Background: The importance of the tumor microenvironment in the biology of mPC has been increasingly recognized. However, immune checkpoint blockade has previously shown limited clinical responses in mPC. Preclinical studies in PC indicate promising anti-tumor effect from acalabrutinib alone and in combination with pembrolizumab. Methods: This was a Phase 2, multicenter, open-label, randomized (1:1; n = 38/arm) study (NCT02362048) evaluating the Btk inhibitor, acalabrutinib (ACP-196) alone (mono) or in combination (combo) with pembrolizumab. This study included a safety run-in that assessed the first 6 patients (pts) enrolled in the combo arm for dose-limiting toxicity (DLT). Adults with histologically confirmed pancreatic ductal adenocarcinoma who had received ≥ 1 prior systemic therapy for mPC were eligible. Acalabrutinib 100 mg PO BID was administered days 1-21 and pembrolizumab 200 mg IV day 1 of each 3-week cycle. Response was assessed every 2 cycles using RECIST 1.1. Blood was collected for exploratory correlative analyses. Results: Preliminary results are provided for the first 58 treated pts (26 mono arm, 32 combo arm). The median number of prior treatments was 2. No DLTs occurred. Grade 3-4 events that occurred in ≥ 2 pts were dehydration (12%), anemia (12%) and hypotension (8%) on the mono arm and were anemia (9%) and abdominal pain (9%) on the combo arm. No Grade 5 treatment-related events were reported. 44 pts (21 mono arm, 23 combo arm) were evaluable for response. In the mono arm, 4 stable disease (SD) were reported. In the combo arm, 3 partial responses (2 PR, 1 PRu), including 1 pt with near resolution of bulky peritoneal disease, and 5 SD were reported. All 3 PRs occurred in pts with a strong family history of pancreatic or breast cancer. Germline testing identified BRCA2VUS in one responder. At the time of the data cut, the median time on study for pts with responses was 3.7 months (range 1.4-4.1). Conclusions: The combination of acalabrutinib and pembrolizumab has a favorable benefit/risk profile and encouraging preliminary antitumor activity in pretreated mPC, particularly in a subpopulation of pts with familial mPC. Clinical trial information: NCT02362048