First-line treatment for metastatic pancreatic ductal adenocarcinoma (PDAC) includes nab-paclitaxel/gemcitabine. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumor activity through tumor microenvironment modulation. The safety and efficacy of first-line ibrutinib plus nab-paclitaxel/gemcitabine treatment in patients with PDAC was evaluated.RESOLVE (NCT02436668) was a phase 3, randomized, double-blind, placebo-controlled study. Patients (histologically-confirmed PDAC; stage IV diagnosis ≥6 weeks of randomization; Karnofsky performance score ≥70) were randomized to once-daily oral ibrutinib (560 mg) or placebo plus nab-paclitaxel (125 mg/m2) and gemcitabine (1,000 mg/m2). Primary endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS); overall response rate (ORR) and safety were assessed.In total, 424 patients were randomized (ibrutinib arm, n=211; placebo arm, n=213). Baseline characteristics were balanced across arms. After median follow-up of 25 months, there was no significant difference in OS between ibrutinib plus nab-paclitaxel/gemcitabine vs placebo plus nab-paclitaxel/gemcitabine (median of 9.7 vs 10.8 months; P=0.3225). PFS was shorter for ibrutinib plus nab-paclitaxel/gemcitabine compared with placebo plus nab-paclitaxel/gemcitabine (median 5.3 vs 6.0 months; P<0.0001). ORRs were 29% and 42%, respectively (P=0.0058). Patients in the ibrutinib arm had less time on treatment and received lower cumulative dose for all agents compared to placebo arm. Most common grade ≥3 adverse events (AEs) for ibrutinib vs placebo arms included neutropenia (24% vs 35%), peripheral sensory neuropathy (17% vs 8%), and anemia (16% vs 17%). Primary reasons for any treatment discontinuation were disease progression and AEs.Ibrutinib plus nab-paclitaxel/gemcitabine did not improve OS or PFS for patients with PDAC. Safety was consistent with known profiles for these agents.