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Pharmacokinetics, Safety, and Antitumor Effect of Apalutamide With Author Manuscript Published OnlineFirst on May 4, 2020; DOI: 10.1158/1078-0432.CCR-19-3402 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Pharmacokinetics, Safety, and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer: Phase 1b Study Edwin M. Posadas,1 Kim N. Chi,2 Ronald de Wit,3 Maja J.A. de Jonge,3 Gerhardt Attard,4 Terence W. Friedlander,5 Margaret K. Yu,6 Peter Hellemans,7 Caly Chien,8 Charlene Abrams,9 Juhui James Jiao,10 and Fred Saad11 1Urologic Oncology Program & Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California; 2Department of Medical Oncology, BC Cancer – Vancouver Centre, Vancouver, Canada; 3Internal Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; 4Department of Oncology, University College London Cancer Institute, London, UK; 5Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco Medical Center, San Francisco, California; 6Oncology, Janssen Research & Development, Los Angeles, California; 7Oncology, Janssen Research & Development, Beerse, Belgium; 8Clinical Pharmacology & Pharmacometrics, Janssen Research & Development, Spring House, Pennsylvania (current affiliation: Hutchison MediPharma, Florham Park, New Jersey); 9Global Trial Management, Janssen Research & Development, Spring House, Pennsylvania; 10Biostatistics, Janssen Research & Development, Raritan, New Jersey; 11Department of Surgery, University of Montréal, Montréal, Québec, Canada Running title: Apalutamide with Abiraterone Acetate and Prednisone in mCRPC Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 4, 2020; DOI: 10.1158/1078-0432.CCR-19-3402 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 2 Keywords: castration-resistant prostate cancer, apalutamide, abiraterone acetate, pharmacokinetics, prednisone Financial Support: This clinical study was supported by Janssen Research & Development. Corresponding Author: Fred Saad, MD, FRCS University of Montréal Hospital Centre Montréal, Québec, Canada Tel: 514 890-8000 Ext 36446 Fax: 514-412-7620 Email address: [email protected] Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 4, 2020; DOI: 10.1158/1078-0432.CCR-19-3402 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 3 Conflict of Interest: EMP has nothing to disclose. KNC has received grant support, consulting fees, and lecture fees from Janssen, Astellas Pharma, and Sanofi; grant support and consulting fees from Essa Pharma, Bayer, Roche, and AstraZeneca; and consulting fees from Pfizer, Point Biopharma, and Daiichi Sanyo. MJAJ has received consulting fees from Faron Pharmaceuticals. GA has received grant support, consulting fees, and lecture fees from Janssen; grant support and consulting fees from AstraZeneca; consulting fees and lecture fees from Astella, Pfizer, Bayer Pharmaceuticals, and Sanofi; grant support from Innocrin Pharma and Arno Therapeutics; and consulting fees from Essa Pharmaceuticals, Veridex, Ventana, and Novartis; holds patents, receives royalties, or has intellectual property with Institute of Cancer Research [ICR] rewards to inventors list of abiraterone acetate; has received travel, accommodations, and expenses from Janssen, Astellas, Pfizer, Ventana, Abbott Laboratories, Bayer Pharmaceuticals, and Essa Pharmaceuticals; and was employed by ICR through January 8, 2018. TWF has received honoraria from Pfizer, EMD Serono, Janssen, AstraZeneca, and Foundation Medicine; has held a consulting or advisory role at AbbVie, Seattle Genetics, and Nektar; has received research funding from Seattle Genetics, Incyte, BMS, and Janssen; and has received travel, accommodations, and expenses from Pfizer/EMD Serono, AstraZeneca, AbbVie, and Nektar. RW has received honoraria from Sanofi and Merck; and has held a consulting or advisory role at Clovis, Janssen, Roche, and Bayer. CC was employed by Janssen Research & Development through September 6, 2019. MKY, PH, CA, and JJJ are employed by Janssen Research & Development or Janssen Global Services (subsidiaries of Johnson & Johnson) and hold stock in Johnson & Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 4, 2020; DOI: 10.1158/1078-0432.CCR-19-3402 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 4 Johnson. FS reports grants, personal fees, and nonfinancial support from Janssen, Astellas, and Bayer during the conduct of the study; and grants, personal fees, and nonfinancial support from Sanofi, AstraZeneca, and BMS, outside the submitted work. Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 4, 2020; DOI: 10.1158/1078-0432.CCR-19-3402 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 5 Translational Relevance: Apalutamide is currently approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) receiving androgen deprivation therapy and for those with metastatic castration-sensitive prostate cancer. However, the combination of apalutamide, a next-generation androgen receptor (AR) inhibitor, and AR signaling inhibitors, such as abiraterone acetate, in CRPC has not been studied extensively. This phase 1b study evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC). No significant pharmacokinetic interaction was observed between apalutamide and abiraterone; however, treatment with apalutamide decreased exposure to prednisone. Treatment with apalutamide plus AA-P was well tolerated, with evidence of antitumor activity in patients with late disease (mCRPC), including those who have disease progression while taking AR signaling inhibitors. Good tolerability plus the lack of clinically relevant pharmacokinetic interaction and antitumor activity of apalutamide combined with AA-P support further clinical development in patients with mCRPC. Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 4, 2020; DOI: 10.1158/1078-0432.CCR-19-3402 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 6 Abstract Introduction: Apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC). Materials and Methods: Multicenter, open-label, phase Ib drug-drug interaction study conducted in 57 mCRPC patients treated with 1,000-mg AA plus 10-mg P daily beginning on cycle 1 day 1 (C1D1) and 240-mg apalutamide daily starting on C1D8 in 28-day cycles. Serial blood samples for pharmacokinetic analysis were collected on C1D7 and C2D8. Results: Systemic exposure to abiraterone, prednisone, and prednisolone decreased 14%, 61%, and 42%, respectively, when apalutamide was coadministered with AA-P. No increase in mineralocorticoid excess–related adverse events was observed. Patients without prior exposure to AR signaling inhibitors had longer median treatment duration and greater mean decrease in prostate-specific antigen (PSA) from baseline compared with those who had received prior therapy. Confirmed PSA reductions of ≥50% from baseline at any time were observed in 80% (12/15) of AR signaling inhibitor–naïve patients and 14% (6/42) of AR signaling inhibitor–treated patients. Conclusion: Treatment with apalutamide plus AA-P was well tolerated and showed evidence of antitumor activity in patients with mCRPC, including those with disease progression on AR signaling inhibitors. No clinically significant pharmacokinetic interaction was observed between abiraterone and apalutamide; however, apalutamide Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 4, 2020; DOI: 10.1158/1078-0432.CCR-19-3402 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 7 decreased exposure to P. These data support development of 1,000-mg AA plus 10-mg P daily with 240-mg apalutamide daily in patients with mCRPC. Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 4, 2020; DOI: 10.1158/1078-0432.CCR-19-3402 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 8 Introduction Prostate cancer remains a global health problem and a leading cause of male morbidity
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