Abiraterone is converted to Δ4-abiraterone (D4A), a metabolite with more potent antitumor activity.

  • Major finding: Abiraterone is converted to Δ4-abiraterone (D4A), a metabolite with more potent antitumor activity.

  • Concept: D4A inhibits multiple steroidogenic enzymes in addition to CYP17A1 and is a competitive AR antagonist.

  • Impact: D4A may be more effective than abiraterone in patients with castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) arises when tumors acquire the ability to synthesize the steroid androgen hormone 5α-dihydrotestosterone (DHT), which binds and activates the androgen receptor (AR). Abiraterone is a 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor that blocks DHT synthesis and increases overall survival in patients with CRPC. Given that abiraterone is itself a steroid with structural similarities to steroid precursors known to be metabolized by 3β-hydroxysteroid dehydrogenase (3βHSD) in the DHT biosynthetic pathway, Li and colleagues hypothesized that 3βHSD would convert abiraterone to a structurally related Δ4,3-keto compound called Δ4-abiraterone (D4A). Indeed, the authors detected D4A in the sera of abiraterone-treated mice and patients with CRPC who were receiving abiraterone. Unlike abiraterone, which is only a potent inhibitor of CYP17A1, D4A inhibits multiple enzymes required for androgen synthesis in addition to CYP17A1, including 3βHSD and steroid-5α-reductase (SRD5A). Moreover, D4A has a significantly greater binding affinity for both wild-type and mutant AR than abiraterone, and competitive AR antagonism by D4A is comparable to the nonsteroidal AR antagonist enzalutamide. Consistent with these findings, D4A is a more potent inhibitor of AR target gene expression than abiraterone and suppresses DHT-induced PSA expression to the same extent as enzalutamide in prostate cancer cell lines in vitro and in vivo. Compared with abiraterone and enzalutamide, D4A also significantly delays growth of prostate cancer xenografts without causing the increase in deoxycorticosterone that is associated with adverse events in patients treated with abiraterone. The observation that abiraterone is converted into a more active metabolite that can simultaneously and directly inhibit androgen synthesis and AR activity suggests that D4A may contribute to the clinical activity attributed to abiraterone and raises the possibility that direct use of D4A may provide more clinical benefit than abiraterone therapy.

Li Z, Bishop AC, Alyamani M, Garcia JA, Dreicer R, Bunch D, et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature 2015 Jun 1 [Epub ahead of print].

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