By ecancer reporter Jo Armstrong

Presentation: Improved inhibition of the androgen receptor - G Attard

Abiraterone acetate is a specific inhibitor of cytochrome P450 17-alpha-hydroxylase-17,20-lyase (CYP17) and results in significant suppression of serum androgenic steroids and oestrogen without causing adrenal insufficiency and is currently undergoing Phase III clinical trials as a potential treatment of androgen-dependent prostate cancer. In pre-clinical studies, abiraterone acetate demonstrated the ability to selectively inhibit the target enzyme, resulting in inhibition of testosterone production in both the adrenals and the testes. Clinical studies demonstrate that abiraterone acetate is well tolerated and results in significant anti-tumour activity in castration-resistant prostate cancer (CRPC), with declines in prostate-specific antigen (PSA) by around 50% to 90% in 50-60% and 20-30% of patients, respectively.² Importantly, declines in PSA were associated with radiological tumour regression, declines in circulating tumour cell (CTC) count and symptomatic benefit.

ERG gene rearrangement has been reported in a third of patients treated with abiraterone acetate who had evaluable tumour tissue, implying a fusion between the androgen-regulated gene, TMPRSS2, and transcription factors of the ETS family (e.g., ERG). In 86% of the patients with an ERG rearrangement, a decline in PSA of at least 50% was reported. This suggests that the TMPRSS2–ERG rearrangement may indicate a continued dependence on androgen-driven growth that confers sensitivity to the androgen-lowering effects of abiraterone acetate.

MDV3100 is another novel androgen receptor antagonist that binds the receptor with an eight-times higher affinity than bicalutamide and blocks nuclear translocation of androgen receptor and DNA binding. In contrast to bicalutamide, MDV3100 has no known agonist activity when the androgen receptor is over expressed. Preliminary results of a Phase I/II study evaluating the safety and efficacy of MDV3100 in 140 patients with CRPC were reported at the ASCO 2009 Annual Meeting, and showed that MDV3100 was generally well tolerated, with a dose-limiting side effect of fatigue. After 12 weeks of treatment, 55% of chemotherapy-naive patients and 36% of post-chemotherapy patients had a PSA response of more than 50% from baseline. Phase III studies are ongoing.

The future development of therapeutics for CRPC should be informed by an understanding of the mechanisms underlying disease progression following treatment with these novel agents. The fact that CRPC is a heterogeneous disease, suggests a need for an individualised treatment approach utilising biomarkers to predict response to therapy. Given the efficacy and tolerability of abiraterone acetate, further studies of abiraterone acetate in combination with other chemotherapeutics and biologic agents are warranted.