Effect of niraparib on cardiac repolarization in patients with platinum-sensitive, recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer
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Anticancer drugs may cause cardiovascular toxicities, including QT interval prolongation. Niraparib, a potent and selective once-daily oral poly (ADP-ribose) polymerase inhibitor, is approved as a maintenance therapy in platinum-sensitive recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC). Here, we present the effects of niraparib on cardiac repolarization, and the correlation between changes in baseline QT interval corrected by Fridericia’s formula (ΔQTcF) and niraparib plasma concentrations.
Patients with EOC from the NOVA study (subset of n = 15), the food effect NOVA substudy (n = 17), and a QTc substudy (n = 26) underwent intensive electrocardiographic (ECG) monitoring that included triplicate ECG testing on Day 1 at baseline (predose) and at 1, 1.5, 2, 3, 4, 6, and 8 h postdose concurrent with time-matched blood sampling for determination of niraparib plasma concentrations. All patients received once-daily 300-mg niraparib until disease progression or toxicity.
Across the 3 substudies, the upper limit of the two-sided 90% confidence interval (CI) of ΔQTcF was ≤ 10 ms at every postdose timepoint, with a maximum upper limit of 4.3 ms, which indicates no clinically meaningful effect on QTc prolongation. No statistically significant relationship between ΔQTcF and niraparib plasma concentration was observed (estimated slope: 0.0049; 95% CI: − 0.0020, 0.0117; P = 0.164). There were no clinically relevant changes in other ECG parameters that could be attributable to niraparib.
Niraparib administration at the recommended daily dose of 300 mg for EOC is not associated with clinically relevant alteration of ECGs, including QTc prolongation.
KeywordsNiraparib PARP inhibitor Cardiac repolarization QTc interval Ovarian cancer
The authors would like to thank Dr. Shefali Agarwal for her contributions to this study and Dr. Ilker Yalcin and Dr. Martin. H. Huber for data review and input. The authors also thank ERT (St. Louis, MO; formerly Biomedical Systems), Agilux Laboratories (Worcester, MA), and Veristat, LLC (Southborough, MA) for data reporting, data analysis, and generation of the substudy report. Medical writing and copyediting support, funded by TESARO, Inc. and coordinated by Hemant Vyas, PhD, of TESARO, Inc, was provided by Swati Ghatpande, PhD, and Ann Marcos, MA, ELS, of Team 9 Science, LLC (Vaniam Group LLC).
This study was sponsored by TESARO, Inc.
Compliance with ethical standards
Conflict of interest
K.M. has served on the advisory borads of and received honoraria from AstraZeneca, Advaxis, Clovis, Genentech/Roche, Immunogen, VBL Therapeutics, Janssen, Tesaro, Merck, Aravive, and OncoMed; K.M. also serves as the USA PI for the Tesaro-sponsored FIRST study using niraparib in front-line ovarian cancer and serves as the national PI for the niraparib study QUADRA. J.K.C. has received honoraria for a consulting role from Tesaro, Acerta, Aravive, Biodesix, Clovis, Janssen/Johnson & Johnson, Oxigen/Mateon, Roche/Genentech, and AstraZeneca, has received honoraria for lectures including speakers’ bureaus from AstraZeneca, Clovis, Merck, Roche/Genentech, and Tesaro. A.S.S. has received grants from AbbVie, Amgen, Astellas Pharma Inc., Astex Pharmaceuticals Inc., AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Endocyte, Exelixis, Incyte, Merck, PharmaMar, Prima Biomed, Roche/Genentech, TapImmune, and honoraria for advisory boards from Tesaro, Alexion, Aravive, Astex, AstraZeneca, Boehringer Ingelheim, Clovis, Janssen/Johnson & Johnson, Merck, Mersano, Myriad, Oncoquest, Precision Therapeutics, and Roche/Genentech. M.R.P. has nothing to disclose. T.C. is an employee of BioTel Research. W.G. and Z.Y.Z. employees of Tesaro, Inc and own stock/have other ownership with Tesaro. Medical writing and copyediting support, funded by TESARO, Inc. and coordinated by Hemant Vyas, PhD, of TESARO, Inc, was provided by Swati Ghatpande, PhD, and Ann Marcos, MA, ELS, of Team 9 Science, LLC (Vaniam Group LLC).
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