GnRH Antagonist: a New and an Effective Way of Treatment of Advanced Prostate Cancer

Abstract

Castration remains the mainstay of treatment in the management of metastatic prostate cancer. Medical castration plays an important role in a majority of these patients. Gonadotropin releasing hormone (GnRH) agonists have been commonly used hitherto to achieve medical castration. Arrival of GnRH antagonists have opened a new approach in the management of these patients with distinct drug-related and cancer-related benefits including prevention of microsurges and reduction in cardiovascular complications. This article elucidates the mechanism of action of GnRH antagonists along with its clinical advantages and demerits.

Introduction

Gonadotropin-releasing hormone (GnRH) receptor antagonist is a new approach to androgen-deprivation therapy in patients with prostate cancer. This class of drugs produces a direct and immediate blockade of GnRH pituitary receptors and produces rapid testosterone suppression without an initial surge or subsequent microsurges [1].

Degarelix is a GnRH receptor antagonist and it is indicated for use as an androgen-deprivation therapy in patients with advanced prostate cancer. Degarelix was approved in the USA in December 2008 for the treatment of advanced prostate cancer. Nowadays, it is available in many countries across America, Europe, Australia, and South America [2]. It is available in the market as powder form (with solvent) for solution for subcutaneous injection at two different doses/concentrations: degarelix 120 mg (concentration of 40 mg/mL) and degarelix 80 mg (concentration of 20 mg/mL) [3]. This review documents the growing body of clinical evidence that supports the use of degarelix in prostate cancer and examines how its pharmacological profile may impact treatment outcomes in prostate cancer therapy.

Mechanism of Action of GnRH Antagonists

GnRH antagonists induce chemical castration. GnRH agonists act on pituitary GnRH receptors to produce an intense initial stimulation of release of LH and FSH resulting in a discernible rise in testosterone. GnRH agonist-induced overstimulation overcomes the natural pulsatile control of LH release, which leads to receptor desensitization or downregulation. This in turn suppresses LH and FSH secretion and consequently reduces testosterone to castrate levels [4].

Mechanism of action of GnRH antagonists has more direct effect on testosterone suppression. So, GnRH antagonists cause a rapid and competitive receptor binding blocking the action of GnRH on the pituitary, with no initial increase in gonadotrophin or testosterone. Testicular testosterone production is rapidly suppressed because the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) is prevented [5].

Animal studies of GnRH antagonists showed suppression of LH and testosterone to castrate levels and also administration on GnRH antagonist before an agonist will blunt the expected characteristic LH and testosterone surge induced by the agonist [6, 7].

Development of GnRH Antagonists

GnRH antagonists were developed because GnRH agonist therapy was associated with counterintuitive testosterone surge. The first clinically tested GnRH antagonist was Cetrorelix which showed clinical improvement in patients with prostate cancer. The first GnRH antagonist available clinically for treatment of prostate cancer Abarelix displayed comparable safety profile to GnRH agonist leuprolide.

Earlier-generation GnRH antagonists like abarelix and cetrorelix were limited by adverse events (AEs) because of their histamine-releasing properties which resulted in problematic systemic or local anaphylactoid reactions. Therefore, newer GnRH antagonist agents such as degarelix was synthetically modified to overcome the histamine-releasing characteristics of the GnRH antagonist drug class. In an animal study, when it was compared with other GnRH antagonists like cetrorelix, abarelix, and ganirelix, it showed very weak histamine-releasing properties and the lowest capacity for histamine release [8]. It acts by immediate and competitive blockade of GnRH receptors in the pituitary. Degarelix does not cause an initial stimulation of LH production via the HPG axis, so it does not cause testosterone surge or clinical flare.

Phase 2 Studies

Three randomized, Phase II clinical trials in Europe/South Africa, North America, and Japan were carried out to assess the efficacy and safety of degarelix (Table 1). All these trials were open-label, randomized, parallel-group studies including adult men with histologically confirmed prostate cancer (all stages requiring hormonal treatment).

Table 1.

Summary of phase II and phase III trials of degarelix in prostate cancer

Author (year)	Study design	Number of participants	Results
van Poppel et al. (2008)9	1-year multicenter, randomized, parallel-group, open-label trial	187	Testosterone suppression: 86% (200 mg) versus 95% (240 mg) after 1 month, 92% (80 mg), 96% (120 mg), 100% (160 mg) after 1 year
			PSA response: median reduction of 97–98% after 1 year
Gittelman et al. (2008)10	1-year multicenter, randomized, parallel-group, open-label trial	127	Testosterone suppression: 88% after 1 month, 93 and 98% (60 and 80 mg) after 1 year
			PSA response: median reduction of 96% after 1 year
Ozono et al. (2012)11	1-year multicenter, randomized, parallel-group, open-label trial	273	Testosterone suppression: 99.3% (240/80 mg) and 98.5% (240/160 mg) after 3 days, and 94.5% (240/80 mg) and 95.2% (240/160 mg) between 28 and 364 days
			PSA response: median reduction of 79–80% after 28 days
Klotz et al. (2008)12	1-year, multicenter, randomized, open-label phase III trial	610	Testosterone suppression: 97.2, 98.3, and 96.4% of patients in the degarelix 240/80 mg, degarelix 240/160 mg and leuprolide groups, respectively after 1 year
			PSA response: PSA decline from baseline was significantly faster in the degarelix groups than with leuprolide

PSA prostate-specific antigen

In the 1-year European study [9], 187 patients were randomized to six degarelix treatment groups. Starting doses of either 200 or 240 mg were followed by monthly maintenance doses of 80, 120, or 160 mg, all given via subcutaneous injection. The median age of patients was 72 years. The median baseline levels of testosterone and prostate-specific antigen (PSA) were 4.13 and 27.6 ng/mL, respectively. A monthly maintenance dosage of 160 mg of degarelix resulted in the testosterone levels ≤0.5 ng/mL until the end of the study in 100% of the patients. There was 97–98% reduction in PSA levels after 1 year.

In the North American trial [10], 127 patients were randomized to two degarelix treatment groups. Starting dose was 200 mg followed by monthly maintenance doses of either 60 or 80 mg all given by subcutaneous injection. The median age was 76 years. The median baseline levels of testosterone were 4.13 ng/mL and PSA were 13.4 ng/mL. Patients receiving the monthly maintenance doses of 60 and 80 mg showed reduction in the testosterone levels at all monthly measurements from 1 month to 1 year. There was reduction in the PSA levels by 96% after 1 year in both the groups.

In the Japanese study [11], 273 patients were treated with an initial dose of 240 mg subcutaneous degarelix followed by monthly maintenance doses of either 80 or 160 mg. The median age was 74 years. The median baseline levels of testosterone and PSA were 4.41 and 22.4 ng/mL, respectively. Both the monthly regimens reduced the levels of testosterone. PSA levels were also reduced rapidly and were low throughout the study.

Phase III Study

In North America/Europe, a 1-year, multicenter, randomized open-label Phase III trial was carried out. A total of 610 patients with histologically confirmed adenocarcinoma of the prostate (any stage) were randomized for comparison of efficacy and safety of degarelix at 240 mg subcutaneous for 1 month followed by monthly maintenance doses of 80 mg (240/80 mg) or 160 mg (240/160 mg) subcutaneous as compared to leuprolide at 7.5 mg intramuscular monthly. The median age was 73 years. The median baseline testosterone and PSA levels were 3.93 and 19.0 ng/mL, respectively. There was suppression of testosterone to ≤0.5 ng/mL at all monthly measurements from day 28 to day 364. PSA suppression was maintained throughout the study. Testosterone and PSA suppression by degarelix was significantly faster than leuprolide [12].

Tolerability

Degarelix was generally well tolerated when given for 1 year. Mild to moderate adverse events were observed. Treatment-emergent adverse events were reported in 79% of degarelix 240/80 mg group, 83% of degarelix 240/160 mg group, and 78% of leuprolide group. Most commonly reported adverse events included injection-site reactions (more in subcutaneous injection group than intramuscular injection group) and hot flushes. In the degarelix group, there was lower incidence of arthralgia and urinary tract infection than leuprolide but there was higher incidence of injection-site reactions and chills in the degarelix group. All other treatment-emergent adverse events occurred similarly in both groups. Serious adverse events were reported by 10% patients in degarelix 240/80 mg group, 12% of degarelix 240/160 mg group, and 14% of leuprolide group in the primary phase. A total of 5% of degarelix 240/80 mg, 7% of degarelix 240/160 mg, and 1% of leuprolide patients discontinued the study because of nonfatal adverse events. A total of 7% of degarelix 240/80 mg, 9% of degarelix 240/160 mg, and 6% of leuprolide patients discontinued the study because of serious adverse events. [12].

In a 5-year study, in patients continuing on degarelix and those switching from leuprolide to degarelix, the incidence of adverse events was similar and no new safety signals associated with degarelix emerged. The common adverse events were initial injection-site reactions, hot flushes, and increased weight [13].

There was higher incidence of injection-site reactions occurring after switching from leuprolide to degarelix than before the switch. The frequency and nature of adverse events occurring during the last 3 months of leuprolide treatment in the primary phase of the study was similar to those occurring in the first 3 months after switching to degarelix in the extension phase. Serious adverse events were reported by 7 and 8% patients who switched from leuprolide to degarelix 240/160 or 240/80 mg groups respectively during the first 3 months of the extension phase. Because of the adverse events during first 3 months of the extension phase, seven patients discontinued the study [14].

Cardiovascular Adverse Events

No significant differences were found between leuprolide and degarelix groups for mean change in Fridericia’s correction of QT interval. A markedly abnormal Fridericia’s correction of QT values occurred in very few patients (≤1%) with either treatment. The most common disorder was ischemic heart disease which occurred in 4% of degarelix patients and 10% of leuprolide patients. In this class, the most frequent events were myocardial ischemia and myocardial infarction (each occurring in 2% of leuprolide patients and in less than 1% of those on degarelix). The most common type of arrhythmia was supraventricular arrhythmias (occurring in 2% of the pooled degarelix and 4% of the leuprolide group). Other arrhythmias included bradycardia, atrioventricular conduction disturbances, ventricular arrhythmias, bundle branch block, and cardiac arrest (all occurring in ≤1% in both groups) [15].

In a pooled analysis of data from nine clinical trials containing 1704 men, the rate of CVD events was similar before and after degarelix treatment in the overall patient population. Traditional CV risk factors of age, obesity, and baseline CVD were associated with a higher CVD risk and regular alcohol consumption was associated with a lower risk. Dose and treatment duration of degarelix were not independently associated with CVD events [16].

In a pooled data of six randomized controlled, phase III trials, post- hoc analysis (n = 2328) shows that treatment with degarelix up to 1 year (including 1- or 3-month formulations; n = 1491) significantly lowered the risk of serious cardiovascular events or all-cause mortality in comparison with GnRH receptor agonist therapy with goserelin or leuprolide (n = 837) in the overall population and in patients with a baseline history of cardiovascular disease. But this was not observed in patients with no pre-existing cardiovascular disease [17].

Advantages and Disadvantages of Degarelix Therapy: [2]

Advantages

1. Rapid suppression of testosterone and PSA, without the initial testosterone surge or microsurges

2. A delay in progression to castration-resistant disease as compared to GnRH agonists

3. Evasion of the negative clinical effects associated with surge-induced flare

4. Monotherapy improves the patient compliance.

5. Prolongation of control of skeletal metastases compared to GnRH agonists

6. Possible clinical benefits associated with improved FSH control

Disadvantages

1. Causes side effects, including hot flushes, weight gain and erection problems

2. Skin near to the injections may become red, swollen or sore for a few days

Summary

Degarelix has shown to retain the efficacy benefits without the systemic allergic reactions associated with the earlier members of the class. The current standard of care in advanced prostate cancer shows that degarelix is at least as effective in achieving and maintaining castrate testosterone levels in patients with prostate cancer. It causes significantly faster suppression of testosterone and PSA levels. Degarelix offers better disease control during the first treatment year. Initial longer term clinical data supporting the use of degarelix as first-line androgen-deprivation therapy because these benefits extend beyond 1 year.

Conclusion

Degarelix represent a pharmacological method of castration for patients with prostate cancer which causes a more direct and logical mechanism of action than GnRH agonists. Currently, degarelix is the most extensively studied and widely available GnRH agent. Degarelix has the benefits like faster onset of testosterone suppression and absence of surge/flare, which makes it the effective and tolerated treatment of prostate cancer.