Abstract Pancreatic ductal adenocarcinoma (PDAC) is a disease with a poor prognosis characterized by a dense stromal fibroinflammatory reaction that is a significant obstacle to effective therapy. The desmoplastic stroma comprises many inflammatory cells, in particular mast cells that are a key component of the PDAC microenvironment and whose infiltration often correlates with poor patient outcome. Reducing the stroma is of key importance for improving the standard of care. We have previously successfully utilized ibrutinib, a clinically-approved Bruton's Tyrosine Kinase inhibitor, as a mast cell blocker in a mouse model of β cell tumorigenesis. Here, we made use of a transgenic mouse model of PDAC and patient derived xenografts (PDXs) to assess ibrutinib's impact on the tumor microenvironment and animal survival. Across these various experimental pre-clinical models, we show that ibrutinib significantly diminishes tissue fibrosis, increases survival and improves the outcome of standard care. Our results suggest that ibrutinib could be deployed to one more type of cancer and open the way to new clinical trials assessing its therapeutic impact in PDAC patients. Citation Format: Daniel Massó-Vallés, Toni Jauset, Erika Serrano, Nicole M. Sodir, Kim Pedersen, Nesrine I. Affara, Jonathan R. Whitfield, Marie-Eve Beaulieu, Gerard I. Evan, Laurence Elias, Joaquín Arribas, Laura Soucek. Ibrutinib exerts potent antifibrotic activity in a mouse model of pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 396. doi:10.1158/1538-7445.AM2015-396