile and clinical activity in metastatic pancreatic ductal adenocarcinoma (mPDAC) in a previously published phase I SEQUENCE trial. Methods: We have compared nab-P/Gem-mFOLFOX to the standard nab-P/Gem in first-line treatment, in an open-label multi-institutional prospective randomised phase II trial in patients with untreated mPDAC from 14 Spanish hospitals. Patients were allocated 1:1 to nab-paclitaxel (125 mg/m2) plus gemcitabine (1000 mg/m2) on days 1, 8 and 15, followed by modified FOLFOX-6 (oxaliplatin [85 mg/m2], L-leucovorin [200 mg/m2] or racemic leucovorin [400 mg/m2], 5-fluorouracil bolus [400 mg/m2], and 5-fluorouracil 48-hour continuous infusion [2400 mg/m2]) on day 29 of a 6-week cycle or nab-paclitaxel (125 mg/m2) plus gemcitabine (1000 mg/m2) on days 1, 8 and 15 of a 4-week cycle. The primary endpoint was the 12-month overall survival rate (OS) in randomised patients. EudraCT number 2014-005350-19; ClinicalTrial.gov identifier NCT02504333. Results: Between July 27, 2017, and April 16, 2019, 182 patients were screened and 157 randomised: 78 to nab-P/Gem-mFOLFOX and 79 to nab-P/Gem. Patients receiving nab-P/Gem-mFOLFOX showed a significantly higher 12-month, and 24-month OS (95% CI): 55.3% (44.2-66.5%) versus 35.4% (24.9-46.0%) (p = 0.016), and 22.4% (13.0-31.8%) versus 7.6% (1.8-13.4%) (p = 0.012), respectively. The median OS (95% CI) reached 13.2 (10.1-16.2) months with nab-P/Gem-mFOLFOX and 9.7 (7.5-12.0) months with nab-P/Gem (HR = 0.676, 95% CI 0.483-0.947, p = 0.023). 39.7% patients in the nab-P/Gem-mFOLFOX group and 54.4% in nab-P/Gem group received subsequent anticancer treatments. Safety was comparable except for grade ≥3 neutropenia (46.1% versus 24.1%, p = 0.004) and grade ≥3 thrombocytopenia (23.7% versus 7.6%, p = 0.007) that were higher in the nab-P/Gem-mFOLFOX regimen. Two (2.6%) patients died due to adverse events in the nab-P/Gem-mFOLFOX arm. Conclusions: Nab-P/Gem-mFOLFOX showed significantly higher clinical activity than the standard nab-P/Gem treatment, with a manageable safety profile. This regimen represents a feasible and efficient new option for first-line treatment of mPDAC. Clinical trial information: NCT02504333.