THE "NEW" PROSTATE CANCER INFOLINK

An article with this title, just published in the British Journal of Urology, addresses the potential of the development-stage agent degarelix as a superior form of hormonal therapy compared to earlier LHRH (or GnRH) agonists.

So here’s the thing. The classic androgen suppressors (Lupron/leuprolide acetate and Zoladex/goserelin acetate, as well as a couple of less commonly used agents) are what is known as LHRH (or GnRH) receptor ”agonists.” They are synthetic analogs of luteinizing hormone releasing hormone and act mainly on the pituitary gland in humans. Continuous treatment produces initial stimulation (3-4 days) then suppression of hormones to castrate levels. In males, the reduction of testosterone to castrate levels occurs within 2-4 weeks.

By comparison, degarelix is a leuteinizing hormone releasing hormone receptor ”antagonist”. LHRH receptor antagonists exert marked inhibitory activity, which occurs immediately postdosing and without the adverse flare effects customarily seen with the agonists. However, clinical development of LHRH receptor antagonists has been  problematic, for a number of reasons, including poor bioavailability. Degarelix has been designed to be a potent, orally active, nonpeptide small-molecule LHRH receptor antagonist with increased binding affinity and bioavailability.

However, the first LHRH receptor antagonist, abarelix (marketed in the USA as Plenaxis) was a huge failure from a clinical point of view. Although it did have an androgen suppression effect, it also had side effect problems that were so potentially severe that no one was keen to use it in clinical practice.

It would certainly be interesting if degarelix could manage to demonmstrate real clinical activity without the clinical problems of abarelix, but there is going to be some real caution in the urology community about the clinical value of this product until we see data from large, randomized, double blind clinical trials.