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Published on 13 July 2009

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The role of degarelix in the treatment of metastatic prostate cancer

teaser

Metastatic prostate cancer is a potentially life-threatening condition. First-line therapy aims to reduce serum testosterone levels either surgically or medically and/or to block the androgen receptor

Christian Doehn
MD PhD

Martin Sommerauer

Dieter Jocham

Department of Urology
University of Lubeck
Medical School
Lubeck
Germany

The incidence of prostate cancer in the USA in 2008 was 186,320, and in the same year 28,660 men died from prostate cancer.[1] Hormonal therapy is the standard of care in patients with metastatic prostate cancer and/or in patients who are not able to undergo other treatment options (eg, radical prostatectomy or radiotherapy) because of their age and/or co-morbidity.[2,3] Hormonal therapy aims to reduce serum testosterone below a certain level (“castrate level”) and/or to block the androgen receptor with an anti-androgen.[2-4] Serum testosterone can be lowered by reducing the luteinising hormone (LH) synthesis in the anterior pituitary gland through administration of gonadotropin-releasing hormone (GnRH) agonists.[2,5,6] Today, several GnRH agonists (eg, buserelin, goserelin, leuprolide, triptorelin) are available in one-month, three-month and six-month formulations that are given subcutaneously (SC) or intramuscularly (IM).

Another method of hormonal therapy is competitive blockade of the androgen receptor with steroidal anti-androgens (eg, cyproterone acetate) or nonsteroidal anti-androgens (eg, flutamide, bicalutamide, nilutamide).[2,4,8] A combination of both approaches (surgical castration or GnRH agonist plus anti-androgen) is called combined androgen blockade (CAB) or maximum androgen blockade (MAB).

Over the last decades, first-, second- and third-generation GnRH antagonists were developed.[7,9-11] The major potential advantage is a rapid blockade of the GnRH receptor. However, only two GnRH antagonists (abarelix and degarelix) are presently approved for the treatment of metastatic prostate cancer.

Main discussion
Degarelix is a third-generation GnRH antagonist that is given SC and currently only available in a one-month formulation. All first- and second-line GnRH antagonists had histamine-releasing properties and lacked potency and water solubility. Problems with the incorporation of sufficient quantities of antagonist peptide into sustained-release formulations also existed.[7,9-13]

Efficacy
The efficacy of degarelix was tested in two phase II trials.[14,15] One open-label, randomised phase II study tested a starting dose of 200 mg degarelix SC and a monthly administration of 60 mg degarelix SC (200/60) or 80 mg degarelix SC (200/80).[14] In total, 127/176 screened patients (median age 76 years) with prostate cancer were enrolled. The primary endpoint was the proportion of patients with serum testosterone ≤0.5 ng/ml at all monthly measurements throughout the entire study period (ie, 12 months). Due to several reasons only 87/127 patients (69%) completed the study. At day 3, 89% of all patients had a testosterone ≤0.5 ng/ml without a statistically significant difference between both groups. After one month, 88% of all patients had a testosterone level ≤0.5 ng/ml (93% of patients in the degarelix 200/60 group, compared with 83% of patients in the degarelix 200/80 group; p = 0.073). Only 86% of patients in the degarelix 200/60 group and 77% of patients in the degarelix 200/80 group remained with their testosterone level ≤0.5 ng/ml during the entire study period.[14]

The second study screened 216 patients with prostate cancer, of whom 189 patients (median age 72 years) were randomised to six different dose regimens with an initial dosage of 200 mg degarelix or 240 mg degarelix followed by monthly maintenance dosage of degarelix 80 mg, degarelix 120 mg or degarelix 160 mg (groups 200/80, 200/120, 200/160, 240/80, 240/120, 240/160), respectively.[15] The primary endpoint was the proportion of patients with testosterone ≤0.5 ng/ml after one month and every month thereafter. Due to several reasons, only 147/187 patients (78%) completed the trial. At day 3, 88% of patients with degarelix 200 mg as initial dose and 92% of patients with degarelix 240 mg as initial dose had testosterone levels ≤0.5 ng/ml. After one month a significantly higher proportion of patients who received degarelix 240 mg vs degarelix 200 mg as initial dose had a testosterone ≤0.5 ng/ml (95% vs 86%; p = 0.048). With different maintenance doses (degarelix 80 mg vs 120 mg vs 160 mg) testosterone level remained equal or below 0.5 ng/ml in 92%, 96% and 100% of patients, respectively, until the end of the study.[15]

A randomised, open-label, three-arm phase III study evaluated the efficacy of degarelix versus leuprolide for achieving and maintaining testosterone suppression in patients with prostate cancer over a period of one year.16 Between February 2006 and October 2007, 620/807 screened patients (median age 72 years) were randomised to one of the three following treatment arms:

Arm A: degarelix 240 mg as initial dosage (2 x 3 ml SC) followed by 80 mg (1 x 4 ml SC) monthly.

Arm B: degarelix 240 mg (2 x 3 ml SC) as initial dosage followed by 160 mg (1 x 4 ml SC) monthly.

Arm C: leuprolide 7.5 mg (1 x 1 ml im) monthly. A flare protection with bicalutamide (1 x 50 mg per os) was allowed at the discretion of the investigator.

Primary endpoint of the study was the cumulative probability of testosterone suppression ≤0.5 ng/ml from 28-364 days at monthly measurements. The primary endpoint was reached. The number of patients within the castrate level in arms A, B and C were 202/207 (97%), 199/202 (98%) and 194/201 (96%), respectively. At day 3, 96.1% and 95.5% of patients
treated with degarelix 240/80 and 240/160 had a testosterone level ≤0.5 ng/ml. In contrast, none of the patients in the leuprolide group achieved this result.[16]

Safety and tolerability
In the two phase II trials most adverse events were mild to moderate, but the exact number of mild, moderate and severe adverse events was not reported.[14,15] In the randomised phase III trial, adverse events were reported in 81% of 330 patients of the pooled degarelix groups and in 78% of 156 patients of the leuprolide group. The intensity of all reported adverse events in the pooled degarelix group versus the leuprolide group was mild in 283 patients (69%) versus 138 patients (69%), moderate in 225 patients (55%) versus 101 patients (50%), and severe in 68 patients (17%) versus 26 patients (13%). Serious adverse events were reported in 21 patients (10%) and 24 patients (12%) in the degarelix 240/80 and degarelix 240/160 groups, respectively, compared with 28 patients (14%) in the leuprolide group.[16] Side-effects are given in Table 1.

[[HPE.31]]

Conclusion
Degarelix is the second GnRH antagonist approved by the Food and Drug Administration (FDA) for the treatment of advanced prostate cancer. Efficacy in terms of LH suppression followed by testosterone suppression within three days could be demonstrated in two phase II trials and one phase III trial. Unfortunately, progression-free survival, cancer-specific survival and overall survival were not addressed in these trials.[14-16] While, in theory, rapid suppression of testosterone and a fast PSA decline is clearly positive, its impact on different survival parameters may be rather small in practice.

GnRH agonists (eg, buserelin, goserelin, leuprolide, triptorelin) initially activate GnRH receptors and “produce” an increase of LH and FSH followed by increase of testosterone (testosterone surge) up to twofold 2-3 days later.[2,17] The latter phenomenon may be associated with occurrence of cancer-related symptoms such as bone pain, spinal cord compression, bladder outlet obstruction, cardiovascular problems and others. Also, a worsening of pre-existing symptoms is possible. There seems to be a correlation of clinical flare and tumour load.[17] To reduce clinical flare, antiandrogens (eg, flutamide, bicalutamide) can be given for the first two weeks. In contrast, GnRH antagonists (eg, degarelix) are associated with an immediate onset of action and flare protection is not required. An initial dose of 240 mg degarelix followed by a maintenance dose of 80 mg and 160 mg every four weeks seems to be best in achieving a profound and sustained testosterone suppression.[14,15] Degarelix 240/80 is the approved regimen. However, most patients with prostate cancer receiving GnRH agonists are treated with a three-month formulation. Therefore, it is a clear disadvantage that degarelix is currently only available as a one-month formulation.

For a long time, GnRH antagonists showed relevant histamine release from mast cells with acute systemic allergic reactions.[7] Indeed, the first approved GnRH antagonist abarelix was associated with systemic allergic reactions in 1-3% of patients.[18] All GnRHantagonists demonstrated a concentration-dependent increased histamine release in the rat model.[19] Degarelix, however, showed the lowest histamine release compared with other GnRH antagonists.[19] In none of the degarelix studies was a systemic allergic reaction reported.[14-16] It must, however, be mentioned that in the randomised phase III trial 4% of patients treated with degarelix had chills of unexplained cause. This was not the case in patients treated with leuprolide. Therefore, further reports on degarelix with long-term follow-up on efficacy and safety – especially concerning the allergic potential – are mandatory.[14,15] Another disadvantage is that degarelix must be given at rather high volumes (ie, initially 2 x 3 ml SC followed by 1 x 4 ml every month thereafter). This may, however, explain why 40% of patients experienced local symptoms, including pain at the SC injection site of degarelix, compared with <1% at the IM injection site of leuprolide.[16]

New classes of drugs claiming to be more selective (while less toxic) are being tested in patients with prostate cancer. For instance, selective modulators of androgen receptors or oestrogen receptors (so-called SARM and SERM) are currently being tested in phase III trials in patients with prostate cancer. If these drugs could demonstrate comparable (or even better) efficacy and fewer adverse events, classical hormonal therapy is challenged. More recently, toremifene (a SERM) was shown to be associated with less decrease (in fact it even was an increase) of bone mineral density in patients with prostate cancer treated within a randomised phase III trial.[20]

Today, degarelix offers only minor – if any – advantages over other hormonal therapies. Whether subgroups of patients with high tumour burden or those undergoing intermittent hormonal blockade may really benefit from the immediate testosterone suppression depends on not yet available data.

References
1. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58(2):71-96.
2. Heidenreich A, Aus G, Bolla M, Joniau S, Matveev VB, Schmid HP, Zattoni F; European Association of Urology. EAU guidelines on prostate cancer. Eur Urol 2008;53(1):68-80.
3. Loblaw DA, Virgo KS, Nam R, et al; American Society of Clinical Oncology. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2007;25(12):1596-605.
4. Seidenfeld J, Samson DJ, Hasselblad V et al. Single therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 2000;132(7):566-77.
5. Labrie F, Bélanger A, Luu-The V, et al. Gonadotropin releasing
hormone agonists in the treatment of prostate cancer. Endocr Rev 2005;26(3):361-79.
6. Charlton H. Hypothalamic control of anterior pituitary function: a history. J Neuroendocrinol 2008;20(6):641-6.
7. Cook T, Sheridan WP. Development of GnRH antagonists for prostate cancer: new approaches to treatment. Oncologist 2000;5(2):162-8.
8. Eder IE, Culig Z, Putz T, et al. Molecular biology of the
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9. Schally AV, Redding TW, Comaru-Schally AM. Inhibition of prostate tumors by agonistic and antagonistic analogs of LH-RH. Prostate 1983;4(6):545-52.
10. Doehn C, Jocham D. Technology evaluation: Abarelix, Praecis Pharmaceuticals. Curr Opin Mol Ther 2000;2(5):579-85.
11. Doehn C, Sommerauer M, Jocham D. Drug evaluation: degarelix – a potential new therapy for prostate cancer. Drugs 2006;9(8):565-72.
12. Bajusz S, Kovacs M, Gazdag M, et al. Highly potent
antagonists of luteinizing hormone-releasing hormone free of edematogenic effects. Proc Natl Acad Sci USA 1988;85(5):1637-41.
13. Jiang G, Stalewski J, Galyean R, et al. GnRH antagonists: a new generation of long acting analogues incorporating p-ureido-phenylalanines at position 5 and 6. J Med Chem 2001;44(3):453-67.
14. Gittelman M, Pommerville PJ, Persson BE, et al; Degarelix Study Group. A 1-year, open label, randomized phase II dose finding study of degarelix for the treatment of prostate cancer in North America. J Urol 2008;180(5):1986-92.
15. Van Poppel H, Tombal B, de la Rosette JJ, et al. 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(4):805-13.
16. Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int 2008;102(11):1531-8.
17. Bubley GJ. Is the flare phenomenon clinically significant? Urology 2001;58(2 Suppl 1):5-9.
18. www.fda.gov/Cder/Drug/infopage/plenaxis/default.htm (assessed 30 April 2009).
19. Broqua P, et al. Pharmacological profile of a new, potent and long-acting gonadotropin-releasing hormone antagonist: degarelix. J Pharmacol Exp Ther 2002;301(1):95-102.
20. Smith MR, et al. Toremifene increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer: interim analysis of a multicenter phase 3 clinical study. J Urol 2008 Jan;179(1):152-5.



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