Enzyme inhibitor effective against refractory prostate cancer

October 1, 2009

In heavily pretreated men with castration-resistant prostate cancer, a specific and irreversible inhibitor of the enzyme CYP17 promotes declines in levels of PSA and the number of circulating tumor cells and an improvement in performance status.

Orlando, FL-In heavily pretreated men with castration-resistant prostate cancer, a specific and irreversible inhibitor of the enzyme CYP17 promotes declines in levels of PSA and the number of circulating tumor cells (CTCs) and an improvement in performance status, according to researchers from Royal Mardsen Hospital in London.

Their findings were presented at the American Society of Clinical Oncology annual meeting.

In a phase II study, more than half of the men treated with abiraterone acetate had declines in total maximum PSA levels of 50% or greater. The findings reinforce previous data, suggesting that castration-resistant prostate cancer remains hormone-dependent.

Previous clinical trials have shown that specific inhibition of CYP17 is safe and has antitumor activity in up to 70% of castrate patients with advanced prostate cancer who were resistant to endocrine therapies.

The phase II study reported here included 47 patients in whom androgen deprivation therapy had failed. All had had prior docetaxel (Taxotere) chemotherapy. They received abiraterone acetate orally, 1,000mg/day in 28-day cycles. Stable doses of glucocorticoids were allowed.

Tangible improvement

A total maximum PSA decline of 50% or greater at any point in the study, the primary endpoint, was achieved by 24 men (51.1%). Thirty-two patients (68.1%) had a total maximum PSA decline of 30% or greater and seven (14.9%) had a total maximum PSA decline of at least 70%. A similar trend in PSA response was observed at week 12, according to first author Alison H. Reid, MD, of the Institute of Cancer Research, Royal Mardsen Hospital.

Thirty-five patients were evaluable by Response Evaluation Criteria In Solid Tumors (RECIST). Of these, six (17.1%) had a partial response and 25 (71.4%) had stable disease.Median time to PSA progression: 169 days.

In all, 35.4% of patients showed improvement on their Eastern Cooperative Oncology Group (ECOG) performance status. Ten of 27 (37%) improved from baseline ECOG 1 to post-baseline ECOG 0, and one of four (25%) improved from baseline ECOG 2 to post-baseline ECOG 1. About half (53%) maintained performance status.

Thirty-four patients had CTCs enumerated. Of the 27 with five or more CTCs at baseline, 11 (41%) had a decline to 5 or less on abiraterone. Nineteen of the 27 (70.3%) patients had a CTC decline of at least 30%.

"CTC declines of 30% or more have previously been shown to correlate with improved survival," Dr. Reid noted.

Toxicities related to mineralocorticoid excess were mainly grade 1-2 (hypokalemia, 57.4%; hypertension, 19.1%; peripheral edema, 21.3%) and were treated with eplerenone or corticosteroids.

Two phase III studies of abiraterone in men with castration-resistant prostate cancer are under way, one in combination with prednisone, comparing it to prednisone alone in patients in whom docetaxel chemotherapy has failed, and the other in patients prior to docetaxel chemotherapy.

Some authors of this study disclose that they own stock in, receive research funding from, act as consultants/advisers for, or are employees of Cougar Biotechnology.