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Abiraterone for the Treatment of Advanced Prostate Cancer.

ABSTRACT: Until recently, treatment options for castration-resistant prostate cancer (CRPC) were limited to only the chemotherapeutic agent docetaxel which demonstrated a survival advantage over palliative chemotherapy. Abiraterone acetate (AA) is an orally available, potent irreversible inhibitor of the adrenal microsomal enzyme cytochrome P450-17 (CYP17). In a large phase III study of AA in docetaxel-pretreated patients, AA demonstrated excellent tolerance and a 4-month survival advantage over placebo, leading to the approval of AA for docetaxel-pretreated patients by the FDA in 2011. More recently, phase III data in docetaxel-naïve patients have become available, showing clear clinical benefits in this population as well, and it is likely that the label for AA will soon be expanded to include men with CRPC who have not yet received chemotherapy. This article summarizes clinical studies of AA in CRPC patients and discusses the emerging treatment paradigm in this rapidly evolving area.

SUBMITTER: Forde PM

PROVIDER: S-EPMC3689308 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Abiraterone for the Treatment of Advanced Prostate Cancer.

Forde Patrick M PM Antonarakis Emmanuel S ES

The International journal of targeted therapies in cancer 20120901 3

Until recently, treatment options for castration-resistant prostate cancer (CRPC) were limited to only the chemotherapeutic agent docetaxel which demonstrated a survival advantage over palliative chemotherapy. Abiraterone acetate (AA) is an orally available, potent irreversible inhibitor of the adrenal microsomal enzyme cytochrome P450-17 (CYP17). In a large phase III study of AA in docetaxel-pretreated patients, AA demonstrated excellent tolerance and a 4-month survival advantage over placebo, ...[more]

PMID: 23795335

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Project description:Androgen deprivation therapy remains the single most effective treatment for the initial therapy of advanced prostate cancer, but is uniformly marked by progression to castration-resistant prostate cancer (CRPC). Residual tumor androgens and androgen axis activation are now recognized to play a prominent role in mediating CRPC progression. Despite suppression of circulating testosterone to castrate levels, castration does not eliminate androgens from the prostate tumor microenvironment and residual androgen levels are well within the range capable of activating the androgen receptor (AR) and AR-mediated gene expression. Accordingly, therapeutic strategies that more effectively target production of intratumoral androgens are necessary. The introduction of abiraterone, a potent suppressor of cytochrome P450 17 α-hydroxysteroid dehydrogenase-mediated androgen production, has heralded a new era in the hormonal treatment of men with metastatic CRPC. Herein, the androgen and AR-mediated mechanisms that contribute to CRPC progression and establish cytochrome P450 17 α-hydroxysteroid dehydrogenase as a critical therapeutic target are briefly reviewed. The mechanism of action and pharmacokinetics of abiraterone are reviewed and its recently described activity against AR and 3-β-hydroxysteroid dehydrogenase is discussed. The Phase I and II data initially demonstrating the efficacy of abiraterone and Phase III data supporting its approval for patients with metastatic CRPC are reviewed. The safety and tolerability of abiraterone, including the incidence and management of side effects and potential drug interactions, are discussed. The current place of abiraterone in CRPC therapy is reviewed and early evidence regarding cross-resistance of abiraterone with taxane therapy, mechanisms of resistance to abiraterone, and observations of an abiraterone withdrawal response are presented. Future directions in the use of abiraterone, including optimal dosing strategies, the role of abiraterone in earlier disease settings, including castration sensitive, biochemically recurrent, or localized disease, and the rationale for combinatorial treatment strategies of abiraterone with enzalutamide and other targeted agents are also discussed.

Dataset Information

Abiraterone for the Treatment of Advanced Prostate Cancer.

Publications

Abiraterone for the Treatment of Advanced Prostate Cancer.

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