Endometrial cancer is a major gynaecological cancer with a high incidence resulting in over 500 Australian women dying every year. Good pre-clinical models are urgently needed to study the biology of this disease, and to develop and test novel treatment strategies. Most current pre-clinical research is conducted in cell lines that often do not resemble the disease on the molecular level and do not recapitulate tumour heterogeneity, which results in untranslatable research findings. Patient-derived xenograft (PDX) models overcome the issues of representing tumour molecular landscape and heterogeneity, making them a translatable pre-clinical cancer model. Here, we generated and genomically characterised 11 PDX models by performing whole genome or whole exome sequencing of primary patient tumours and matched PDX samples. We performed a detailed genomic characterisation of these models to determine their suitability as pre-clinical models, study tumour heterogeneity and identify biomarkers of response and resistance. PDX models were successfully generated from all four molecular subtypes of EC and uterine carcinosarcomas, and they recapitulated morphology and the molecular landscape of primary tumors without major genomic drift. We also observed a wide range of inter-tumor and intra-tumor heterogeneity, well captured by different PDX lineages, which could lead to different treatment responses. An in vivo response to talazoparib was detected in two p53mut models consistent with stable disease, however both lacked the HR deficiency genomic signature. EC PDX models represent the four molecular subtypes of disease and can capture intra-tumoral heterogeneity of the original primary tumor. PDXs of the p53mut molecular subtype showed sensitivity to PARPi, however, deeper and more durable responses will likely require combination of PARPi with other agents. Citation Format: Olga Kondrashova, Vanessa F. Bonazzi, Deborah Smith, Katia Nones, Asmerom Sengal, Robert Ju, Leisl M. Packer, Lambros T Koufariotis, Stephen H. Kazakoff, Aimee L. Davidson, Priya Ramarao-Milne, Vanessa Lakis, Felicity Newell, Rebecca Rogers, Claire Davies, Naven Chetty, Lewis Perrin, John Pearson, Ann-Marie Patch, Andrea Garrett, Nicola Waddell, Pamela Pollock, James Nicklin. Genomic characterization of endometrial cancer patient-derived xenografts reveals intratumor heterogeneity [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PR007.