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Androgen Deprivation Therapy in 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 - 25th Congress of the European Association of Urology

Barcelona, Spain / April 16-20, 2010

Until recently, gonadotropin-releasing hormone (GnRH) agonists have been the preferred approach for reducing testosterone levels in patients with advanced prostate cancer, but these agonists initially stimulate GnRH receptors, producing a spike in production of testosterone and other sex-related hormones before instigating downregulation. With GnRH agonists, castration levels are not usually achieved for at least 30 days. The recently approved GnRH receptor blocker degarelix has shown that it suppresses testosterone faster than GnRH agonists without surges (Klotz et al. BJU Int 2008;102:1531-8) and new data suggest it remains effective even when employed as a second-line agent.

After GnRH Agonist Failure

According to a study led by Dr. Kurt Miller, Urology Clinic, Charité Hospital, Berlin, Germany, there is a need for non-cytotoxic second- and third-line therapies for prostate cancer showing signs of hormone resistance. The primary objective of the study was to explore whether degarelix, a new GnRH receptor blocker, could stabilize or reverse disease progression as defined by prostate-specific antigen (PSA) levels after failure of GnRH agonist treatment. Investigators reported that the hormonal data indicated that any slight failure in complete castration might predict a good second-line response to degarelix.

In this open-label, multicentre study, 25 patients with prostate cancer previously treated for at least one year with a GnRH agonist (mean time to agonist failure was 4 years) and experiencing PSA progression (at least two consecutive increases in PSA at a level of 50% above nadir with at least one PSA =2.5 ng/mL) were initiated on a subcutaneous (s.c.) injection of degarelix 240 mg followed by a monthly maintenance dose of 80 mg. Most patients had either metastatic (28%) or locally advanced prostate cancer (44%) with a Gleason score between 7 and 10 (76%).

After the switch to degarelix there was a prolongation in PSA doubling time in 64% of patients, 88% achieved undetectable luteinizing hormone (LH) levels and 84% achieved a fall in follicle-stimulating hormone (FSH) levels relative to treatment on the GnRH agonist. Four patients (16%) achieved stabilization or reversal of prostate cancer progression based on PSA levels within one month and 40% of patients achieved a fall in testosterone. Other patients appeared to have a late response (>3 months) to degarelix. The switch to degarelix was well tolerated with all adverse events described as mild or moderate and none leading to discontinuation of therapy.

The activity of this GnRH receptor blocker in prostate cancer after treatment with a GnRH agonist is further supported by new extension data from the pivotal CS21 phase III study of degarelix (Klotz et al. BJU Int 2008). In that study, 610 patients with advanced prostate cancer, including metastatic cancer, were randomized to s.c. degarelix (240 mg loading dose followed by one of two monthly maintenance doses of 160 mg or 80 mg) or to the GnRH agonist leuprolide 7.5 mg intramuscular (i.m.) monthly injection. As expected from the differences in the mechanism of action, degarelix achieved a much faster decline in testosterone and was not inferior at providing sustained testosterone suppression at the end of 12 months of treatment. Although injection-site reactions were more common on degarelix (40% vs. 1%; P<0.001, 4% after the first injection), urinary tract infections (3% vs. 9%; P<0.01) and arthralgia (4% vs. 9%; P<0.05) were less common and hormone-related side effects were similar. The authors also associated degarelix with less need for anti-androgen supplements to prevent flares.

Evaluating Treatment Switch

In the newly reported CS21 extension study led by senior investigator Dr. Jean de la Rosette, Department of Urology, AMC University Hospital, Amsterdam, The Netherlands, 134 patients who were originally randomized to leuprolide and completed one year of therapy were switched in a randomized fashion to either 80 mg or 160 mg degarelix after a starting dose of 240 mg. After 84 days following the switch, the reductions in testosterone, PSA and LH achieved with leuprolide from baseline had been maintained on degarelix. It is notable that although the FSH levels were decreased by 50% from baseline on leuprolide, they decreased further after the switch to degarelix reaching an 80% reduction from baseline. The pattern of adverse events was similar to that observed during the original one-year randomization with more injection-site reactions with degarelix, including three patients who discontinued therapy for this reason, but a similar pattern of hormone-related side effects.

Researchers reported that after switching from leuprolide to degarelix, testosterone, PSA and LH suppression was maintained and degarelix was well tolerated by prostate cancer patients. While these data reinforce the initial findings that degarelix is an effective option in patients with advanced prostate cancer, they suggest that the clinical significance of the larger effect of degarelix on serum FSH levels, such as the potential for direct tumour effects, merits further exploration.

The data showing persistent suppression by degarelix are reassuring, but it is also possible that degarelix will result in a better long-term outcome. In his evaluation of the data, Prof. Hein van Poppel, University Hospital Gasthuisberg, Leuven, Belgium, concentrated on the differences in the mechanism of action, particularly the much faster decline in hormone levels. “A consequence of this fast reduction in testosterone is that we have a fast reduction in PSA for degarelix compared to LHRH agonists,” he remarked. Although PSA progression-free survival was not a primary study end point, he noted that “there was a significant effect in favour of degarelix.” Moreover, “if we look at the data by baseline PSA level, we see the differences in favour of degarelix are maintained [over time].”

Now that survival of prostate cancer patients is measured in years rather than months, it is important to have data on long-term use of these agents, particularly given the concerns about safety, but one issue is how hormone suppression will be employed early in the disease, such as an adjunct to radiation in localized disease. Some argue for short-term use because of the increased risk of cardiovascular (CV) events from prolonged exposure, but others, such as Prof. Laurent Boccon-Gibod, CHU-Bichat-Claude Bernard, Paris, France, have suggested that a more individualized approach might be appropriate. He noted that in patients without CV risk factors, the benefit:risk ratio appears to favour long-term hormone suppression. Although he cautioned that oncologists “should consult a cardiologist when faced with patients with CV risk factors” who are being considered for extended hormone suppression therapy, he indicated that drugs suppressing GnRH activity should not be overlooked even at early stages of prostate cancer.

Indeed, the treatment of prostate cancer, particularly in advanced disease, should be a multidisciplinary effort with dialogue between the urologist, radiologist and medical oncologist, according to Dr. Francesco Montorsi, Vita-Salute University San Raffaele, Milan, Italy. He indicated that the advances in this field have been substantial and are accelerating. Although the introduction of a new GnRH receptor blocker is just one addition to the options for controlling advanced disease, the increasing array of choices makes collaboration among specialists essential for rendering the best possible care to the patient.

Summary

New data on the GnRH blocker degarelix as a second-line approach to suppression of testosterone to prevent prostate cancer progression has reinforced the earlier phase III data that demonstrated that this agent was at least as effective as leuprolide, a commonly employed GnRH agonist. The persistent suppression of testosterone, PSA and LH over extended periods is similar with degarelix and leuprolide, but unlike the agonist, the receptor blocker provides a more rapid suppression of testosterone and appears to provide better FSH suppression. Together, these data suggest that degarelix can be used as a substitute for GnRH agonists either for treatment initiation or in the event of GnRH agonist failure.

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