Abstract 2134: Niraparib combined with abiraterone acetate inhibits the growth of BRCA2wtprostate tumors

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Patients with metastatic prostate cancer may initially respond well to first- and second-generation androgen receptor (AR)-targeted therapies, but many will experience disease progression, indicating a need for alternative therapies. A subset of these patients bears prostate tumors that harbor deleterious mutations in DNA damage repair (DDR) pathway genes, such as BRCA2. These DDR mutations render the tumors sensitive to drugs that inhibit poly (ADP-ribose) [PAR] polymerase-1 (PARP1), inducing synthetic lethality. Studies indicate that there are interactions between AR signaling pathways and DDR pathways in prostate cancer cells, supporting the hypothesis that dual AR/PARP inhibition could inhibit prostate tumor growth more potently than single agents, regardless of the DDR status of the tumor. This hypothesis was tested using well-known human and mouse prostate tumor models that are sensitive to androgen deprivation. Genotyping of the models confirmed that none of them carried homozygous pathogenic mutations in DDR genes, including BRCA1, BRCA2, and ATM. When the cell lines were incubated in vitro with niraparib, a potent and highly selective PARP1/2 inhibitor, PAR formation was significantly inhibited, and there was induction of γH2AX in treated cells, indicating the drug induced DNA double-stranded breaks. In addition, the cytotoxicity IC50 values for niraparib were in the range of 1-10 µM, as expected for cells that are DDRwt. In vivo efficacy studies demonstrated that the VCaP and Myc-CaP tumor models were insensitive or modestly sensitive to single agent treatment with niraparib or abiraterone acetate (AA). In contrast, the combination treatment of niraparib plus AA significantly reduced tumor growth and increased survival (p<0.05) as compared with control or single agent arms. Studies are ongoing to understand the mechanisms of tumor growth control mediated by the combination of these two agents. The results support the hypothesis that prostate tumors may respond to a combination treatment with niraparib, a PARP inhibitor, and AA, an androgen synthesis inhibitor, even in the absence of DDR anomalies. A Phase 3 study is planned to evaluate this hypothesis and the safety and efficacy of this combination in humans.Citation Format: Rajendra N. Damle, Rebecca Hawkins, Jennifer Hosbach, Georges Habineza Ndikuyeze, Jenny Driscoll, Natalie L. Fulton, David Derosa, Anna Hughes, Gerald Chu, Karl Calara-Nielsen, Denis Smirnov, Dong Shen, Linda A. Snyder. Niraparib combined with abiraterone acetate inhibits the growth of BRCA2wt prostate tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2134.

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