Abstract
Abstract Introduction The incidence of brain metastases among breast and ovarian cancer patients with germline BRCA mutations (gBRCAmut) is significantly higher than those with gBRCA wild-type tumors (gBRCAwt), and has been estimated to be greater than 50%. gBRCAmut patients with brain metastases have a worse prognosis, and limited therapeutic options. The potential of two poly-ADP-ribose polymerase 1 inhibitors, niraparib and olaparib, were evaluated for their ability to target a gBRCAmut intracranial xenograft tumor model. Methods Pharmacokinetic (pk) studies were conducted in rat to determine the brain and plasma levels of niraparib following a single oral dose of 10 or 30 mg/kg. The BRCA2-mutant Capan-1 human pancreatic cancer xenograft model was utilized to evaluate efficacy. Briefly, randomized cohorts of Balb/c nude mice bearing either subcutaneous Capan-1 tumors, or intracranial Capan-1-luc tumors were dosed orally for up to 50 days with Niraparib (15, 30, or 45 mg/kg qd) or Olaparib (75 mg/kg qd). Tumor growth was monitored by either weekly physical measurement or quantification of bioluminescent signal in subcutaneous and intracranial models, respectively. Results Concentration-time profiles of niraparib in the brain were similar to those observed in the plasma after oral gavage dosing in rats, with an increase in Tmax observed for brain concentrations. Mean brain-to-plasma concentration ratios for niraparib following a single oral dose to rats were 0.85-0.99 of the brain Tmax. After a single oral dose, brain Ctrough levels (24hrs) were 2-4 times greater than observed in plasma, indicating niraparib is able to penetrate the brain in rodents. To evaluate activity in the brain response to niraparib was determined in a single xenograft model implanted either subcutaneously or intracranially. In the subcutaneous model, niraparib at 15, 30, or 45 mg/kg produced antitumor activity with tumor growth inhibition (TGI) values of 13, 49, or 54%, respectively (p < 0.001 for 30 and 45 mg dose vs. vehicle control). In contrast, treatment with olaparib at 75 mg/kg exhibited minor tumor activity with a TGI value of 26% (P = 0.177). In the intracranial model, niraparib at three dose levels of 15, 30, and 45 mg/kg (p.o., qd × 5 weeks) inhibited tumor growth with TGI values of 55%, 56% and 83%, respectively. In contrast, a 75 mg/kg dose of olaparib (p.o., qd x 5 weeks) produced moderate antitumor activity with a TGI value of 49%. Conclusions These data indicate that niraparib has sufficient exposure in rodent brains to have therapeutic benefit in an intracranial BRCA-mutant human xenograft model shown to be moderately sensitive to PARP inhibition. These results support the clinical investigation of niraparib against BRCAmut tumors that have metastasized to the brain. Citation Format: Keith Mikule, Keith Wilcoxen. The PARP inhibitor, niraparib, crosses the blood brain barrier in rodents and is efficacious in a BRCA2-mutant intracranial tumor model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B168.