Castration-resistant prostate cancer: hormonal treatment (mdv3100) shows antitumor activity

Castration-resistant prostate cancer: hormonal treatment (mdv3100) shows antitumor activity

An article published Online First and in an upcoming edition of The Lancet reports that hormonal treatment (MDV3100) has shown encouraging antitumor activity against castration-resistant prostate cancer in a phase 1/2 trial. The article is the work of Professor Howard I Scher, Memorial Sloan-Kettering Cancer Center, New York, USA, and colleagues.

Prostate tumors rely on testosterone for growth which is an androgen hormone. Early treatment consists in lowering the levels of androgens with an analogue that competes with testosterone binding. Another treatment option is surgical removal of the testicles with or without an antiandrogen such as bicalutamide. It blocks the binding of testosterone to the androgen hormone receptor. With this treatment, a certain proportion of cancer cells die. This results in a shrinking of the tumor and a reduction in the levels of prostate specific antigen (PSA) which is a marker of prostate cancer. However, a portion of the tumor cells remain alive but are dormant. Testosterone levels fall to those expected after castration. However, they are still detectable.

Eventually, these sleeping cells can regrowwhen they have adapted to the low testosterone environment. At this point, they are considered castration resistant. However, these cells do still respond the hormonal agents MDV3100. This is an androgen-receptor antagonist. It works by blocking androgens from binding to the androgen receptor in tumour cells. In addition, it induces tumour-cell death. The authors set out to evaluate the antitumour activity and safety of MDV3100 in men with this disease.

This study included 140 patients with progressive, metastatic, castration-resistant prostate cancer, in five US centres. The final daily doses studied were 30 mg (n=3), 60 mg (27), 150 mg (28), 240 mg (29), 360 mg (28), 480 mg (22), and 600 mg (3). The primary objective was to identify the safety and tolerability profile of MDV3100. The researchers were also determined to establish the maximum tolerated dose.

Findings indicate that antitumour effects were detected at all doses, including:

• Decreases of 50 percent or more in serum prostate-specific antigen (PSA) which is a marker of prostate cancer, in 78 (56 percent) patients.

• Responses in soft tissue in 13 (22 percent) of 59 patients.

• Stabilised bone disease in 61 (56 percent) of 109 patients.

• Conversion from unfavourable to favourable circulating tumour cell counts in 25 (49 percent) of 51 patients.

The maximum tolerated dose for sustained treatment (>28 days) was 240 mg.

The most common serious adverse event was dose-dependent fatigue which was detected in 16 (11 percent) patients. This effect was generally resolved after dose reduction.

The authors explain: "We recorded encouraging antitumour activity with MDV3100 in patients with castration-resistant prostate cancer [both before and after chemotherapy]. The results of this phase 1-2 trial validate in man preclinical studies implicating sustained androgen-receptor signalling as a driver in this disease."

They say in closing: "A phase 3 randomised trial has been started to examine MDV3100 versus placebo in men with progressive advanced prostate cancer...with a primary endpoint of overall survival."

In an associated note, Dr William L Dahut, and Dr Ravi A Madan, National Cancer Institute, Bethesda, MD, USA, comments: "Now is an exciting time to revisit targeted treatments in castration-resistant prostate cancer. Abiraterone, a modern inhibitor of androgen synthesis... has activity similar to that of MDV3100.These findings seem to validate the hypothesis that androgens and the androgen receptor are vital to progression of metastatic castration-resistant prostate cancer. Both MDV3100 and abiraterone are in phase 3 studies designed to indicate increased survival."

"Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study"

Howard I Scher, Tomasz M Beer, Celestia S Higano, Aseem Anand, Mary-Ellen Taplin, Eleni Efstathiou, Dana Rathkopf, Julia Shelkey, Evan Y Yu, Joshi Alumkal, David Hung, Mohammad Hirmand, Lynn Seely, Michael J Morris, Daniel C Danila, John Humm, Steve Larson, Martin Fleisher,Charles L Sawyers, the Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium

DOI: 10.1016/S0140-6736(10)60172-9

The Lancet

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