Background: Defects in DNA damage response genes, including BRCA1/2 and ATM, confer sensitivity to PARP inhibitors. Talazoparib is a potent, oral PARP inhibitor with a dual mechanism of action (PARP enzyme inhibition and PARP trapping). Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody with a wild-type Fc region that has shown clinical activity in multiple tumor types. Preclinical and early clinical data suggest that combining a PARP inhibitor with an immune checkpoint inhibitor may provide improved activity. Methods: JAVELIN BRCA/ATM (NCT03565991) is an ongoing, open-label, multicenter, phase 2 trial assessing the combination of avelumab and talazoparib. Enrollment of ≈200 patients with a histologically confirmed locally advanced or metastatic solid tumor that has progressed on > 1 line of standard-of-care treatment for locally advanced or metastatic disease and has a germline or somatic defect in BRCA1 or 2 (cohort 1) or ATM (cohort 2) genes is planned. Patients with concomitant defects in > 1 gene (BRCA1, BRCA2, or ATM) will be enrolled in cohort 1. Exclusion criteria include prior treatment with an immune checkpoint or PARP inhibitor, prior treatment with any other anticancer or radiation therapy within 2 weeks prior to enrollment, a known history of an immune-mediated or autoimmune condition, and known symptomatic brain metastases requiring steroids. The primary endpoint is confirmed objective response by blinded independent central review according to RECIST v1.1 and according to the Prostate Cancer Working Group 3 (PCWG3) for patients with metastatic castration-resistant prostate cancer (mCRPC). Secondary endpoints include safety; investigator-assessed confirmed objective response, time to tumor response, duration of response, and progression-free survival (per RECIST v1.1 and per PCWG3 for patients with mCRPC); overall survival; pharmacokinetic parameters; and potential predictive biomarkers. The study is currently enrolling patients at centers in the United States and Europe. Clinical trial information: NCT03565991