The exposure-response relationship of niraparib in patients with gBRCAmut and non-gBRCAmut: Results from the ENGOT-OV16/NOVA Trial

Abstract

Background: Niraparib (ZEJULA™) is a selective PARP1/2 inhibitor approved for maintenance treatment of adults with recurrent ovarian cancer who are in a complete or partial response to platinum-based chemotherapy. In preclinical studies, niraparib concentrates in the tumor versus plasma, delivering ≥90% durable PARP1/2 inhibition and a persistent antitumor effect. We report the relationship between exposure and response of niraparib in patients (pts) enrolled in the ENGOT-OV16/NOVA trial. Methods: Preliminary modeling for niraparib was performed using Phase 1 study data (N=104) to identify the initial parameters for the pharmacokinetic model, which was developed using combined Phase 1 and Phase 3 data (N=512 pts) and the first-order conditional estimation with interaction method within NONMEM. Exposure-efficacy relationships were evaluated in the gBRCAmut and non-gBRCAmut cohorts separately; the efficacy was compared in pts with high exposure (> median exposure) vs low exposure (≤ median exposure). Maximum plasma concentration (Cmax) and area under the curve over the dosing interval (AUCtau) at steady state (SS) were the exposure metrics. Progression-free survival (PFS) was used as efficacy endpoint. Hazard ratios (HRs) and 95% confidence intervals (CI) for the low and high niraparib exposure groups in each cohort were provided, with exposure group as the independent variable and PFS as the dependent variable. Exposure and safety data of gBRCAmut and non-gBRCAmut cohorts were combined to evaluate exposure-safety relationships using logistic regression. Results: In the gBRCAmut cohort, the HR was 0.91 (95% CI, 0.54-1.52) for niraparib exposure as measured by the SS AUCtau for pts in the high exposure vs. the low exposure group. In the gBRCAmut cohort, the HR was 0.70 (95% CI, 0.49-0.99). Logistic regression analysis did not show any significant relationship between the incidence of thrombocytopenia or anemia Grade ≥ 3 and the SS Cmax or AUC increase. Conclusions: Observed exposure-response relationships support the selection of 300 mg as the starting dose in both gBRCAmut and non-gBRCAmut pt populations. A trend towards increased efficacy associated with increased exposure was observed in the non-gBRCAmut cohort.