Abstract 4353: Preclinical evaluation of the PARP inhibitor niraparib and cytotoxic chemotherapy alone or in combination in a panel of 25 triple-negative breast cancer PDX models: Relevance of BRCA mutations, HRD status and other biomarkers
Authors: Deas Olivier , Cairo Stefano , Wilcoxen Keith , Mikule Keith , Tran Truong-An , Timms Kirsten , Judde Jean-Gabriel 
Published: July 2016

Poly-ADP-ribose polymerase 1 (PARP) inhibitors are therapeutically effective in a subset of breast and high-grade ovarian cancers harboring deleterious BRCA1/2 mutations. Recently, several studies have tried to identify other molecular markers of HRD in BRCA1/2 wild-type (wt) breast and ovarian cancers to identify patients that could benefit from PARP inhibitor treatment. Most clinical studies of single-agent PARP inhibitors are therefore focused on breast or ovarian cancer with BRCA1/2 mutations and/or identified as HRD. Preclinical evidence also indicates that PARP inhibitors have therapeutic potential in combination with genotoxic chemotherapy. However, the toxicity associated with such combinations has generally imposed dose reduction of the chemotherapy, possibly explaining why the clinical activity observed with the combinations has in general not been superior to that of the corresponding single agents given at full dose.

In a panel of 25 triple negative breast cancer (TNBC) PDX models, we investigated the antitumor efficacy of the PARP inhibitor niraparib used alone or in combination with cyclophosphamide, a backbone genotoxic drug of TNBC standard chemotherapy. Responses were correlated with both BRCA1/2 mutations and HRD status as defined by the myChoice HRD™ test from Myriad Genetics and with other HRD markers.

Responses to cyclophosphamide ranged from progression to partial or complete tumor regression. Responses to niraparib were also variable and occurred only in tumors with BRCA mutations or a high HRD score. High sensitivities to niraparib and cyclophosphamide were tightly associated, suggesting that they may both be a result of a defect in a BRCA1/2-related pathway. We tested if niraparib could potentiate the efficacy of cyclophosphamide in TNBC models that initially regressed on cyclophosphamide but eventually relapsed. We chose a gapped sequential design in which treatment with niraparib was initiated 14 days after a full dose of cyclophosphamide, to avoid toxicity associated with concomitant administration. Potentiation with inhibition of tumor relapse was observed in tumors sensitive to single-agent niraparib, but not in tumors refractory to single-agent niraparib. In responder tumors, the cyclophosphamide-niraparib sequential combination was superior to sequential cycles of cyclophosphamide in preventing tumor relapse.

These results show that a gapped sequential combination of full dose cyclophosphamide and niraparib is well tolerated and demonstrates remarkable efficacy in a subset of TNBCs. The data will be discussed with regard to potential adjuvant treatment strategies with PARP inhibitors in TNBC and the value of myChoice HRD™ as a biomarker in predicting response to PARP inhibition alone and in combination with chemotherapy.

Citation Format: Olivier Deas, Stefano Cairo, Keith Wilcoxen, Keith Mikule, Truong-An Tran, Kirsten Timms, Jean-Gabriel Judde. Preclinical evaluation of the PARP inhibitor niraparib and cytotoxic chemotherapy alone or in combination in a panel of 25 triple-negative breast cancer PDX models: Relevance of BRCA mutations, HRD status and other biomarkers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4353.