Background: Approximately 20% of breast cancers (BC) express the human epidermal growth factor receptor 2 (HER2). Although HER2-directed therapies result in improved patient outcome, resistance ultimately occurs. Poly (ADP-Ribose) polymerase (PARP) inhibitors are currently indicated in cancers that express germline mutations in the DNA repair proteins BRCA1/2 due to their synthetic lethality against the homologous recombination repair (HR) pathway. In addition to its role in DNA damage repair, PARP1 has also been implicated in other cellular functions, including co-activation of genes such as NF-κB, which regulate tumor proliferation and HER2 drug resistance. Our group identified that HER2+ BC overexpress the PARP1 and phospho-p65 protein. In HER2+ BC cells and animal models, PARP inhibitors initiated apoptosis independent of a DNA repair deficiency, via inhibition of NF-kB signaling. Key proteins (p65, IKK-α) of the NF-κB-mediated growth pathways were reduced and IκBα was increased in the presence of PARPi, implicating another oncologic pathway in which HER2+ BC cells may be dependent. Methods: The study is a phase 1b/2, multicenter, single arm clinical trial evaluating the safety and efficacy of niraparib 200 mg orally days 1-21 with trastuzumab 6 mg/kg (cycle 1 loading dose of 8 mg/kg) intravenously on day 1 of a 21-day cycle for patients with unresectable or metastatic HER2+ BC. Eligible patients include metastatic HER2+ BC, progression on at least 1 prior HER2-targeted therapy, measurable disease, ECOG PS 0-1, and LVEF ≥ 50%. Stable/treated CNS disease allowed. Prior PARPi and known germline BRCA 1/2 excluded. Forty patients will be enrolled at 7 US sites within the Translational Breast Cancer Research Consortium. The primary objectives are determining the dose-limiting toxicity (DLT) of the combination and assessing the objective response rate. The phase 1b cohort has been completed (N=6). Enrollment in phase 2 began February 2021 with a total accrual goal of 40. Gehan’s two-stage design will be used assuming the response rate is at least 24% and the response rate will be estimated with Clopper-Pearson exact method. Correlative aims include assessing blood and tissue biomarkers (e.g. PARP1, p65, phosphor-p65, let-7a miRNA, NF-kB, ctDNA, etc.) for association with clinical benefit and to predict response to therapy. Clinical trial information: NCT03368729.