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Effect of niraparib on cardiac repolarization in patients with platinum-sensitive, recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

Niraparib administration at the recommended daily dose of 300 mg for EOC is not associated with clinically relevant alteration of ECGs, including QTc prolongation.

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References

  1. Morales J, Li L, Fattah FJ, Dong Y, Bey EA, Patel M, Gao J, Boothman DA (2014) Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit Rev Eukaryot Gene Expr 24(1):15–28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD, Miranda S, Hylands L, Riisnaes R, Forster M, Omlin A, Kreischer N, Thway K, Gevensleben H, Sun L, Loughney J, Chatterjee M, Toniatti C, Carpenter CL, Iannone R, Kaye SB, de Bono JS, Wenham RM (2013) The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol 14(9):882–892. https://doi.org/10.1016/S1470-2045(13)70240-7

    Article  CAS  PubMed  Google Scholar 

  3. Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I, Ben-Baruch NE, Marth C, Madry R, Christensen RD, Berek JS, Dorum A, Tinker AV, du Bois A, Gonzalez-Martin A, Follana P, Benigno B, Rosenberg P, Gilbert L, Rimel BJ, Buscema J, Balser JP, Agarwal S, Matulonis UA, Investigators E-ON (2016) Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 375(22):2154–2164. https://doi.org/10.1056/NEJMoa1611310

    Article  CAS  PubMed  Google Scholar 

  4. Shinn EH, Lenihan DJ, Urbauer DL, Basen-Engquist KM, Valentine A, Palmero L, Woods ML, Patel P, Nick AM, Shahzad MM, Stone RL, Golden A, Atkinson E, Lutgendorf SK, Sood AK (2013) Impact of cardiovascular comorbidity on ovarian cancer mortality. Cancer Epidemiol Biomark Prev 22(11):2102–2109. https://doi.org/10.1158/1055-9965.EPI-13-0625

    Article  Google Scholar 

  5. Woopen H, Inci G, Richter R, Chekerov R, Ismaeel F, Sehouli J (2016) Elderly ovarian cancer patients: an individual participant data meta-analysis of the North-Eastern German Society of Gynecological Oncology (NOGGO). Eur J Cancer 60:101–106. https://doi.org/10.1016/j.ejca.2016.03.008

    Article  CAS  PubMed  Google Scholar 

  6. Accordino MK, Neugut AI, Hershman DL (2014) Cardiac effects of anticancer therapy in the elderly. J Clin Oncol 32(24):2654–2661. https://doi.org/10.1200/JCO.2013.55.0459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Duan J, Tao J, Zhai M, Li C, Zhou N, Lv J, Wang L, Lin L, Bai R (2018) Anticancer drugs-related QTc prolongation, torsade de pointes and sudden death: current evidence and future research perspectives. Oncotarget 9(39):25738–25749. https://doi.org/10.18632/oncotarget.25008

    Article  PubMed  PubMed Central  Google Scholar 

  8. Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM (2010) Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst 102(1):14–25. https://doi.org/10.1093/jnci/djp440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Coppola C, Rienzo A, Piscopo G, Barbieri A, Arra C, Maurea N (2018) Management of QT prolongation induced by anti-cancer drugs: target therapy and old agents. Different algorithms for different drugs. Cancer Treat Rev 63:135–143. https://doi.org/10.1016/j.ctrv.2017.11.009

    Article  CAS  PubMed  Google Scholar 

  10. ICH Harmonised Tripartite Guideline (2005) The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs E14. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Guideline.pdf. Accessed 6 Sept 2018

  11. Swaisland H, Plummer R, So K, Garnett S, Bannister W, Fabre MA, Dota C, Fielding A (2016) Olaparib does not cause clinically relevant QT/QTc interval prolongation in patients with advanced solid tumours: results from two phase I studies. Cancer Chemother Pharmacol 78(4):775–784. https://doi.org/10.1007/s00280-016-3124-5

    Article  CAS  PubMed  Google Scholar 

  12. Bednar MM, Harrigan EP, Anziano RJ, Camm AJ, Ruskin JN (2001) The QT interval. Prog Cardiovasc Dis 43(5 Suppl 1):1–45

    CAS  PubMed  Google Scholar 

  13. Strevel EL, Ing DJ, Siu LL (2007) Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol 25(22):3362–3371. https://doi.org/10.1200/JCO.2006.09.6925

    Article  CAS  PubMed  Google Scholar 

  14. Giorgi MA, Bolanos R, Gonzalez CD, Di Girolamo G (2010) QT interval prolongation: preclinical and clinical testing arrhythmogenesis in drugs and regulatory implications. Curr Drug Saf 5(1):54–57

    Article  PubMed  Google Scholar 

  15. US Food and Drug Adminstration: Application number 208447Orig1s000—NDA/BLA multi-disciplinary review and evaluation of niraparib. Reference ID: 4074987. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208447Orig1s000MultidisciplineR.pdf. Accessed 12 Sept 2018

  16. Zejula® (niraparib) prescribing information (2018) TESARO IW, MA. https://www.zejula.com/prescribing-information. Accessed 6 Sept 2018

  17. Prat J, Oncology FCoG (2015) Staging classification for cancer of the ovary, fallopian tube, and peritoneum: abridged republication of guidelines from the International Federation of Gynecology and Obstetrics (FIGO). Obstet Gynecol 126(1):171–174. https://doi.org/10.1097/AOG.0000000000000917

    Article  PubMed  Google Scholar 

  18. Moore K, Zhang ZY, Agarwal S, Burris H, Patel MR, Kansra V (2018) The effect of food on the pharmacokinetics of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, in patients with recurrent ovarian cancer. Cancer Chemother Pharmacol 81(3):497–503. https://doi.org/10.1007/s00280-017-3512-5

    Article  CAS  PubMed  Google Scholar 

  19. Fingert H, Varterasian M (2006) Safety biomarkers and the clinical development of oncology therapeutics: considerations for cardiovascular safety and risk management. AAPS J 8(1):E89–E94. https://doi.org/10.1208/aapsj080110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. van Andel L, Rosing H, Zhang Z, Hughes L, Kansra V, Sanghvi M, Tibben MM, Gebretensae A, Schellens JHM, Beijnen JH (2018) Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a (14)C-microtracer and therapeutic dose in cancer patients. Cancer Chemother Pharmacol 81(1):39–46. https://doi.org/10.1007/s00280-017-3455-x

    Article  CAS  PubMed  Google Scholar 

  21. Lynparza® (olaparib) prescribing information (2018) AstraZeneca Pharmaceuticals (Wilmington, DE). https://www.azpicentral.com/lynparza_tb/pi_lynparza_tb.pdf#page=1. Accessed 24 Oct 2018

  22. Rubraca® (rucaparib) prescribing information (2018) Clovis Oncology, Inc. (Boulder, CO). http://www.clovisoncology.com/media/1094/rubraca-prescribing-info.pdf. Accessed 6 Sept 2018

  23. European Medicines Agency: EMA/CHMP/238139/2018—Assessment report of the European Medicines Agency (2018) Procedure No. EMEA/H/C/004272/0000. https://www.ema.europa.eu/documents/assessment-report/rubraca-epar-public-assessment-report_en.pdf. Accessed 6 Sept 2018

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Acknowledgements

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).

Funding

This study was sponsored by TESARO, Inc.

Author information

Authors and Affiliations

  1. Stephenson Cancer Center, University of Oklahoma HSC, 800 NE 10th St #2500, Oklahoma City, OK, 73104, USA

    Kathleen Moore

  2. Sarah Cannon Research Institute, Nashville, TN, USA

    Kathleen Moore & Manish R. Patel

  3. Palo Alto Medical Foundation, California Pacific Medical Center, Sutter Health Sutter West Bay, San Francisco, CA, USA

    John K. Chan

  4. Duke Cancer Institute, Durham, NC, USA

    Angeles Alvarez Secord

  5. Florida Cancer Specialists and Research Institute, Sarasota, FL, USA

    Manish R. Patel

  6. BioTel Research, Rockville, MD, USA

    Timothy Callahan

  7. TESARO, Inc, Waltham, MA, USA

    Wei Guo & Zhi-Yi Zhang

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  1. Kathleen Moore
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Corresponding author

Correspondence to Kathleen Moore.

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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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Appendix

Appendix

See Tables 3 and 4.

Table 3 Absolute mean QTcF and mean ΔQTcF at postdose time points in the NOVA main and QTc substudy
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Table 4 Absolute mean QTcF and mean ΔQTcF at postdose time points in the food effect study
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Moore, K., Chan, J.K., Secord, A.A. et al. Effect of niraparib on cardiac repolarization in patients with platinum-sensitive, recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer. Cancer Chemother Pharmacol 83, 717–726 (2019). https://doi.org/10.1007/s00280-019-03774-w

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