Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy

Zhenfei Li, Mohammad Alyamani, Jianneng Li, Kevin Rogacki, Mohamed Abazeed, Sunil K. Upadhyay, Steven P. Balk, Mary Ellen Taplin, Richard J. Auchus, Nima Sharifi

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73 Scopus citations

Abstract

Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ4-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.

Original languageEnglish (US)
Pages (from-to)547-551
Number of pages5
JournalNature
Volume533
Issue number7604
DOIs
StatePublished - May 25 2016

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ASJC Scopus subject areas

  • General
  • Medicine(all)

Cite this

Li, Z., Alyamani, M., Li, J., Rogacki, K., Abazeed, M., Upadhyay, S. K., Balk, S. P., Taplin, M. E., Auchus, R. J., & Sharifi, N. (2016). Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. Nature, 533(7604), 547-551. https://doi.org/10.1038/nature17954