Background: Immune checkpoint blockade (ICB) antibodies have made a major impact in a wide range of cancers. However, only subsets of patients across all malignancies benefit from ICB. In particular, metastatic castrate-resistant prostate cancer (mCRPC) and advanced endometrial cancers (EC) have shown very limited responses to ICB. The central hypothesis of this trial is that the combination of PARP inhibitor (rucaparib) with PD-1 inhibitor (nivolumab) will enhance ICB efficacy in mCRPC and mEC patients. Given that PTEN loss has also been associated with poor response to ICB, a secondary hypothesis of this study is that the combination therapy will have differing efficacy based on the PTEN mutation status of the tumor. Methods: This is an investigator-initiated Phase 1b/IIa clinical trial of rucaparib and nivolumab singly and in combination, in mCRPC and mEC patients. Patients are randomized to one of three arms – rucaparib, nivolumab, or both drugs in combination for 4 weeks. Metastatic biopsy samples are collected at baseline and after 4 weeks on treatment, after which all arms will switch to combination therapy. The primary objective is to assess feasibility of the combination, and to elucidate changes in immune infiltrates by Nanostring RNA sequencing, multiplex immunofluorescence, 3D mapping, IHC, and flow cytometry. Secondary objectives are to assess clinical response, and correlate changes in TME with PTEN status. We have currently enrolled 4 patients to the study, and collected pre- and 4 week on-treatment biopsies. This study presents an opportunity for in-depth TME analysis that will enable the delineation of the effects of PARP inhibition singly and in combination with PD-1 blockade, on immune subsets within the TME. The correlative analyses will also lead to the discovery of novel biomarkers of response/resistance, and suggest additional immunooncology combinations for specific molecular subsets of prostate and endometrial cancers. Clinical trial information: NCT03572478