A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models

// Kaiming Sun 1 , Keith Mikule 1 , Zebin Wang 1 , Grace Poon 1 , Aparajitha Vaidyanathan 2 , Gillian Smith 2 , Zhi-Yi Zhang 1 , Jeffrey Hanke 1 , Sridhar Ramaswamy 1 and Jing Wang 1 1 TESARO Inc, Waltham, MA, USA 2 Division of Cellular Medicine, School of Medicine, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, Dundee, UK Correspondence to: Jing Wang, email: jwang2@tesarobio.com Keywords: niraparib; tumor exposure; brain exposure; BRCA wt tumor; intracranial tumor Received: September 05, 2018     Accepted: October 28, 2018     Published: December 14, 2018 ABSTRACT Niraparib is an orally bioavailable and selective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of both BRCA mutant (mut) and BRCA wildtype (wt) adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers who have demonstrated a complete or partial response to platinum-based chemotherapy. In patients without germline BRCA mutations (non-g BRCA mut), niraparib improved progression-free survival (PFS) by 5.4 months, whereas another PARP inhibitor (PARPi) olaparib supplied only 1.9 months of improvement in a similar patient population. Previous studies revealed higher cell membrane permeability and volume of distribution (V D ) as unique features of niraparib in comparison to other PARPi including olaparib. Here, we explore the potential correlation of these pharmacokinetic properties to preclinical antitumor effects in BRCA wt tumors. Our results show that at steady state, tumor exposure to niraparib is 3.3 times greater than plasma exposure in tumor xenograft mouse models. In comparison, the tumor exposure to olaparib is less than observed in plasma. In addition, niraparib crosses the blood-brain barrier and shows good sustainability in the brain, whereas sustained brain exposure to olaparib is not observed in the same models. Consistent with its favorable tumor and brain distribution, niraparib achieves more potent tumor growth inhibition than olaparib in BRCA wt models and an intracranial tumor model at maximum tolerated doses (MTD). These findings demonstrate favorable pharmacokinetic profiles and potent antitumor effects of niraparib in BRCA wt tumors, consistent with its broader clinical effect in patients with both BRCA mut and BRCA wt tumors.