Abstract 2813: Efficacy and pharmacokinetics of niraparib in BRCA-mutant and wild-type intracranial triple negative breast cancer murine models

Introduction: Brain metastases arising from triple negative breast cancer (TNBC BM) are common and typically occur in the setting of progressive extracranial metastases. No targeted systemic therapy is approved to control both intra- and extracranial TNBC. Poly (ADP-ribose) polymerase (PARP) inhibition has emerged as a promising anti-cancer agent to treat BRCA-associated TNBC, as well as TNBC with homologous recombination deficiency (HRD). Niraparib is a brain permeable and selective PARP-1/-2 inhibitor that has shown activity across many solid tumor types, including TNBC. We sought to define the efficacy and intracranial exposure of niraparib in several BRCA-mutant (mut) and wild-type (WT) intracranial mouse models of TNBC. Experimental Procedures: Niraparib (50mg/kg by oral gavage daily) was tested in 2 BRCAmut (SUM149, MDA-MB-436) and one BRCA-WT (MDA-MB-231BR) intracranial models of TNBC. Efficacy was assessed by serial in vivo bioluminescence and overall survival (OS). Whole cell lysates of intracranial tumors were used to determine drug penetrance and PARP inhibition. Niraparib concentrations were measured after protein precipitation and HPLC with positive ion electrospray mass spectroscopy (Q1/Q3:321.09/304.10 Da). PARP inhibition was measured using a PAR ELISA (HT PARP in vivo Pharmacodynamic Assay II, #4520-096-K, Trevigen). Results: Treatment with niraparib compared with vehicle control resulted in improvement in OS in the MDA-MB-436 model (undefined at day 80 v. 50 days, p Conclusions: Niraparib illustrates intracranial exposure and target inhibition in several models of TNBC BM. Efficacy was variable across BRCAmut models, which could be explained by the known inherent resistance of the SUM149 cell line to PARP inhibition via RAD51 (Liu et al, CCR 2017). Thus, studies evaluating mechanisms of response and resistance of TNBC, beyond BRCA1 and RAD51, to niraparib are warranted. Citation Format: Maria Sambade, Amanda Van Swearingen, Kaiming Sun, Jing Wang, Kevin Mikule, Carey K. Anders. Efficacy and pharmacokinetics of niraparib in BRCA -mutant and wild-type intracranial triple negative breast cancer murine models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2813.