Prostate cancer - degarelix

Prostate cancer is the second most common cancer in men, and 80% of cases are androgen dependent. The luminal cells in the prostate gland produce prostate-specific antigen, and elevated levels are characteristic of prostate cancer.

Its expression is regulated by androgens, which bind to the androgen receptor in a process that is an essential part of the formation of both normal and cancerous cells. In the early stages, blocking or removing androgens can be an effective treatment, but once the cancer reaches the hormone refractory stage, it becomes extremely difficult to treat.

Numerous agents are available that reduce androgen levels, including progesterones, oestrogens, antiandrogens, aromatase inhibitors and gonadotropin-releasing hormone (GnRH) analogues. GnRH analogues have received much attention, as they have potent antiproliferative and antimetastatic activity by inhibiting the plasminogen activator system, and may even have some effect in hormone refractory cases.

Both GnRH agonists and antagonists can have the desired effect, but antagonists tend to work better and produce a therapeutic response more rapidly. Several GnRH antagonists are being developed, including Ferring's degarelix.¹ It was designed to have improved water solubility, as low solubility and a tendency to form gels has been a particular problem with GnRH antagonists.

An open label Phase I study was carried out in 36 healthy young males to look at its pharmacokinetics, pharmacodynamics and safety in single doses between 1.5 and 30µg/kg given intravenously over 45 minutes, or 20mg by intramuscular or subcutaneous injection.² It was well tolerated, and castrate testosterone levels were reached by 21 of the 24 subjects given the higher i.v. or the injected dose.

In a randomised dose-escalating Phase II study, 172 patients with prostate cancer were given single subcutaneous doses of 120 to 320mg degarelix.³ The best response was achieved in those subjects initially given a dose of 240mg, and the most common adverse events were associated with androgen deprivation.

Various different subcutaneous dosing regimens were examined in a dose finding trial.⁴ Subjects with prostate cancer were given doses on days 0 and 3, and then maintenance doses every 28 days, in doses of 80, 80 and 40mg; 40, 40 and 40mg; and 80, 0 and 20mg. Of the 102 evaluable patients, the highest testosterone suppression was seen in the first group.

Its longer term efficacy has also been studied.⁵ A total of 187 patients with prostate cancer were given subcutaneous initiation doses of 200 or 240mg, followed by maintenance doses of 80, 120 or 160mg every 28 days. It was well tolerated, though 12 patients withdrew because of adverse events. All of those patients given the 160mg maintenance dose had testosterone levels of 0.5ng/l or less from day 28 to day 365. Phase III trials are under way.