Degarelix: A New Approach For The Treatment Of Prostate Cancer

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 16 Nov 2009 - 4:00 PST

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UroToday.com - Gonadotrophin-releasing hormone (GnRH) agonists are currently the 'standard of care' for androgen deprivation therapy (ADT) in prostate cancer. Improvements in ADT would have a great value for many patients. The agonists are associated with an initial testosterone surge, which delays castration and may stimulate tumor growth and induce 'clinical flare' in patients with symptomatic advanced disease.¹ Consequences of flare include skeletal pain, ureteral obstruction, and spinal cord compression.

GnRH receptor blockers (antagonists) are a new class of agent that act via immediate and competitive blockade of pituitary GnRH receptors. GnRH blockers directly block the release of luteinizing hormone and follicle-stimulating hormone, producing rapid testosterone suppression without initial stimulation of the hypothalamic-pituitary-gonadal axis and the testosterone surge associated with GnRH agonists. ² GnRH blockers thus avoid the need for concomitant antiandrogen flare protection.

Degarelix is a new synthetic GnRH blocker modeled on natural GnRH. Degarelix has a direct and logical mechanism of action with strong GnRH receptor binding. Phase II dose-finding studies in Europe, South Africa and North America established 240 mg as the most effective starting dose, with 80 and 160 mg the most suitable monthly maintenance doses ^3,4 these doses were investigated in a phase III trial.

In a 1-year randomized phase III trial (CS21) involving 610 prostate cancer patients requiring ADT, the efficacy and safety of degarelix was compared with the GnRH agonist leuprolide with respect to achieving and maintaining testosterone suppression. ⁵ Patients received either degarelix 240 mg for 1 month, followed by monthly maintenance doses of 80 or 160 mg, or monthly doses of leuprolide 7.5 mg. Both degarelix doses were at least as effective as leuprolide at inducing and sustaining testosterone suppression to castrate levels (≤0.5 ng/mL) throughout the treatment period. Degarelix achieved fast testosterone suppression; by day 3, testosterone levels were ≤0.5 ng/mL in ~96% of degarelix-treated patients in contrast to none of those receiving leuprolide (Figure 1). With leuprolide, median testosterone levels <0.5 ng/mL were first found on day 28.

No patients receiving degarelix experienced a testosterone surge, compared with 81% of those receiving leuprolide. The occurrence of testosterone stimulation or surge after repeat injections (microsurges), as opposed to the initial testosterone surge, was also investigated. To assess microsurges, testosterone was measured 3 and 7 days after the ninth degarelix/leuprolide injection. While almost all leuprolide patients experienced a testosterone rise, eight patients (4%) receiving leuprolide had a rise >0.25 ng/mL, of whom four experienced testosterone breakthrough (testosterone >0.5 ng/mL). There were no microsurges with degarelix.

Breakthrough testosterone that increases androgen-independent progression has been studied in patients with nonmetastatic prostate cancer receiving medical castration, 38.4% of whom also received antiandrogen. ⁶ Patients with breakthrough testosterone increases >32 ng/dL had a significantly shorter survival free of androgen-independent progression than patients with smaller or no breakthrough (88 vs. 137 months; p <0.03).6

In CS21, degarelix achieved a more rapid reduction in PSA than leuprolide after 14 and 28 days (p <0.001) (Figure 2). After 14 days, PSA levels had declined by 64% and 18% from baseline in the degarelix 240/80 mg and leuprolide groups, respectively; after 28 days, the PSA declines were 85% and 68%, respectively. In both treatment groups, PSA suppression was maintained throughout the study.

Based on the pivotal phase III trial results, degarelix 240/80 mg was approved for the treatment of patients with advanced prostate cancer in December 2008 in the United States and in February 2009 in the European Union. More recently, additional analyses of PSA and serum alkaline phosphatase (S-ALP) data (secondary endpoints) from this trial have been conducted. These showed a significantly lower PSA progression-free survival for the ITT population during this 1-year study. Patients with baseline PSA >20 ng/mL have a significantly lower risk of PSA failures with degarelix 240/80 mg compared with leuprolide 7.5 mg.7

Elevated S-ALP is associated with progression of bone metastases and reduced overall survival. ^8,9 Patients with metastatic disease or those with PSA ≥50 ng/mL at baseline experienced greater reductions in ALP with degarelix than leuprolide. Patients receiving degarelix maintained a suppressed ALP throughout the study and did not display a significant increase in ALP, as seen for the leuprolide patients. These results suggest better control of skeletal metastases (ALP) with degarelix than with leuprolide. ¹⁰

Trials to date show degarelix to be an effective and well-tolerated pharmacological alternative to GnRH agonists for the long-term hormonal treatment of prostate cancer. There is an active ongoing clinical trial program, including studies further assessing long-term efficacy and safety of degarelix and also assessing effectiveness in a number of different treatment settings such as neoadjuvant therapy prior to radiotherapy, treatment for locally advanced symptomatic disease, and in intermittent therapy regimes. The efficacy and safety of a 3-monthly depot regimen is also being evaluated.

References

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2. Broqua P, Riviere PJM, Conn PM, Rivier JE, Aubert ML, Junien JL. Pharmacological profile of a new, potent, and long-acting gonadotropin- releasing hormone antagonist: degarelix. J Pharmacol Exp Ther. 2002;301:95-102.
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4. Van Poppel H, Tombal B, de la Rosette JJ, Persson BE, Jensen JK, Kold Olesen T. Degarelix: a novel gonadotropin-releasing hormone (GnRH) receptor blocker - results from a 1-yr, multicentre, randomised, phase 2 dosage-finding study in the treatment of prostate cancer. Eur Urol. 2008;54:805-813.
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6. Morote J, Orsola A, Planas J, et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol. 2007;178:1290-1295.
7. Tombal B, Miller K, Boccon-Gibod L, et al. Degarelix vs. leuprolide treatment in patients with advanced prostate cancer: PSA failures during a randomised, phase III trial (CS21) [abstract]. Eur Urol Suppl. 2009;8(4):130.
8. Lein M, Wirth M, Miller K, et al.: Serial markers of bone turnover in men with metastatic prostate cancer treated with zoledronic acid for detection of bone metastases progression. Eur Urol. 2007:52:1381-1387.
9. Johansen JS, Brasso K, Iversen P, et al. Changes of biochemical markers of bone turnover and YKL-40 following hormonal treatment for metastatic prostate cancer are related to survival. Clin Cancer Res. 2007:13:3244-3249.
10. Schröder FH, Boccon-Gibod L, Tombal B, et al. Degarelix versus leuprolide in patients with prostate cancer: Effect in metastatic patients as assessed by serum alkaline phosphatase [abstract]. Eur Urol Suppl. 2009;8(4):130.

Written by Bo-Eric Persson, MD as part of Beyond the Abstract on UroToday.com.

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