A new hormonal treatment—MDV3100—has shown encouraging antitumour activity against castration-resistant prostate cancer in a phase 1/2 trial. The findings are reported in an article in an upcoming edition of The Lancet, written by Professor Howard I Scher, Memorial Sloan-Kettering Cancer Center, New York, USA, and colleagues.

Prostate tumours are dependent on testosterone (an androgen hormone) for growth. The initial treatment is to lower the levels of androgens with a analogue that competes with testosterone binding ,or surgical removal of the testicles with or without an antiandrogen such as bicalutamide, which blocks the binding of testosterone to the androgen hormone receptor. With this treatment, a certain proportion of cancer cells die, resulting in a shrinkage of the tumour and a reduction in the levels of prostate specific antigen (PSA)- a marker of prostate cancer. However, a portion of the tumour cells remain alive but are dormant. Testosterone levels fall to those expected after castration, but are still detectable.

Over time, these sleeping cells then regrow, having adapted to the low testosterone environment, at which point they are considered castration resistant. However, these cells do still respond the hormonal agents MDV3100—an androgen-receptor antagonist, that works by blocking androgens from binding to the androgen receptor in tumour cells. It also induces tumour-cell death. The authors assessed the antitumour activity and safety of MDV3100 in men with this disease.

This study was undertaken in five US centres in 140 patients with progressive, metastatic, castration-resistant prostate cancer. 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 and to establish the maximum tolerated dose.

There were antitumour effects at all doses, including decreases in serum prostate-specific antigen (PSA-a marker of prostate cancer) of 50% or more in 78 (56%) patients, responses in soft tissue in 13 (22%) of 59 patients, stabilised bone disease in 61 (56%) of 109 patients, and conversion from unfavourable to favourable circulating tumour cell counts in 25 (49%) 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 (16 [11%] patients), which generally resolved after dose reduction.

The authors say: "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 conclude: "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 accompanying comment, Dr William L Dahut, and Dr Ravi A Madan, National Cancer Institute, Bethesda, MD, USA, say: "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."



Source: The Lancet