Abiraterone Acetate Has Antitumour Activity in Prostate Cancer: Presented at EORTC-NCI-AACR

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Title: Abiraterone Acetate Has Antitumour Activity in Prostate Cancer: Presented at EORTC-NCI-AACR
URL: http://www.pslgroup.com/dg/23154E.htm
Doctor's Guide
October 24, 2008

By Chris Berrie

GENEVA -- October 24, 2008 -- Abiraterone acetate, the irreversible inhibitor of 17alpha-hydroxylase/C17,20-lyase (CYP17), is well tolerated and has significant and durable antitumour activity both in patients with chemotherapy-naïve prostate cancer and in docetaxel-treated patients with castration-resistant prostate cancer (CRPC).

These phase 2 results were presented here on October 22 at the 20th International Symposium of the European Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI), and the American Association for Cancer Research (AACR).

In patients with hormone-resistant CRPC, despite androgen-deprivation therapy, intratumoural androgen levels remain high, with continued androgen receptor signalling.

As the source of these androgens could be adrenal or de novo intratumoural synthesis, researchers tried to inhibit CYP17, the key enzyme responsible for androgen synthesis, using abiraterone acetate, which is >10-fold more potent than ketoconazole, another inhibitor of CYP17.

Alison Reid, MD, Royal Marsden Hospital, Institute of Cancer Research, London, United Kingdom, conducted the study with researchers at Royal Marsden NHS Foundation Trust and Cougar Biotechnology, Inc., Los Angeles, California.

After completing a dose-finding, 54 chemotherapy-naïve and 34 docetaxel-experienced patients with progressive disease and rising prostate specific antigen (PSA) levels were enrolled and treated with abiraterone acetate in a phase 2 study. Median baseline PSA levels in the 2 groups were 75 and 536 ng/mL, respectively; range, 8.8 to 964 ng/mL and 26.4 to 10,325 ng/mL, respectively.

Abiraterone acetate was administered at the optimal dose of 1,000 mg daily in both groups.

The primary endpoint was a PSA decline of 50% or more. The secondary endpoints were objective radiological responses, circulating tumour cells (CTCs), duration of treatment, and identification of predictors of response.

At 12 weeks of treatment, PSA declined by 50% or more in 67% of the chemotherapy-naïve patients and in 38% of docetaxel-treated patients. Dr. Reid also noted that 11 of 34 patients (32%) continued to receive the drug beyond a year.

For assessment of predictors of response, in patients receiving single-agent abiraterone acetate, pretreatment serum levels of dehydroepiandrosterone (DHEA), DHEA-sulphate, androstenedione, and oestradiol were significantly linked to the probability of a PSA decline of 50% or greater (odds ratios, respectively: 4.84, P = .01; 3.60, P = .029; 4.64, P = .008; 5.15, P = .018).

Other routine parameters, such as alkaline phosphatase, lactate dehydrogenase, and PSA were not linked significantly to a probability of PSA decline, Dr. Reid said.

The combined data showed a significant survival benefit for patients with CTC count of <5/7.5 mL compared with those with counts of 5 to 49/7.5 mL and those with >=50/7.5 mL (P < .0001 for both). Indeed, for the low CTC group, median overall survival (OS) was not reached, while for the other 2 groups, overall survival was 496 and 308 days, respectively.

For patients with a >=30% decrease in CTCs when taking abiraterone acetate (n = 36), there was a survival benefit over those showing <30% decline (n = 11; median OS, 551 vs 195 days).

Dr. Reid indicated, "We are incorporating CTCs into the new phase 3 study that is actively recruiting now in post-docetaxel patients, to ask the question of whether CTCs can be a predictor of outcome."

Funding for this study was provided by Cougar Biotechnology, Inc.

[Presentation titles: Selective CYP17 Inhibition With Abiraterone Acetate in Castration-Resistant Prostate Cancer (CRPC). Abstract 26. Selective Inhibition of CYP17 With Abiraterone Acetate Is Highly Active in the Treatment of Castration-Resistant Prostate Cancer. Abstract 158]

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