Phase Ib study evaluating the effect of apalutamide, at therapeutic exposure, on ventricular repolarization by applying time-matched pharmacokinetics and electrocardiography (ECG) in patients with castration-resistant prostate cancer. Safety of daily apalutamide was also assessed.
Patients received 240 mg oral apalutamide daily. Time-matched ECGs were collected via continuous 12-lead Holter recording before apalutamide (Day − 1) and on Days 1 and 57 (Cycle 3 Day 1). Pharmacokinetics of apalutamide were assessed on Days 1 and 57 at matched time points of ECG collection. QT interval was corrected for heart rate using Fridericia correction (QTcF). The primary endpoint was the maximum mean change in QTcF (ΔQTcF) from baseline to Cycle 3 Day 1 (steady state). Secondary endpoints were the effect of apalutamide on other ECG parameters, pharmacokinetics of apalutamide and its active metabolite, relationship between plasma concentrations of apalutamide and QTcF, and safety.
Forty-five men were enrolled; 82% received treatment for ≥ 3 months. At steady state, the maximum ΔQTcF was 12.4 ms and the upper bound of its associated 90% CI was 16.0 ms. No clinically meaningful effects of apalutamide were reported for heart rate or other ECG parameters. A concentration-dependent increase in QTcF was observed for apalutamide. Most adverse events (AEs) (73%) were grade 1–2 in severity. No patients discontinued due to QTc prolongation or AEs.
The effect of apalutamide on QTc prolongation was modest and does not produce a clinically meaningful effect on ventricular repolarization. The AE profile was consistent with other studies of apalutamide.
Ferlay JSI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2012) GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. http://globocan.iarc.fr. Accessed 28 Feb 2018
ERLEADA [prescribing information] (2018). Available via Janssen website. http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/ERLEADA-pi.pdf. Accessed 2 July 2018
Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, Chen Y, Grillot K, Bischoff ED, Cai L, Aparicio A, Dorow S, Arora V, Shao G, Qian J, Zhao H, Yang G, Cao C, Sensintaffar J, Wasielewska T, Herbert MR, Bonnefous C, Darimont B, Scher HI, Smith-Jones P, Klang M, Smith ND, De Stanchina E, Wu N, Ouerfelli O, Rix PJ, Heyman RA, Jung ME, Sawyers CL, Hager JH (2012) ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res 72(6):1494–1503. https://doi.org/10.1158/0008-5472.CAN-11-3948CrossRefPubMedPubMedCentral
Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ, Investigators S (2018) Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 378(15):1408–1418. https://doi.org/10.1056/NEJMoa1715546CrossRefPubMed
Rathkopf DE, Morris MJ, Fox JJ, Danila DC, Slovin SF, Hager JH, Rix PJ, Chow Maneval E, Chen I, Gonen M, Fleisher M, Larson SM, Sawyers CL, Scher HI (2013) Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer. J Clin Oncol 31(28):3525–3530. https://doi.org/10.1200/JCO.2013.50.1684CrossRefPubMedPubMedCentral
Levine GN, D’Amico AV, Berger P, Clark PE, Eckel RH, Keating NL, Milani RV, Sagalowsky AI, Smith MR, Zakai N (2010) Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. CA Cancer J Clin 60(3):194–201. https://doi.org/10.3322/caac.20061CrossRefPubMedPubMedCentral
CASODEX [prescribing information] (2017). Available via AZ PI Central website. https://www.azpicentral.com/casodex/casodex.pdf. Accessed 2 July 2018
Garnick MB, Pratt CM, Campion M, Shipley J (2004) The effect of hormonal therapy for prostate cancer on the electrocardiographic QT interval: phase 3 results following treatment with leuprolide and goserelin, alone or with bicalutamide, and the GnRH antagonist abarelix. J Clin Oncol 22(14_suppl):4578. https://doi.org/10.1200/jco.2004.22.14_suppl.4578CrossRef
CASODEX summary of product characteristics (2018). Available via emc+ website. https://www.medicines.org.uk/emc/product/3805/smpc. Accessed 2 July 2018
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Flechon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS, Investigators A (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367(13):1187–1197. https://doi.org/10.1056/NEJMoa1207506CrossRefPubMed
Siemens DR, Klotz L, Heidenreich A, Chowdhury S, Villers A, Baron B, van Os S, Hasabou N, Wang F, Lin P, Shore ND (2018) Efficacy and safety of enzalutamide vs bicalutamide in younger and older patients with metastatic castration resistant prostate cancer in the TERRAIN trial. J Urol 199(1):147–154. https://doi.org/10.1016/j.juro.2017.08.080CrossRefPubMed
Camm AJ (2005) Clinical trial design to evaluate the effects of drugs on cardiac repolarization: current state of the art. Heart Rhythm 2(2 Suppl):S23–S29. https://doi.org/10.1016/j.hrthm.2004.09.019CrossRefPubMed
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) (2012) E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs—questions and answers (R1). October 2012 ICH. Available via the US Food and Drug Administration website. https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm323656.htm. Accessed 3 July 2018
Rathkopf DE, Antonarakis ES, Shore ND, Tutrone RF, Alumkal JJ, Ryan CJ, Saleh M, Hauke RJ, Bandekar R, Maneval EC, de Boer CJ, Yu MK, Scher HI (2017) Safety and Antitumor Activity of Apalutamide (ARN-509) in metastatic castration-resistant prostate cancer with and without prior abiraterone acetate and prednisone. Clin Cancer Res 23(14):3544–3551. https://doi.org/10.1158/1078-0432.CCR-16-2509CrossRefPubMedPubMedCentral
Smith MR, Antonarakis ES, Ryan CJ, Berry WR, Shore ND, Liu G, Alumkal JJ, Higano CS, Chow Maneval E, Bandekar R, de Boer CJ, Yu MK, Rathkopf DE (2016) Phase 2 study of the safety and antitumor activity of apalutamide (ARN-509), a potent androgen receptor antagonist, in the high-risk nonmetastatic castration-resistant prostate cancer cohort. Eur Urol 70(6):963–970. https://doi.org/10.1016/j.eururo.2016.04.023CrossRefPubMedPubMedCentral
- An open-label, multicenter, phase Ib study investigating the effect of apalutamide on ventricular repolarization in men with castration-resistant prostate cancer
Bodine P. S. I. Belderbos
Ronald de Wit
Margaret K. Yu
W. Jeffrey Edenfield
- Springer Berlin Heidelberg
Neu im Fachgebiet Onkologie
e.Med Kampagnen-Visual, Mail Icon II