Abstract A102: A comparative pharmacokinetic-pharmacodynamic-treatment study of PARP inhibitors demonstrates favorable properties for niraparib activity in preclinical tumor models

Abstract

Abstract Introduction: Niraparib is an orally bioavailable and selective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. This study examined the pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of niraparib as compared to two other approved PARP inhibitors, olaparib and rucaparib, in several ovarian cancer and triple-negative breast cancer xenograft models. Experimental Procedures: Niraparib, olaparib, and rucaparib were administered orally to mice at near maximum tolerated dose (MTD) for each drug in the BRCA1 deficient MDA-MB-436 cell line-derived triple-negative breast cancer model, BRCA wildtype A2780 cell line-derived ovarian cancer model, and two BRCA wildtype patient-derived ovarian cancer xenograft models. Tumor growth was monitored twice per week post randomization for the efficacy studies. Tumor growth inhibition was calculated after prolonged treatment at the end of study for each model. For PK and PD analysis, plasma, tumor, and brain tissue samples were collected at 7 different time points on the 5th day of continuous treatment. Results: Niraparib demonstrated potent antitumor activities in both the BRCA deficient and BRCA wildtype models tested. Among the 3 clinically approved PARP inhibitors, niraparib consistently demonstrated a high level of antitumor activity at a relatively lower dose. Niraparib showed high tumor exposure (AUC0-24h: 213,959 ng/g•hr) and high brain exposure (AUC0-24h: 18,721 ng/g•hr) as compared to rucaparib (tumor AUC0-24h: 74,338 ng/g•hr; brain AUC0-24h: 4,380 ng/g•hr) and olaparib (tumor AUC0-24h: 7,586 ng/g•hr; brain AUC0-24h: 336 ng/g•hr) in MDA-MB-436 xenograft model at steady state. A unique feature of niraparib was that its exposure in tumor was more than 3 times higher than that in plasma, which is consistent with its high volume of distribution in the animal models and the clinical setting. Pharmacodynamic analysis indicated that niraparib is able to deliver ~90% PARP inhibition for 24 hours at steady state. Conclusions: Niraparib treatment induces potent antitumor activities in multiple ovarian and breast cancer models regardless of BRCA status. The potent antitumor activity induced by niraparib is consistent with its high exposure and durable PARP inhibition in tumor. Our nonclinical findings suggest that niraparib exhibits unique pharmacologic properties within the PARP class of inhibitors. Citation Format: Kaiming Sun, Grace Poon, Sarah Wang, Paul Vancutsem, Sridhar Ramaswamy, Jeffrey Hanke, Jing Yu Wang. A comparative pharmacokinetic-pharmacodynamic-treatment study of PARP inhibitors demonstrates favorable properties for niraparib activity in preclinical tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A102.