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GnRH Antagonists: Advances in Androgen Deprivation Therapy for Prostate Cancer

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 - 105th Annual Meeting of the American Urological Association

San Francisco, California / May 29-June 3, 2010

GnRH agonists have been widely used in the treatment of prostate cancer, achieving effective testosterone suppression in >90% of patients. However, these agents can require as much as 30 days to achieve their full suppressive effects. During that time, testosterone levels actually increase. The impact of this testosterone surge on prostate cancer remains unclear, but it could potentially stimulate prostate cancer cells and lead to clinical exacerbation. Concomitant use of antiandrogens is intended to mitigate the flare although flares have been reported in patients treated with combined androgen ablation. Moreover, antiandrogens increase the cost of therapy and may produce unwanted side effects. According to Dr. Judd Moul, Duke University, Durham, North Carolina, a promising development in androgen deprivation therapy (ADT) is the GnRH antagonist degarelix. This agent binds immediately but reversibly to GnRH receptors, resulting in a rapid, reversible drop in LH, FSH and testosterone.

Pharmacokinetic data from a pivotal phase III trial (BJU Int 2008;102:1531-8), showed that half of patients treated with degarelix achieved castrate testosterone levels by day 1. Testosterone levels <0.5 ng/mL were achieved in 96% of degarelix patients by day 3 compared to none of those receiving the GnRH agonist leuprolide. Testosterone levels in the two treatment groups did not reach equivalence until 28 days, stated Dr. Moul.

After 12 months of treatment, patients randomized to the GnRH antagonist had a significantly lower risk of prostatespecific antigen (PSA) failure or death compared with the GnRH agonist group (P=0.049). “Degarelix maintained castrate levels of testosterone to day 365 with about a 2% rate of testosterone breakthrough and no testosterone surges,” he told the audience. In comparison, 80 % of patients on leuprolide had testosterone surges and 4% had a testosterone breakthrough.

Adverse events occurred in 79% of patients in the GnRH antagonist group and 78% of the GnRH agonist treatment arm. Degarelix was associated with a 35% incidence of injection site reactions with initial treatment, declining to 4% during maintenance therapy. “Most of the reactions were transient, mild to moderate in intensity, and led to discontinuation of <1% of patients, and no systemic allergic reactions were observed,” stated Dr. Moul.

Long-term Testosterone Suppression

After the one year randomized phase, patients in both treatment groups had the option to enter an extension phase of open-label degarelix therapy. Patients in the degarelix arm of the study continued treatment at the same dosage. Patients from the leuprolide arm started degarelix at a dose of 240 mg and were randomized to maintenance therapy with 80 or 160 mg, reported Dr. E. David Crawford, University of Colorado, Denver.

At the end of the first year, the PSA progression-free survival (PFS) hazard rates (HR) in the degarelix and leuprolide arms were 0.11/year and 0.20/year, respectively. After a median follow-up of 840 days, the rates were 0.14 events/year in those who were maintained on degarelix treatment and decreased significantly to 0.08/year in patients switched from leuprolide to the GnRH antagonist (P=0.0029). “These data support the statistically significant benefit for degarelix treatment over… leuprolide seen during the first treatment year and further support the use of degarelix as first-line ADT,” concluded Dr. Crawford.

A separate analysis of the trial data examined PSA failure and serum alkaline phosphatase (ALP) levels. “Total serum ALP is a bone-formation marker used in the diagnosis and followup of bone metastases in prostate cancer patients,” Dr. Crawford explained. “Elevated ALP can be associated with progression of bone metastases and reduced overall survival.”

Investigators defined PSA failure as two consecutive PSA increases of 50% and =5 ng/mL from the nadir level on two consecutive occasions at least two weeks apart. The analysis showed an overall PSA failure rate of 7.7% with degarelix vs. 12.9% with leuprolide. The incidence of PSA failure was lower with degarelix across the range of baseline disease stages and PSA levels, noted Dr. Crawford. Among patients with a baseline PSA >20 ng/mL, those treated with the GnRH antagonist had a significant reduction in the risk of PSA progression (P=0.04).

Reducing Musculoskeletal Risk

Baseline ALP levels were elevated in patients with metastatic disease, consistent with bone metastases. At the end of randomized treatment, degarelix was associated with a significant reduction in ALP levels compared with leuprolide (P=0.014). Moreover, ALP levels tended to rise near the end of the study in the leuprolide group but not in the degarelix arm.

Baseline PSA levels >50 ng/mL were associated with threeto fourfold higher ALP levels. In that patient subgroup, those in the degarelix arm had significantly greater reductions in serum ALP levels compared with leuprolide-treated patients (P=0.007). The greater suppression of ALP levels was associated with a significant reduction in the incidence of adverse musculoskeletal events, with an overall incidence of 17% vs. 26% with leuprolide (P=0.001). “Disease-related symptoms such as arthralgia, back pain, and pain in the extremities occurred more frequently in leuprolide-treated patients with metastatic prostate cancer than in patients receiving degarelix,” stated Dr. Crawford. He concluded, “These data indicate the potential for significantly longer disease control with degarelix compared with leuprolide. The significantly fewer adverse musculoskeletal events reported with degarelix support this finding.”

Optimal Testosterone Suppression

Although the study showed greater testosterone suppression with degarelix, the optimal level of testosterone suppression has remained controversial, particularly as ADT options have increased, noted Dr. Juan Morote, Servicio de Urologia y Transplante Renal, Vall d’Hebron Hospital, Barcelona, Spain. A recent review by Tombal assessing GnRH agonists and castrate levels reported that 2% to 13% of patients had testosterone breakthrough >0.5 ng/mL, whereas 13% to 35% of patients had testosterone breakthroughs >0.2 ng/mL.

In an effort to eliminate some of the uncertainty, Dr. Morote and colleagues evaluated the clinical significance of various castrate levels of testosterone in prostate cancer patients on continuous ADT (Morote et al. J Urol 2007;178(4 Pt 1):1290-5). The main objective was to determine whether survival free of androgen-independent progression (AIP) could be associated with a specific testosterone threshold level.

In 73 patients on continuous ADT, all of whom had three serum testosterone determinations within a six-month period, AIP was defined as three increases in serum PSA after the nadir level had been reached. AIP-free survival was defined as the time to first PSA increase after the nadir. The investigators identified the breakthrough serum testosterone level beyond which an AIP event increased as 0.32 ng/mL. AIP-free survival averaged 88 months in patients who had one or more testosterone values >0.32 ng/mL vs. 137 months in patients whose values remained <0.32 ng/mL at all time points (P=0.03). “This retrospective analysis is the first report to suggest a direct relationship between testosterone increases and AIP,” explained Dr. Morote. “Ineffective testosterone suppression therapy may result in higher prostate cancer mortality.”

Cardiovascular Safety

There have been safety concerns regarding cardiovascular (CV) events and GnRH antagonism, including an increased risk of myocardial infarction and sudden cardiac death and possibly prolongation of the QT interval. However, it should be noted that both arms of the randomized trial comparing the two agents involved patients with high rates of CV comorbidity, including CV disease, diabetes and hypertension. ECGs carried out every three months until study end also showed no difference between treatment groups in mean QT interval over the course of the study. The frequency of marked changes in QT interval from baseline among patients with a QRS complex =120 msec was similar across treatment groups. Rates of CV events were low and comparable for both treatment arms.

Summary

Consistent suppression of serum testosterone is essential for effective ADT in patients with prostate cancer. Testosterone surge, a common phenomenon with conventional GnRH agonists, has a concerning but uncertain impact on the clinical course of prostate cancer. The GnRH antagonist degarelix induces rapid suppression of testosterone that is maintained during long-term treatment. The optimal level of suppression has been controversial, but recent data suggest that the risk of AIP begins to increase at testosterone levels =0.32 ng/mL. Data from a randomized clinical trial showed that degarelix more effectively reduces testosterone, PSA and ALP compared with leuprolide and affords a reduced risk of musculoskeletal adverse events in men with advanced prostate cancer.

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