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Application and clinical benefits of degarelix, a GnRH antagonist, in the treatment of advanced prostate cancer, "Beyond the Abstract," by Neal D. Shore, MD, FACS

Truckee, CA (UroToday.com) - Degarelix is the most widely available and extensively studied gonadotrophin-releasing hormone (GnRH) antagonist for the treatment of advanced prostate cancer (PCa).  Degarelix displays a different pharmacological profile to luteinizing hormone-releasing hormone (LHRH) agonists which suggests several potential clinical advantages.


Effect on testosterone

In the one-year pivotal phase III trial (CS21), degarelix was as effective as leuprolide in suppressing testosterone to ≤ 0.5 ng/mL.[1] However, degarelix achieved faster testosterone suppression without a testosterone surge or microsurges. In contrast, 80% of leuprolide recipients experienced an initial testosterone surge and, in the week following the ninth injection, 4% experienced microsurges. Rapid testosterone suppression with degarelix allows for rapid relief of PCa-related symptoms when present while avoiding the risk of cancer stimulation and worsening of clinical status via a surge-induced clinical flare in patients with advanced PCa. The fast onset of castration with degarelix is particularly beneficial in symptomatic patients. Indeed, the absence of surge-induced tumor-promoting effects with degarelix makes it a preferred androgen deprivation therapy (ADT) option in men with a high tumor burden and risk of acute problems (e.g. pain or spinal cord compression, or urinary tract symptoms). Degarelix also obviates the need for concurrent antiandrogens for flare protection.

Effect on prostate-specific antigen (PSA)

In the CS21 trial, degarelix suppressed PSA faster than leuprolide. Thus, with degarelix 240/80mg, median PSA decreased by 64% after 14 days and by 85% after 28 days compared with decreases of 18% and 68%, respectively, with leuprolide.[1] Also, during the first year, PSA progression-free survival (PFS; PSA failure or death from any cause) was significantly greater with degarelix 240/80 mg versus leuprolide.[2] After adjusting for baseline PSA and disease stage, the hazard ratio indicated a 34% lower risk of PSA failure or death with degarelix. Furthermore, data from a long-term extension study (CS21A) showed improved PSA PFS in patients who, after 1 year, crossed over from leuprolide to degarelix.[3] Thus, after 27.5 months’ follow-up, risk of PSA progression in 1 year was more than halved. The improved PSA PFS with degarelix versus leuprolide in CS21, and in patients crossing over from leuprolide to degarelix in CS21A, is indicative of delayed progression to castration-resistant disease with degarelix. The faster PSA suppression with degarelix may also have prognostic significance. In CS21, the PSA half-life for degarelix (the time required for the PSA concentration to decline by exactly one-half) was shorter[4] and some studies suggest that a shorter PSA half-life is associated with improved progression and survival,[5, 6] although conflicting results have been reported.[7]

Effect on follicle-stimulating hormone (FSH)

In CS21, degarelix produced profound and persistent FSH suppression whereas leuprolide produced an initial FSH surge and levels did not fall to the same extent as with degarelix.[1] In patients who crossed over from leuprolide to degarelix in CS21A, FSH was further decreased within one month to levels similar to those receiving continuous degarelix.[3] While the implications of persistent FSH suppression with antagonists are not fully understood, several studies suggest a link between FSH and PCa.[8, 9, 10, 11, 12]

Serum alkaline phosphatase (S-ALP)

In CS21, patients with baseline metastatic disease or baseline PSA > 50 ng/mL, experienced earlier suppression of the bone marker S-ALP with degarelix 240/80 mg than with leuprolide and reduction in S-ALP was significantly greater with degarelix versus leuprolide at day 364.[13] These subgroups also experienced a late increase in S-ALP with leuprolide (possibly suggestive of treatment failure) but not with degarelix towards the end of the one-year trial period. A reduction in bone turnover marker levels may delay progression of bone metastases and improve survival.

Survival

Preliminary data presented at recent congresses, based on a pooled analysis of 2 328 patients with PCa in 6 clinical trials, indicate that, compared with LHRH agonists, degarelix was associated with significantly higher overall survival during the first year of treatment.[14, 15, 16]

Safety

In CS21, both degarelix and leuprolide were well tolerated.[1] Injection-site reactions occurred in 40% of the pooled degarelix groups versus < 1% of the leuprolide group. These reactions (mostly mild or moderate and occurring predominantly after the first injection) may reflect the different administration route (subcutaneous degarelix versus intramuscular leuprolide) and a higher injection volume of degarelix. Local injection-site reactions have previously been reported with subcutaneously administered GnRH agonists.[17] In the long-term extension trial, the overall incidence of adverse events (AEs) was similar in patients continuing on degarelix and those crossing over from leuprolide to degarelix, and decreased as the study progressed.[3] In patients who crossed from leuprolide to degarelix there was an improved musculoskeletal AE rate after crossover.

Similarities have been noted between cardiovascular (CV) risk factors in the general population and in patients receiving degarelix. In a pooled analysis (n=1 704), the rate of CV disease (CVD) events was similar before and after degarelix treatment in the overall patient population;[18] degarelix dose and treatment duration were not independently associated with CVD events. Traditional CV risk factors of age, obesity and baseline CVD were associated with a higher CVD risk, while regular alcohol consumption was associated with a lower risk. In contrast, the US FDA has highlighted an increased risk of diabetes, heart attack, stroke and sudden death with LHRH agonists, with the requirement to add warnings of such risks to LHRH agonist labels.[19] Moreover, preliminary data presented at 2013 Congresses, based on a pooled analysis of 2 328 patients with PCa in 6 clinical trials, indicate that, in patients with a history of CV disease, degarelix was associated with a significantly lower risk of subsequent serious CV event or death of > 50% over one year of treatment compared with LHRH agonists.[20, 21, 22] Also, this pooled analysis showed that degarelix was associated with lower ALP, significantly fewer fractures, and a lower incidence of urinary tract symptoms versus LHRH agonists, indicative of improved disease control.[14, 15, 16]

Conclusions

Degarelix offers an additional option to LHRH agonists as a first-line ADT for hormonal management of PCa. Moreover, the unique pharmacological profile of degarelix versus agonists is associated with clinical benefits including: improved PSA PFS versus agonists, avoiding the risk of surge-induced flare and the need for concomitant antiandrogens, prolonging control of skeletal metastases in metastatic disease versus agonists, and possible clinical benefits associated with improved FSH control. Degarelix is generally well tolerated; with the exception of injection-site reactions, most AEs reflect androgen suppression or the underlying condition. Treatment with degarelix is associated with a significantly lower risk of subsequent CV events than LHRH agonists, especially in those patients with an existing history of CV disease. References:

  1. Klotz, L., Boccon-Gibod, L., Shore, N.D., Andreou, C., Persson, B.E., Cantor, P. et al. (2008) The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in prostate cancer patients. BJU Int 102: 1531–1538.
  2. Tombal, B., Miller, K., Boccon-Gibod, L., Schröder, F., Shore, N., Crawford, E.D. et al. (2010) Additional analysis of the secondary end point of biochemical recurrence rate in a Phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol 57: 836–842.
  3. Crawford, E.D., Tombal, B., Miller, K., Boccon-Gibod, L., Schröder, F., Shore, N. et al. (2011) A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer. J Urol 186: 889–897.
  4. Van Poppel, H. and Klotz, L. (2012) Gonadotropin-releasing hormone: An update review of the antagonists versus agonists. Int J Urol;19(7):594-601.
  5. Hanninen, M., Venner, P. and North, S. (2009) A rapid PSA half-life following docetaxel chemotherapy is associated with improved survival in hormone refractory prostate cancer. Can Urol Assoc J 3: 369–374.
  6. Lin, G.W., Yao, X.D., Zhang, S.L., Dai, B., Ma, C.G., Zhang, H.L. et al. (2009) Prostate-specific antigen half-life: a new predictor of progression-free survival and overall survival in Chinese prostate cancer patients. Asian J Androl 11: 443–450.
  7. Park, Y.H., Hwang, I.S., Jeong, C.W., Kim, H.H., Lee, S.E. and Kwak, C. (2009) Prostate specific antigen half-time and prostate specific antigen doubling time as predictors of response to androgen deprivation therapy for metastatic prostate cancer. J Urol 181: 2520–2524.
  8. Ben-Josef, E., Yang, S.Y., Ji, T.H., Bidart, J.M., Garde, S.V., Chopra, D.P. et al. (1999) Hormone-refractory prostate cancer cells express functional follicle-stimulating hormone receptor (FSHR). J Urol 161: 970–976.
  9. Heracek, J., Urban, M., Sachova, J., Kuncova, J., Eis, V., Mandys, V. et al. (2007) The endocrine profiles in men with localized and locally advanced prostate cancer treated with radical prostatectomy. Neuro Endocrinol Lett 28: 45–51.
  10. Mariani, S., Salvatori, L., Basciani, S., Arizzi, M., Franco, G., Petrangeli, E. et al. (2006) Expression and cellular localization of follicle-stimulating hormone receptor in normal human prostate, benign prostatic hyperplasia and prostate cancer. J Urol 175: 2072–2077.
  11. Radu, A., Pichon, C., Camparo, P., Antoine, M., Allory, Y., Couvelard, A. et al. (2010) Expression of follicle-stimulating hormone receptor in tumor blood vessels. N Engl J Med 363: 1621–1630.
  12. Gartrell, B.A., Tsao, C.-K. and Galsky, M.D. (2012) The follicle-stimulating hormone receptor: A novel target in genitourinary malignancies. Urol Oncol Apr 16. [Epub ahead of print]
  13. Schröder, F.H., Tombal, B., Miller, K., Boccon-Gibod, L., Shore, N.D., Crawford, E.D. et al. (2010) Alkaline phosphatase changes in prostate cancer patients receiving degarelix or leuprolide: results from a 12-month, comparative, phase III study (CS21). BJU Int 106: 182–187.
  14. Miller K. et al. Disease control-related outcomes from an analysis of six comparative randomised clinical trials of degarelix versus luteinising hormone-releasing hormone (LHRH) agonists. European Association of Urology 28th Annual Congress, Milan 2013, abstract 678
  15. Crawford ED, et al. Degarelix versus LHRH agonists: Differential skeletal and urinary tract outcomes from an analysis of six comparative randomized clinical trials. American Society of Clinical Oncology Genitourinary Cancers Symposium, Orlando 2013, abstract 68
  16. Shore N, et al. Analysis of disease control-related outcomes from six comparative randomised clinical trials of degarelix versus luteinising hormone-releasing hormone agonists American Urological Association Annual Meeting, San Diego 2013, abstract 716
  17. Oka, D., Shiba, M., Arai, Y., Nakayama, M., Takayama, H., Inoue, H. et al. (2006) Skin reactions to 3-month depot type of luteinizing hormone-releasing hormone agonist therapy. JMAJ 49: 48–54.
  18. Smith, M.R., Klotz, L., van der Meulen, E., Colli, E. and Tankó, L. (2011) Gonadotropin-releasing hormone blockers and cardiovascular disease risk: analyses of prospective clinical trials of degarelix. J Urol 186: 1835–1842.
  19. US Food and Drug Administration (FDA). FDA Drug Safety Communication 10-20-2010. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm229986.htm. Accessed July 2012
  20. Tombal B. et al. Lower risk of cardiovascular (CV) events and death in men receiving ADT by gonadotropin releasing hormone (GnRH) antagonist, degarelix, compared with luteinising hormone-releasing (LHRH) agonists. European Association of Urology 28th Annual Congress, Milan 2013, abstract 677
  21. Albertsen PC et al. Comparison of the risk of cardiovascular events and death in patients treated with degarelix compared with LHRH agonists. American Society of Clinical Oncology Genitourinary Cancers Symposium, Orlando 2013, abstract 42
  22. Albertsen P, et al. Androgen deprivation therapy by a gonadotropin releasing hormone antagonist, degarelix, lowers the risk of cardiovascular events or death when compared to luteinising hormone-releasing agonists American Urological Association Annual Meeting, San Diego 2013, abstract 781
Written by:

Neal D. Shore, MD, FACS  - Medical Director for the Carolina Urologic Research Center and Atlantic Urology Clinics, Myrtle Beach, SC USA

 

Experience with degarelix in the treatment of prostate cancer - Abstract