Abstract 2742: The PARP inhibitor niraparib demonstrates robust activity in a subset of patient-derived triple-negative breast cancer xenograft models

Abstract

Abstract Triple negative breast cancer (TNBC), which comprises 15% of all breast cancers, has a poor prognosis and currently lacks effective treatment. TNBCs are highly proliferative, genomically unstable and share molecular characteristics with BRCA1-/- breast cancer. Poly(ADP-ribose) polymerase-1 (PARP) is a key DNA repair enzyme that mediates single strand break (SSB) repair through the base excision repair (BER) pathway. PARP inhibitors have been demonstrated to selectively kill tumor cells that harbor BRCA1 and BRCA2 mutations. In addition, pre-clinical and preliminary clinical data suggest that PARP inhibitors are selectively cytotoxic for tumors with homologous recombination repair deficiency caused by mutations in genes other than BRCA1 or BRCA2. Niraparib is a potent, orally active PARP inhibitor that is being evaluated in Phase 3 clinical studies for ovarian cancer and BRCA related breast cancer. In exploring additional tumor indications that may be sensitive to niraparib, we investigated niraparib monotherapy activity in a panel of 17 basal breast cancer (BBC) patient-derived xenograft (PDX) models. Thirteen of the seventeen BBC models are TNBC models. Niraparib was administered po at a dose of 50 mg/kg once per day for 28 consecutive days, and tumor volume and body weight were measured twice weekly. Niraparib was well tolerated in nude mice bearing human TNBC PDXs growing subcutaneously, as there was no indication of body weight loss or decreased body weight gain relative to the vehicle control. Niraparib exhibited robust efficacy in five of the seventeen models tested. All five responsive models were TNBC. To understand the selectivity observed, a comprehensive analysis of the tumors was conducted which included analysis of gene mutation, gene copy number, gene expression and miRNA expression. A number of individual biomarkers and gene expression signatures were identified consistent with niraparib sensitivity across the 17 PDX models and will be discussed. In conclusion, in vivo activity of niraparib in TNBC was demonstrated in a panel of breast cancer PDX models, and several potential markers of niraparib sensitivity have been identified. Collectively this data supports the clinical investigation of niraparib in a subset of TNBC patients. Citation Format: Yan Wang, Stefano Cairo, Delphine Nicolle, Razvan Cristescu, Andrey Loboda, Michael Nebozhyn, Theresa Zhang, Jean-Gabriel Judde, Keith Wilcoxen. The PARP inhibitor niraparib demonstrates robust activity in a subset of patient-derived triple-negative breast cancer xenograft models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2742. doi:10.1158/1538-7445.AM2014-2742