Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer

Abstract

The drug abiraterone is converted to Δ4-abiraterone (D4A) in mice and patients with prostate cancer, which has more potent anti-tumour activity and may lead to more effective therapies. Abiraterone has been designed as a drug to treat patients with co-called castration-resistant prostate cancer — cancers that don't respond to androgen antagonists. Abiraterone works instead by blocking the formation of androgens via inhibition of the enzyme CYP17A1, a key step in the biosynthesis of testosterone and other androgens. In a new twist to these findings, Nima Sharifi and colleagues now show that abiraterone is itself metabolized in prostate tumours, giving rise to D4A which inhibits several enzymes in the androgen synthesis pathway including CYP17A1 and also antagonizes the androgen receptor. D4A has more potent anti-tumour activity in animal models, and may lead to more efficient therapies, in particular in the light of certain restrictions to the availability of abiraterone. Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5α-dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer1,2,3. Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly requires enzymatic reactions by 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes4,5. Abiraterone, a steroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival6,7. We hypothesized that abiraterone is converted by an enzyme to the more active Δ4-abiraterone (D4A), which blocks multiple steroidogenic enzymes and antagonizes the androgen receptor, providing an additional explanation for abiraterone’s clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3βHSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive androgen receptor antagonism by D4A is comparable to the potent antagonist enzalutamide. D4A also has more potent anti-tumour activity against xenograft tumours than abiraterone. Our findings suggest an additional explanation—conversion to a more active agent—for abiraterone’s survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment.