The standard first port of call in treating metastatic prostate cancer is to remove the androgen source by castration, whether physical or chemical. However, even when testosterone levels are dramatically lowered, in most cases the cancer progresses within a couple of years because of the presence of androgens from non-gonadal sources. A chemical way of continuing to suppress the androgen response in these cases could be of good therapeutic benefit, and several novel secondary hormone therapies are being developed. These include abiraterone, which was licensed by Cougar Biotechnologies from BTG, having been initially synthesised at the Institute of Cancer Research in the UK.1
The drug works by inhibiting the cytochrome P450 17 gene, which encodes for an enzyme which plays an essential role in the creation of androgens and oestrogens in the adrenal glands and tumours. Inhibiting this enzyme suppresses the production of androgens in all endocrine organs, and it is a selective, irreversible inhibitor of CYP17. It is administered as an acetate prodrug.
In a two stage Phase II trial, 1000mg was initially given by continuous infusion once a day to 35 docetaxel treated patients with castration resistant prostate cancer.2 The primary endpoint was a decline of at least 50% in prostate specific antigen in at least seven patients; this was seen and more patients were enrolled. It was expanded to a total of 47 patients, and of these 24 had a PSA decline of at least 50%. A total of 35 were evaluable and six had a partial response, with 23 achieving stable disease. The median duration of treatment was 167 days.
In another Phase II trial, 33 chemotherapy naïve patients were given 100mg of abiraterone acetate plus 5mg prednisone; 24 of the 27 evaluable patients showed a decline in PSA levels, all but one of them falling by at least 50%, and this was maintained for at least 12 weeks in 21 patients.3 Two Phase III trials are now under way.
References
1. G.A. Potter et al. J. Med. Chem. 1995, 38, 2463
2. A.H. Reid et al. J. Clin. Oncol. 2010, 28, 1489
3. C. Ryan et al. J. Clin. Oncol. 2009, 27 (15, Suppl.), Abst 5046