SFEBES2009 Poster Presentations Endocrine tumours and neoplasia (32 abstracts)
Abiraterone acetate: the novel application of a CYP450c17 inhibitor to the treatment of both prostate and breast cancer
E Folkerd 1 , G Attard 1,2 , D Dearnaley 1 , J Hunt 2 , G Maier 2 , A Molina 3 , D Olmos 2 , N Oomen 2 , C Parker 2 , A Reid 1,2 , E Thompson 2 , J De Bono 1,2 & M Dowsett 1,2
1Institute for Cancer Research, London, UK; 2The Royal Marsden Hospital, London, UK; 3Cougar Biotechnology, Los Angeles, California, USA.
Abiraterone acetate is a potent, selective inhibitor of CYP17, a key enzyme that catalyses the conversion of pregnenolone to dehydroepiandrosterone (DHEA) and progesterone to androstenedione. Inhibition of this enzyme causes suppression of the synthesis of both androgens and oestrogens. Hence treatment with abiraterone acetate could impact on the development and progression of hormone-dependent breast and prostate cancers.
In a phase I/II1,2 study of daily continuous treatment with abiraterone acetate in chemotherapy-naïve, castration-resistant prostate cancer patients we have demonstrated that the treatment is safe and well tolerated. CYP17 inhibition resulted in a 2× decrease in serum cortisol and a consequent 5x elevation of ACTH, compensated for by a 10× (range 4–50) increase in deoxycorticosterone and 40x (range 10–95) increase in corticosterone concentrations potentially preventing adrenocortical insufficiency. Testosterone, DHEA, dehydroepiandrosterone sulphate, androstenedione and oestradiol were profoundly suppressed in all patients; there was a decline in prostate specific antigen levels (≥50% in 57% of patients) and radiological regression indicating anti-tumour activity.
The acquisition of resistance to treatment with aromatase inhibitors for hormone-sensitive breast cancer is well documented. It has been suggested that in some breast cancer patients, androgenic steroids up-stream of aromatase may drive steroid receptor signalling involved in tumour growth, contributing to clinical resistance3,4. Potentially, abiraterone may override this mechanism of resistance whilst simultaneously depriving the tumour of oestrogen and hence prolong time to progression. Abiraterone acetate is a novel drug with anti-tumour activity in prostate cancer and potential application in breast cancer.
References:
1. Attard G et al. J Clin Oncol 2008 26 4563–4571.
2. Attard G et al. J Clin Oncol 2008 in press.
3. Maggiolini M et al. Cancer Res 1999 59 4864–4869.
4. Sikora MJ et al. Breast Cancer Res Treat 2008 in press.
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