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Androgen Deprivation Therapy for Prostate Cancer: From Hormonal Agonism to Antagonism

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 104th Annual Meeting of the American Urological Association

Chicago, Illinois / April 25-30, 2009

The role of hormonal therapy for prostate cancer has expanded to include patients with metastatic disease and locally advanced disease. Moreover, the National Comprehensive Cancer Network guidelines suggest hormone therapy as an option for selected patients with localized disease, although that is not yet an approved indication, Dr. Evan Goldfischer, Director of Research, Hudson Valley Urology, Poughkeepsie, New York, told delegates here.

Hormonal agonists competitively bind to receptors but can stimulate receptor-mediated activity (testosterone surge of >65% from baseline), leading to a delayed therapeutic effect, he said. Conversely, degarelix binds immediately and reversibly to gonadotropin-releasing hormone (GnRH) receptors in the anterior pituitary, suppressing testosterone to castrate levels within three days in 96% of patients. “Degarelix rapidly reduces the release of luteinizing hormone and follicle-stimulating hormone,” stated Dr. Goldfischer. “It induces a reduction in prostate-specific antigen [PSA] levels and is not associated with systemic anaphylactic reactions.” The principal adverse effects are transient injection-site reaction, hot flashes and loss of libido, he added.

Rapid, Profound and Sustained Testosterone Suppression

Results of a randomized clinical trial showed that degarelix resulted in a 90% reduction in testosterone levels within three days of starting therapy compared with a 65% increase in patients treated with leuprolide, a highly significant (P<0.001) difference (Klotz et al. BJU Int 2008;102(11):1531-8). No patient treated with leuprolide achieved castrate levels of testosterone by day 3, whereas 96% of those treated with degarelix did. By day 28, testosterone levels in the two groups were equal. Moreover, degarelix resulted in a 64% reduction in PSA values by day 14, 85% at 28 days and 95% at 84 days. From day 28 through day 364, it achieved castrate levels of testosterone (£50 ng/mL) in 97.2% of patients vs. 96.4% of patients treated with leuprolide, Dr. Goldfischer reported. In the leuprolide arm, PSA reductions were 18% (P<0.001) at day 14 and 68% (P<0.001) at day 28.

Adverse events occurred in about 80% of patients in both groups, he remarked. The most notable difference between groups related to injection-site reaction, which occurred in 35% of the degarelix group and <1% of leuprolide-treated patients. Virtually all of the injection-site reactions occurred during administration of the initial dose of degarelix. Only 4% of maintenance doses were associated with injection-site reaction. No serious adverse events occurred in either treatment group.

The GnRH antagonist class emerged from relatively recent advances in the understanding of sex-hormone biology, commented Dr. Judd Moul, Director, Duke Prostate Center, Duke University, Durham, North Carolina. Intuitively, receptor antagonism should result in more effective suppression of testosterone compared with agonism. However, the knowledge to develop a receptor agonist preceded that of a receptor antagonist. “If a GnRH receptor antagonist had come first, I doubt that GnRH agonists would ever have been developed,” Dr. Moul suggested.

Key Clinical Data

Several clinical trials contributed to the approval of degarelix in the US for treatment of advanced prostate cancer. One of the key investigations compared its anti-androgen effects to leuprolide (Boccon-Gibod et al. EAU 2008, Milan, Italy). The study involved 610 patients who had adenocarcinoma of the prostate of any stage. Investigators randomized the patients to subcutaneous degarelix 240 mg or leuprolide 7.5 mg. Patients then received monthly maintenance doses of degarelix (160 mg or 80 mg) or leuprolide (7.5 mg).

The primary end point was the probability of a testosterone level of <u><</u>0.5 ng/mL at all monthly measurements from day 28 through day 364, noted Dr. E. David Crawford, University of Colorado, Denver. Key secondary end points were the proportion of patients who had a testosterone surgery, the proportion of patients with a testosterone level of <u><</u>0.5 ng/mL on day 3, per cent change in PSA from baseline to day 28, time to PSA failure and the frequency and severity of adverse events.

Analysis of the primary end point showed that 98.3% of patients who received the 160-mg maintenance dose had testosterone levels £0.5 ng/mL on days 28 through 364, compared with 97.2% of patients who received the 80-mg maintenance dose and 96.4% of patients treated with leuprolide. “Degarelix had an immediate onset of action and no patient had a testosterone surge,” Dr. Crawford reported. “In contrast, testosterone levels increased in patients treated with leuprolide and no patient achieved a castrate level of testosterone by day 3.”

The GnRH antagonist resulted in consistent suppression of testosterone from day 3 through 28. Testosterone levels began to fall gradually after three days in leuprolide-treated patients and the two groups had equal levels by day 28. Both agents maintained suppression of testosterone to castrate levels during one year of follow-up. The average PSA level decreased by 90% at day 28 in patients on both degarelix doses, noted Dr. Crawford. Leuprolide-treated patients required twice as long to achieve castrate levels of testosterone (P<0.001). Moreover, 11% of leuprolide patients required bicalutamide for flare protection.

As anticipated, injection-site reactions (P<0.001) and chills (P<0.01) occurred significantly more often in patients treated with degarelix. Arthralgia and urinary tract infection occurred more often in leuprolide patients (P<0.05 and P<0.01, respectively). The frequency of other adverse events was similar between treatment groups, including hot flashes, weight gain, back pain, hypertension, fatigue, nausea, constipation and hypercholesterolemia. Moreover, a similar proportion of patients in each group withdrew because of adverse events.

“In summary, degarelix suppressed testosterone to castration levels significantly faster than did leuprolide,” stated Dr. Crawford. “The profound suppression of testosterone was sustained for one year. Unlike leuprolide, degarelix did not cause testosterone surges or microsurges. It induced a significantly faster reduction in PSA compared with leuprolide.” The trial was statistically powered to demonstrate the noninferiority of degarelix to leuprolide and that goal was achieved, he added. “The incidence of adverse events was similar with degarelix and leuprolide,” Dr. Crawford added. “No immediate-onset systemic allergic reactions or serious drug-related adverse events occurred in patients treated with degarelix.”

Intermittent vs. Continuous Androgen Ablation

Urologic cancer specialists have yet to determine the relative safety and efficacy of intermittent vs. continuous androgen deprivation therapy (ADT). As reported here this week, the next phase of clinical evaluation of degarelix will examine that issue. Patients with biochemical failure after localized therapy for prostate cancer will be randomized to intermittent therapy with degarelix or to continuous treatment with leuprolide or degarelix. “The primary objective will be to determine whether intermittent ADT with degarelix will maintain castrate levels of testosterone, resulting in persistent low PSA levels, as compared to continuous ADT with degarelix or leuprolide depot,” researchers explained.

The trial’s primary end point is the proportion of patients who achieve a serum PSA level <u><</u>4 ng/mL at 14 months with intermittent vs. continuous ADT, they added. Secondary end points include quality of life, sexual function and the proportion of patients in each of the three treatment groups with a serum PSA <u><</u>4 ng/mL.

Summary

ADT remains an integral component of therapy for hormone-sensitive prostate cancer. Conventional hormone therapy with GnRH agonists causes a disconcerting surge in testosterone before the agents terminate the rise and drive down testosterone levels. The clinical implications of the surge remain incompletely understood. Degarelix, a fourth-generation GnRH antagonist, produces rapid and dramatic reductions in testosterone within the first few days of treatment. Recent clinical studies have confirmed the more favourable testosterone and PSA profile achieved by degarelix, and ongoing studies are examining the agent’s potential when used in combination with other therapies for advanced, hormone-sensitive prostate cancer.

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