Doehn et al Based on these ﬁndings, lowering testosterone levels either medically or surgically and/or blockade of the andro- gen receptor represents the principal mechanism of androgen deprivation therapy of prostate cancer.10 Surgical castration can be done by bilateral orchiectomy. This is an effective procedure and not associated with relevant complications. The disadvantages are the possible negative psychological effects and the fact that no intermittent androgen deprivation therapy can be applied.11 Similar effects can be achieved by suppression of the gonadotropins luteinizing hormone (LH) and follicle- stimulating hormone (FSH) with gonadotropin-releasing hormone (GnRH) agonists (eg, buserelin, goserelin, leupro- lide, triptorelin) that desensitize the pituitary gland. This leads to a suppression of the LH synthesis and secretion followed by decreased stimulus for testosterone synthesis within the testicles. Another medical manipulation of this hormonal regulation can be achieved by blocking the androgen receptor with steroidal antiandrogens (eg, cyproterone acetate) or nonsteroidal antiandrogens (eg, bicalutamide, ﬂutamide).10 However, the effect from androgen receptor blockade is considered to be less effective compared to LH-releasing hormone (LHRH) agonists (at least in metastatic disease). Blocking the GnRH receptor with an antagonist in the pituitary gland is obviously the most logical way to achieve a fast and reversible decrease of LH, FSH, and testosterone without any clinical ﬂare. For a long time, however, GnRH antagonists showed relevant release of histamine from mast cells with acute systemic allergic reactions.12 Another constriction for clinical usefulness was limited solubility.13 Degarelix (Ferring Pharmaceuticals, Kiel, Germany) is the second GnRH antagonist that has been tested in a phase III trial.14 Degarelix has also proven its potential in achieving testosterone suppression without any evidence of clinical ﬂare. Additionally, no acute systemic allergic reactions were observed in patients treated with degarelix.15–17 This review aims to summarize phase II and III trials on degarelix for the treatment of patients with prostate cancer. Efﬁcacy Phase II dose-ﬁnding studies There are four phase II dose-ﬁnding studies in the literature. Two of them are only available in abstract form and the remaining are full publications. Data from a randomized phase II trial were presented by Weston and colleauges at the SIU congress in 2004.18 In this trial, 129 patients (age 55–87 years) with prostate cancer of all stages who were candidates for androgen deprivation 216 therapy were treated in three different dose regimens between 20 mg and 80 mg (arm A: degarelix 80/80/40 (ie, 80 mg on day 0, 80 mg on day 3, and 40 mg on day 28); arm B: degarelix 80/–/20; arm C: degarelix 40/40/40) administered on day 0, 3, and 28, respectively, and every 28 days thereafter. At baseline the median PSA level was 61 ng/ml. In this study, arm A was the most effective in achieving castration levels. At six-month follow-up 87.5%, 72.2%, and 58.8% of patients in arms A, B, and C had a testosterone 0.5 ng/ml.18 Results from a phase II multicenter, randomized dose- escalating study testing degarelix in patients with prostate cancer were presented by Tammela and colleagues at the EAU congress in 2005.19 In this trial, 172 patients (age 48–89 years) with prostate cancer were included. These patients had a baseline median testosterone of 4.16 ng/ml and a median PSA of 38 ng/ml. Patients with metastatic prostate cancer (31%), locally advanced prostate cancer (36%), and local- ized prostate cancer (26%) were included. Degarelix was administered sc at doses between 120 mg and 320 mg. The concentrations varied between 20 mg/ml and 60 mg/ml. The efﬁcacy could be evaluated in 169 patients at day 3 and day 28 by measurement of testosterone and PSA. Degarelix showed a dose- and concentration-dependent effect. A dose of 240 mg (40 mg/ml) resulted in castration (deﬁned as testosterone 0.5 ng/ml) in 96% of the patients and was the most effective regimen.19 Two phase II studies have been conducted to evaluate the efﬁcacy of degarelix in different doses regimen in long-term follow-up.20,21 One open label, randomized phase II study with a starting dose of 200 mg degarelix sc and a monthly administration of 60 mg degarelix sc (200/60, arm A) or 80 mg degarelix sc (200/80, arm B) was conducted in North America.20 In total, 127/176 screened patients with prostate cancer were enrolled. Patients had a median age of 76 years (range 47–93 years). Inclusion criteria were testosterone 2.2 ng/ml, PSA 2 ng/ml, and Eastern Coop- erative Oncology Group (ECOG) score of 2 or less. The primary endpoint was the proportion of patients with serum testosterone 0.5 ng/ml at all monthly measurements throughout the entire study period (ie, 12 months) and the proportion of patients with testosterone 0.5 ng/ml at all monthly measurements throughout the entire study period for those patients who had a testosterone 0.5 ng/ml after one month. Secondary endpoints included: • The proportion of patients with a testosterone 0.5 ng/ml at day 3 • Time to 50% and 90% reduction in PSA Clinical Interventions in Aging 2009:4