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

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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)
JournalClinical Genitourinary Cancer
DOIs
StateAccepted/In press - 2017

Fingerprint

Castration
Prostatic Neoplasms
Prostate-Specific Antigen
Therapeutics
Androgens
Pharmacokinetics
Circulating Neoplastic Cells
Abiraterone Acetate
Dehydroepiandrosterone
Prednisone
Tumor Burden
Disease Progression
Survival

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Friedlander, T. W., Graff, J., Zejnullahu, K., Anantharaman, A., Zhang, L., Paz, R., ... Ryan, C. J. (Accepted/In press). High-Dose Abiraterone Acetate in Men With Castration Resistant Prostate Cancer. Clinical Genitourinary Cancer. https://doi.org/10.1016/j.clgc.2017.05.026

High-Dose Abiraterone Acetate in Men With Castration Resistant Prostate Cancer. / Friedlander, Terence W.; Graff, Julie; Zejnullahu, Kreshnik; Anantharaman, Archana; Zhang, Li; Paz, Rosa; Premasekharan, Gayatri; Russell, Carly; Huang, Yong; Kim, Won; Aggarwal, Rahul R.; Lin, Amy M.; Fong, Lawrence; Alumkal, Joshi; Beer, Tomasz (Tom); Sharifi, Nima; Alyamani, Mohammad; Dittamore, Ryan; Small, Eric J.; Paris, Pamela L.; Ryan, Charles J.

In: Clinical Genitourinary Cancer, 2017.

Research output: Contribution to journalArticle

Friedlander, TW, Graff, J, Zejnullahu, K, Anantharaman, A, Zhang, L, Paz, R, Premasekharan, G, Russell, C, Huang, Y, Kim, W, Aggarwal, RR, Lin, AM, Fong, L, Alumkal, J, Beer, TT, Sharifi, N, Alyamani, M, Dittamore, R, Small, EJ, Paris, PL & Ryan, CJ 2017, 'High-Dose Abiraterone Acetate in Men With Castration Resistant Prostate Cancer', Clinical Genitourinary Cancer. https://doi.org/10.1016/j.clgc.2017.05.026
Friedlander, Terence W. ; Graff, Julie ; Zejnullahu, Kreshnik ; Anantharaman, Archana ; Zhang, Li ; Paz, Rosa ; Premasekharan, Gayatri ; Russell, Carly ; Huang, Yong ; Kim, Won ; Aggarwal, Rahul R. ; Lin, Amy M. ; Fong, Lawrence ; Alumkal, Joshi ; Beer, Tomasz (Tom) ; Sharifi, Nima ; Alyamani, Mohammad ; Dittamore, Ryan ; Small, Eric J. ; Paris, Pamela L. ; Ryan, Charles J. / High-Dose Abiraterone Acetate in Men With Castration Resistant Prostate Cancer. In: Clinical Genitourinary Cancer. 2017.
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abstract = "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.",
keywords = "Acquired resistance, Androgen receptor, Androgens, Hormonal therapy, Primary resistance",
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AU - Graff, Julie

AU - Zejnullahu, Kreshnik

AU - Anantharaman, Archana

AU - Zhang, Li

AU - Paz, Rosa

AU - Premasekharan, Gayatri

AU - Russell, Carly

AU - Huang, Yong

AU - Kim, Won

AU - Aggarwal, Rahul R.

AU - Lin, Amy M.

AU - Fong, Lawrence

AU - Alumkal, Joshi

AU - Beer, Tomasz (Tom)

AU - Sharifi, Nima

AU - Alyamani, Mohammad

AU - Dittamore, Ryan

AU - Small, Eric J.

AU - Paris, Pamela L.

AU - Ryan, Charles J.

PY - 2017

Y1 - 2017

N2 - 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.

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KW - Androgen receptor

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KW - Hormonal therapy

KW - Primary resistance

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