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GnRH Antagonists Relugolix and Degarelix: Mechanism and Side Effects

Currently approved GnRH antagonists for the treatment of advanced prostate cancer are degarelix (approved in Germany 2009) and the orally available drug Relugolix (approved in the USA in 2020 and in Europe in 2023). Other formulations are under development or used in assisted fertilization, such as Cetrorelix and Ganirelix. Abarelix was withdrawn from the market due to side effects.

Mechanism of Action of GnRH Antagonists

Gonadotropin-releasing hormone antagonists bind to the GnRH receptor without activation, they stop secretion of LH and FSH with a dramatic reduction of the testosterone concentration.

Indications for GnRH antagonists

Relugolix 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 Relugolix and Degarelix

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).

Relugolix:

Oral administration, half-time 25 hours, 98% of patients reach castration level within 14 days (Shore et al., 2020).

Side Effects of GnRH Antagonists

GnRH antagonists 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.

Further Side Effects:

• Systemic allergic reactions of the immediate-type after injection of degarelix: urticaria, pruritus, hypotension and syncope. Degarelix is reported to cause significantly less allergic side effects compared to abarelix.
• Prolongation of the QT interval or elevated liver enzymes are mainly caused by hypogonadism. In the pivotal trial of Relugolix, however, the risk of relevant cardiovascular events was halved compared to leuprorelin (Shore et al., 2020).

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 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.

Dosage of Relugolix:

360 mg orally as a starting dose, then 120 mg daily.

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

N. D. Shore et al., “Oral Relugolix for Androgen deprivation therapy in Advanced Prostate Cancer.,” NEJM, vol. 382, no. 23, pp. 2187–2196, 2020.

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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