Abstract

The clinical data from abiraterone acetate and MDV -3100 confirm continued androgen receptor (AR) addiction in a significant proportion of castration-resistant prostate cancers (CRPC). Abiraterone acetate is a highly specific inhibitor of CYP17 and results in significant suppression of serum androgenic steroids and oestrogens1. Declines in PSA by ≥50% and ≥90% with abiraterone acetate have been reported in 50-60% and 20-30% of CRPC patients respectively, despite prior progression while castrate on several hormonal agents2. Importantly, declines in PSA were associated with radiological tumour regression, declines in circulating tumour cell (CTC) count and symptomatic benefit2. Moreover, prior treatment with docetaxel chemotherapy did not significantly alter sensitivity to abiraterone acetate3. MDV -3100 is a potent AR antagonist which also induces tumour responses in CRPC patients4. Both these agents are now undergoing evaluation in large, randomized, global, phase III studies designed to identify a survival benefit and obtain regulatory approval to treat CRPC . However, resistance to these agents commonly develops within 18 months and is nearly invariably characterized by a rising PSA , suggesting resumption of transcription of hormone-regulated genes. In fact, although ETS gene fusions appear to be an early event in prostate carcinogenesis, hormone-regulated over-expression of ERG persists in end-stage CRPC5 . Also, CRPC patients with a hormone-dependent ERG gene fusion are significantly more likely to have a ≥90% PSA decline with abiraterone acetate5. The future development of therapeutics for CRPC should be informed by the molecular classification of CRPC using analytically validated predictive biomarkers in a combination of tumour tissue and CTC and by a better understanding of the mechanisms underlying disease progression following treatment with these novel, hormonal agents.

References:

1. Attard G et al, J Clin Oncol 26:4563-71, 2008

2. Attard G et al, J Clin Oncol, 2009 XXX

3. Attard G et al, Cancer Res 69:4937-40, 2009

4. Tran C et al, Science, 2009 XXX

5. Attard G et al, Cancer Res 69:2912-8, 2009