title: Degarelix: a gonadotropin-releasing hormone antagonist for the management of prostate cancer.
abstract: BACKGROUND
  Prostate cancer is the most commonly diagnosed cancer among men. Treatment can include surgery, radiation, chemotherapy, or hormonal manipulation. Gonadotropin-releasing hormone (GnRH) analogues are used to manage prostate cancer by desensitizing the stimulus to synthesize and release gonadotropins, such as luteinizing hormone (LH), which stimulate the synthesis and release of androgens, in turn stimulating the growth of prostate cancer cells. Although effective, these agents have limitations, such as a flare-up of cancer symptoms within the first 2 weeks of starting the drug.
  
  
  OBJECTIVE
  This article reviews the pharmacology, pharmacokinetic and pharmacodynamic characteristics, and clinical data available on the newly approved drug degarelix for use in treating prostate cancer.
  
  
  METHODS
  A search of the medical literature was performed in January 2009 with the databases MEDLINE and EMBASE (1950-present) and International Pharmaceutical Abstracts (1970-November 2008) using the terms degarelix and FE200486; follow-up searches using the same strategy were conducted in May 2009 and August 2009. Additional sources were identified by scanning available references and online journals and textbooks.
  
  
  RESULTS
  GnRH antagonists, such as degarelix, offer clinicians another means to reduce the level of circulating androgens and limit this growth stimulus directed at malignant prostate tissue. Degarelix has been shown in animal studies to antagonize GnRH receptors in the pituitary gland, resulting in a significant reduction in circulating LH and a subsequent decrease in the synthesis of testosterone. Pharmacokinetic analysis suggests that upon subcutaneous administration, degarelix forms a gel depot, from which the drug then distributes to the rest of the body in a first-order manner. A Phase II study of the effect of degarelix in 187 men with prostate cancer found a loading dose of 240 mg to be not significantly better than 200 mg in reducing serum testosterone concentrations to < or =0.5 ng/mL within 3 days of dosing (200 mg, 88%; 240 mg, 92%). This difference in percentage of patients with testosterone suppression became statistically significant when measured again 1 month into the study (200 mg, 86%; 240 mg, 95%; P = 0.048). Evaluation of 80-, 120-, and 160-mg maintenance doses found all doses effective in maintaining suppression of testosterone, LH, and prostate-specific antigen (PSA); only minor differences were observed during the study period. In a Phase III study of 610 patients with prostate cancer, a loading dose of degarelix 240 mg SC followed by monthly maintenance doses of either 80 or 160 mg was compared with monthly doses of leuprolide 7.5 mg IM. Degarelix was found to be at least as effective as leuprolide in the ability to suppress serum testosterone to < or =0.5 ng/mL for up to 1 year (degarelix response rate, 80 mg, 97.2%; 95% CI, 93.5%-98.8%; degarelix 160 mg, 98.3%; 95% CI, 94.8%-99.4%; leuprolide response rate, 96.4%; 95% CI, 92.5%-98.2%). Other studies investigating various doses and schedules of degarelix have also been conducted. Adverse effects of degarelix in clinical trials were mild and relatively uncommon and included flushing reactions, injection-site pain, weight gain, and increases in serum transaminase levels.
  
  
  CONCLUSIONS
  Degarelix offers another option for chemical castration to reduce the androgenic growth stimulus on prostate cancer cells. The manufacturer of degarelix recommends a loading dose of 240 mg SC followed by the first monthly maintenance dose of 80 mg 28 days later. Serum testosterone and PSA concentrations must be obtained to monitor the response during treatment with degarelix.
authors.affiliation: Massachusetts College of Pharmacy and Health Sciences, Worcester, Massachusetts 01608, USA. michael.steinberg@mcphs.edu
authors.forename: Michael
authors.initials: M
authors.lastname: Steinberg
mesh_terms: D004305:Dose-Response Relationship, Drug; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006727:Hormone Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy*
chemical_list: D006727:Hormone Antagonists; D009842:Oligopeptides; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D007987:Gonadotropin-Releasing Hormone