This site is intended for health professionals only
Hein Van Poppel
Reducing circulating testosterone to castrate levels via androgen deprivation therapy is a common goal in the management of advanced prostate cancer. Because of the permanency and psychological problems associated with bilateral orchiectomy, gonadotrophin-releasing hormone (GnRH) receptor agonists have been the treatment of choice for most patients for a number of years. GnRH receptor agonists reduce serum testosterone to castrate levels in 90-100% of patients, but only after a delay of 7-21 days and they also lead to an initial surge in testosterone levels, which may stimulate prostate cancer cells and exacerbate clinical symptoms.
In patients with advanced disease, this ‘flare’ phenomenon can precipitate a range of clinical symptoms- such as skeletal pain, ureteral obstruction, and spinal cord compression-and can lead to paralysis and, in rare cases, death.
The clinical effects of flare can be limited by concomitant antiandrogen treatment (such as bicalutamide, flutamide), which acts to inhibit the stimulatory effect of the testosterone surge, but this may be associated with increased side-effects.
Mode of action of GnRH receptor blockers
GnRH receptor blockers (antagonists) are a new type of hormonal therapy for prostate cancer that, competitively and reversibly, bind to GnRH receptors in the pituitary, blocking the release of luteinising hormone and follicle-stimulating hormone and, thereby, suppressing testosterone release (Figure 1)., This occurs without the initial stimulation of the hypothalamic- pituitary-gonadal axis associated with GnRH agonists and therefore these agents do not cause clinical flare.
Degarelix (Firmagon) is a new GnRH receptor blocker with an immediate onset of action that induces a fast, profound and sustained testosterone suppression, without a surge. Previous GnRH antagonists have been associated with side effects such as immediate-onset systemic allergic reactions resulting from histamine release, which limited their usefulness. The degarelix molecule was designed to limit histamine release and is not associated with systemic allergic reactions.
Administration and pharmacokinetics
On subcutaneous injection, degarelix forms a gel that results in a sustained release into the circulation, providing a half life of 23-61 days. The bioavailability of degarelix when administered subcutaneously is influenced by the dose volume and concentration: small injection volumes increase its subcutaneous release compared with large volumes, and dose concentration is negatively correlated with bioavailability.
Degarelix is supplied as a powder which is reconstituted in sterile water prior to administration via a subcutaneous injection into the abdominal region- injection should occur immediately following reconstitution. The EMEA approved degarelix dose is a starter dose of 240 mg given as two 3 ml subcutaneous injections of 120 mg (40 mg/ml) followed by monthly maintenance doses of 80 mg, each given as one 4 ml subcutaneous injection (20 mg/ml).
The efficacy and safety of degarelix have recently been examined in a 12-month randomised open-label, parallel-group Phase III study (CS21). In CS21, 610 patients with prostate cancer (any stage), for whom androgen deprivation therapy was indicated were randomised to treatment with: subcutaneous degarelix at a starter dose of 240 mg followed by monthly maintenance doses of either 80 mg (240/80 mg group; n=207) or 160 mg (240/160 mg group; n=202), or monthly intramuscular depot injections of the GnRH receptor agonist, leuprolide (7.5 mg; n=201).
Both degarelix doses were as effective as leuprolide for the primary endpoint-suppression of testosterone to castrate levels (<0.5 ng/ml) from day 28 to study end (day 364) (Table 1). Furthermore, degarelix resulted in a more rapid treatment response compared with leuprolide. At day 3, testosterone levels were <0.5 ng/ml in 96.1%, 95.5% and 0% in the degarelix 240/80 mg, degarelix 240/160 mg and leuprolide 7.5 mg groups, respectively. At day 14 the corresponding numbers were: 100%, 99.5% and 18.2%, respectively. At day 3, median testosterone levels were reduced on average by over 90% in patients receiving degarelix, whereas the GnRH-agonist induced surge was demonstrated by a 65% increase of testosterone levels in those receiving leuprolide (p<0.001). Overall, 80% of patients in the leuprolide group experienced a testosterone surge and 5% experienced microsurges on repeat injections. In contrast, no surges or microsurges were noted in patients receiving degarelix.
Prostate-specific antigen (PSA) levels also fell more rapidly during degarelix treatment; at day 14, PSA levels had declined by 64%, 65% and 18% in the degarelix 240/80 mg, degarelix 240/160 mg and leuprolide 7.5 mg groups, respectively (p<0.001).
At day 28 PSA declines were 85%, 83% and 68%, respectively (p<0.001).
Beyond day 28, PSA was suppressed to very low levels, irrespective of treatment received. PSA failure (two consecutive increases of 50% and at least 5 ng/ml compared with nadir at least two weeks apart) occurred in 8.9%, 14.2% and 14.1% of the degarelix 240/80 mg, degarelix 240/160 mg and leuprolide 7.5 mg groups, respectively. Results of an exploratory analysis showed that PSA failure occurred more frequently in patients with advanced disease and higher baseline PSA level, across all treatment groups.
Numerically fewer PSA failures occurred with degarelix 240/80 mg than with leuprolide 7.5 mg in patients with metastatic disease (22% vs 36%) or PSA levels >20 ng/ml at baseline (16% vs 28%). Similarly, patients with metastatic disease or those with PSA levels â‰¥50 ng/ml at baseline experienced greater reductions in total serum alkaline phosphatase (SALP) with degarelix 240/80 mg than leuprolide.
Patients in the degarelix group maintained S-ALP suppression throughout the 1-year study and did not display the signs of therapy failure, as demonstrated by the late rises in S-ALP levels, which were observed in the leuprolide group.
Most adverse events reported in CS21 were of mild to moderate intensity, irrespective of treatment received. Hormonal side effects such as hot flushes and weight gain were two of the most common adverse events across treatment groups (Table 2). Patients receiving degarelix had a significantly higher incidence of injection-site reactions (40% vs <1%; p<0.001) and chills (4% vs 0%; p<0.01) compared with those in the leuprolide group. These local reactions predominantly occurred after the first dose and were mild or moderate in intensity. The chills typically occurred 5–10 hours after administration of degarelix and lasted less than 24 hours. In contrast to previous GnRH antagonists, no systemic allergic reactions were reported during degarelix treatment. Compared with leuprolide, degarelix was associated with a significantly lower incidence of disease-related side effects such as urinary tract infection (3% vs 9%; p<0.01) and arthralgia (4% vs 9%; p<0.05). Overall, musculoskeletal and connective tissue disorders occurred in 17% vs 26% of patients in the degarelix and leuprolide groups, respectively. Cardiovascular side effects (eg, angina pectoris, atrial fibrillation, cardiac failure, and myocardial ischaemia) were also less common with degarelix compared with leuprolide (9% vs 13%; p=0.089).
Degarelix is a new GnRH receptor blocker with an immediate onset of action that induces a fast, profound and sustained testosterone suppression, without a surge, thereby providing effective and well tolerated therapy for patients with prostate cancer requiring androgen deprivation. The achievement of castrate testosterone levels without a surge means there is no requirement for concomitant antiandrogen therapy and no risk of initial stimulation of the cancer. Furthermore, exacerbation of clinical symptoms such as bone pain and urinary retention are avoided.
The immediate onset of action of degarelix may also result in more rapid symptom relief compared with GnRH agonists and potential quality-of-life benefits for the patient. Degarelix has been shown to be at least as effective and well tolerated as leuprolide in a large, phase II trial, with exploratory analyses suggesting particular benefits in those with more advanced disease. Based on the phase II results, degarelix 240/80 mg was recently approved by the FDA and EMEA offering patients with advanced, hormonesensitive prostate cancer a valuable new treatment option.
1. Lepor H. Rev Urol 2005;7 Suppl 5:S3-S12.
2. Van Poppel H, et al. Urology 2008;71:1001-6.
3. Thompson IM, et al. J Urol 1990;144:1479-80.
4. Perlmutter MA, et al. Rev Urol 2007;9 Suppl 1:S3-S8.
5. Gittelman M, et al. J Urol 2008;180:1986-92.
6. Van Poppel H, et al. Eur Urol 2008;54:805-13.
7. Balchen T, et al. Pharmacokinetics, pharmacodynamics, and safety of a novel fast-acting gonadotropin-releasing hormone receptor blocker, degarelix, in healthy men. 2005 Oct 2; 2005.
8. Princivalle M, et al. J Pharmacol Exp Ther 2007;320:1113-8.
9. Debruyne F, et al. Future Oncol 2006;2:677-96.
10. Broqua P, et al. J Pharmacol Exp Ther 2002;301:95-102.
11. European Medicines Agency. Assessment report for Firmagon (Doc.Ref: EMEA/CHMP/635761/2008). 2008.
12. Doehn C, et al. Drugs 2006;9:565-72.
13. Klotz L, et al. BJU Int 2008;102:1531-8.
14. Tombal B, et al. EAU 2009, abstract 38.
15. Schröder FH, et al. EAU 2009, abstract 40.