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GnRH Antagonists Abarelix and Degarelix

Currently approved GnRH antagonists for the treatment of advanced prostate cancer are abarelix (approved in Germany since 2008) and degarelix (approved in Germany 2009). Other GnRH antagonists are in development or are being used for fertility treatment (cetrorelix and ganirelix) (Debruyne et al., 2006).

Mechanism of Action of GnRH Antagonists

Degarelix and abarelix are gonadotropin-releasing hormone antagonists, they stop secretion of LH and FSH with a dramatic reduction of the testosterone concentration.

Indications for GnRH antagonists

Abarelix and degarelix are used for hormone therapy of advanced or metastatic prostate cancer, as an alternative to surgical castration or treatment with GnRH analogs. The advantage of GnRH antagonists is an immediate, fast and reliable decrease in serum testosterone concentration (usually below 0.2 ng/ml). A short-term increase in testosterone, which is typical for GnRH analogs, does not occur. Thus, GnRH antagonists are ideal in patients who are at risk by a testosterone surge (e.g., symptomatic bone metastases with spinal cord compression). Disadvantages of GnRH antagonists is the limited data on long term safety, particularly concerning the immediate type allergic reaction or the cardiac side effects.

Pharmacokinetics of Abarelix and Degarelix

Abarelix:

Abarelix is a synthetic decapeptide, which is administered as an intramuscular depot preparation. After treatment with abarelix, 94% of the patients reach castration level (<0.5 ng/ml testosterone) within 4 weeks (Trachtenberg et al., 2002) .

Degarelix:

Degarelix is a synthetic peptide derivative of the natural GnRH, which is administed as a subcutaneous depot preparation. After treatment with degarelix, 99% of patients reach castration level within 7 days (Klotz et al., 2008).

Side Effects of GnRH Antagonists

Abarelix and Degarelix cause a pronounced hypogonadism with the following side effects (similar to GnRH agonist or surgical castration): osteoporosis, hot flashes, decreased libido, loss of erectile function, impaired memory function, physical weakness, fatigue, depression, increased cardiovascular risk, elevated transaminases and gynecomastia.

Specific side effects of abarelix:

• Systemic allergic reactions of the immediate-type: urticaria, pruritus, hypotension and syncope. The frequency of severe allergic reaction after a year of therapy with abarelix is 1.7%. Due to the possible severity of allergic reactions, the administration of abarelix is controversial.

Specific side effects of degarelix:

• Allergic reactions: degarelix is reported to cause significantly less allergic side effects compared to abarelix.

Contraindications of Degarelix and Abarelix

• GnRH antagonists are contraindicated (and useless) after surgical castration.
• Children and Women
• Severe allergic reactions after injection.
• QT interval exceeding 450 msec.
• Persistently increased transaminase concentrations (twice of the standard value).
• Hepatic and renal insufficiency.

Dosage of Abarelix:

Intramuscular injection of 100 mg abarelix on days 1, 15, 29 and every 4 weeks thereafter. Monitoring of therapy success: testosterone and PSA concentration.

Dosage of Degarelix:

Subcutaneous injection of 2 × 120 mg degarelix at day 1 (two injections), followed by 80 mg s.c. every 4 weeks. Monitoring of therapy sucess: testosterone and PSA concentration.

References

Debruyne u.a. 2006 DEBRUYNE, Frans ; BHAT, Gajanan ; GARNICK, Marc B.: Abarelix for injectable suspension: first-in-class gonadotropin-releasing hormone antagonist for prostate cancer.
In: Future Oncol
2 (2006), Dec, Nr. 6, S. 677–696. -
URL http://dx.doi.org/10.2217/14796694.2.6.677

Klotz u.a. 2008 KLOTZ, L. ; BOCCON-GIBOD, L. ; SHORE, N. D. ; ANDREOU, C. ; PERSSON, B.-E. ; CANTOR, P. ; JENSEN, J.-K. ; OLESEN, T. K. ; SCHRöDER, F. H.: The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer.
In: BJU Int
102 (2008), Dec, Nr. 11, S. 1531–1538. -
URL http://dx.doi.org/10.1111/j.1464–410X.2008.08183.x

Trachtenberg u.a. 2002 TRACHTENBERG, J. ; GITTLEMAN, M. ; STEIDLE, C ; BARZELL, W. ; FRIEDEL, W. ; PESSIS, D. ; FOTHERINGHAM, N. ; CAMPION, M. ; GARNICK, M. B. ; GROUP, Abarelix S.: A phase 3, multicenter, open label, randomized st.udy of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer.
In: J Urol
167 (2002), Apr, Nr. 4, S. 1670–1674

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