Significant and Sustained Antitumor Activity in Post-Docetaxel, Castration-Resistant Prostate Cancer With the CYP17 Inhibitor Abiraterone Acetate

Abstract

Abiraterone acetate has significant antitumor activity in post-docetaxel patients with CRPC. Randomized, phase III trials of abiraterone acetate are underway to define the future role of this agent.

AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function In Vitro and In Vivo

“…The change in terminology reflects emerging data that show prostate cancer in this resistant state to have a continued dependency upon AR signaling. This is exemplified by the recent overall survival benefit shown in patients with CRPC following treatment with either abiraterone acetate or enzalutamide (17)(18)(19)(20)(21)(22). Abiraterone acetate inhibits 17-a-hydroxylase/17,20-lyase (CYP17) activity resulting in a reduction in residual androgens synthesized by the adrenals and potentially the prostate tumor itself (23).…”

Hits identified in library screening demonstrate selective CYP17A1 lyase inhibition

“…Abiraterone is a more potent inhibitor of the hydroxylase reaction (IC 50; hydroxylase = 1.7 nM) which is in consistence with the observation of secondary mineralocorticoid excess reported in clinical trials (e.g. [23,24]). By comparison compounds 1, 3, 4 and 5 are potent lyase inhibitors and show IC 50 values less than 40 nM, while compound 2 is less potent (IC 50 = 2936 nM).…”

Medical strategies for treatment of castration resistant prostate cancer (CRPC) docetaxel resistant

“…Moreover, ≥ 30% or ≥ 90% PSA decline was reported in 68% and 15% of patients respectively; 27% of patients with measurable disease had PR defined by RECIST criteria. 24 The second trial, evaluating the activity of abiraterone acetate plus prednisone, reported a ≥ 50% PSA decline in 36% of patients and a ≥ 30% or ≥ 90% PSA decline in 47% and 16% of patients, respectively; PR was observed in 18% of patients with soft tissue measurable lesions. Both studies showed a period of 169 days TTPP.…”

“…23 The other two studies tested the activity of abiraterone acetate in 105 patients with docetaxel-treated CRPC. 24,25 The first trial reported a ≥ 50% PSA decline from baseline in 51% of patients. Moreover, ≥ 30% or ≥ 90% PSA decline was reported in 68% and 15% of patients respectively; 27% of patients with measurable disease had PR defined by RECIST criteria.…”