High-Dose Abiraterone Acetate in Men With Castration Resistant Prostate Cancer

Terence W. Friedlander, Julie N. Graff, Kreshnik Zejnullahu, Archana Anantharaman, Li Zhang, Rosa Paz, Gayatri Premasekharan, Carly Russell, Yong Huang, Won Kim, Rahul Aggarwal, Amy M. Lin, Lawrence Fong, Joshi J. Alumkal, Tomasz M. Beer, Nima Sharifi, Mohammad Alyamani, Ryan Dittamore, Eric J. Small, Pamela L. ParisCharles J. Ryan

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Micro-Abstract Abiraterone acetate with prednisone prolongs progression-free and overall survival in men with advanced prostate cancer, but most eventually acquire resistance to treatment. In this study we evaluated the clinical benefit of increasing the dose of abiraterone acetate in patients who develop acquired resistance to standard-dose therapy while exploring the pharmacokinetics and pharmacodynamics of resistance. Background Abiraterone acetate (AA) inhibits androgen biosynthesis and prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) when combined with prednisone (P). Resistance to therapy remains incompletely understood. In this open-label, single-arm, multicenter phase II study we investigated the clinical benefit of increasing the dose of AA at the time of resistance to standard-dose therapy. Patients and Methods Eligible patients had progressive mCRPC and started AA 1000 mg daily and P 5 mg twice daily. Patients who achieved any prostate-specific antigen (PSA) decline after 12 weeks of therapy continued AA with P until PSA or radiographic progression. At progression, AA was increased to 1000 mg twice daily with unchanged P dosing. Patients were monitored for response to therapy for a minimum of 12 weeks or until PSA or radiographic progression. The primary end point was PSA decline of at least 30% after 12 weeks of therapy at the increased dose of AA. Results Forty-one patients were enrolled from March 2013 through March 2014. Thirteen men experienced disease progression during standard-dose therapy and were subsequently treated with AA 1000 mg twice per day. Therapy was well tolerated. No PSA declines ≥ 30% nor radiographic responses were observed after 12 weeks of dose-escalated therapy. Higher baseline dehydroepiandrosterone levels, lower circulating tumor cell burden, and higher pharmacokinetic levels of abiraterone and abiraterone metabolites were associated with response to standard-dose therapy. Conclusion Increasing the dose of abiraterone at the time of resistance has limited clinical utility and cannot be recommended. Lower baseline circulating androgen levels and interpatient pharmacokinetic variance appear to be associated with primary resistance to AA with P.

Original languageEnglish (US)
Pages (from-to)733-741.e1
JournalClinical Genitourinary Cancer
Volume15
Issue number6
DOIs
StatePublished - Dec 2017
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by Department of Defense grant P0043122 , the Prostate Cancer Foundation Young Investigator Grant A119352 , Bernard Schwartz philanthropy , and by Janssen Pharmaceuticals . The authors acknowledge Jessica Louw for the CTC analysis using the Epic Sciences platform.

Funding Information:
T.M.B. receives research funding from Janssen Research & Development , Astellas , and Medivation , and is a consultant for Astellas and Johnson & Johnson. C.J.R. receives honoraria from Janssen Pharmaceuticals and Astellas. J.N.G. receives research funding from BMS , Medivation , Merck , Janssen , and receives travel funding from Merck and Astellas , and serves as a consultant for Bayer and Dendreon, and has received honoraria from Astellas. L.F. receives research support from BMS , Merck , Dendreon , Genentech , and Abbvie . W.K. is a consultant for Genetech, Bayer, and Dendreon. N.S. receives research support from Janssen . T.W.F. receives research funding from Janssen Research & Development and honoraria from Astellas. The remaining authors have stated that they have no conflicts of interest.

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

  • Acquired resistance
  • Androgen receptor
  • Androgens
  • Hormonal therapy
  • Primary resistance

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