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PRIORITY PRESS - 9th Annual Society of Urologic Oncology Winter Meeting

Bethesda, Maryland / December 4-6, 2008

In prostate cancer patients requiring androgen-deprivation therapy (ADT), gonadotropin-releasing hormone (GnRH) antagonists achieve androgen suppression more rapidly and without the testosterone surge and microsurge that accompany administration of agonists. However, they are often poorly tolerated due to allergic reactions. In a clinical development programme, more than 2000 patients have been administered the new GnRH antagonist degarelix. According to findings to date, the agent consistently and rapidly suppressed testosterone to castrate levels without any testosterone flare or histamine side effects.

Phase III Trial Results

The current standard hormone therapy for treatment of prostate cancer in patients requiring ADT is the GnRH agonist leuprolide. A one-year phase III, open-label, multicentre, parallel-group trial was designed to demonstrate statistical non-inferiority of degarelix to leuprolide in patients with histologically-confirmed adenocarcinoma (any stage) of the prostate. As noted by lead investigator Dr. Neal Shore, Carolina Urologic Research Center, Myrtle Beach, South Carolina, “Degarelix was investigated in patients with all stages of prostate cancer deemed clinically appropriate for ADT by the investigator/trial site.”

A total of 610 patients were randomized to one of three treatment regimens: a single subcutaneous (s.c.) injection of degarelix 240 mg followed by 12 injections q28 days of maintenance doses of 80 mg or 160 mg; or 13 intramuscular (i.m.) injections of leuprolide 7.5 mg q28 days. Eligible patients had indications for androgen ablation treatment due to rising prostate-specific antigen (PSA) (<u>></u>2 ng/mL) and serum testosterone (>1.5 ng/mL) levels following prostatectomy or radiotherapy with curative intent.

Baseline characteristics were similar across treatment arms: a median age of 73 (range 50-98 years), a median serum testosterone level of 3.93 ng/mL (range 2.89-5.10) and a median PSA level of 19.0 ng/mL (range 8.7-57). Patients had to have an Eastern Cooperative Oncology Group score <u><</u>2. Patients requiring neoadjuvant hormone therapy were excluded as well as patients considered candidates for curative therapy. The primary end point was treatment response defined as suppression of testosterone to <u><</u>0.5 ng/mL at all monthly measurements from day 28 to day 364.

Results showed that there was a more rapid reduction in PSA levels at day 14 in the degarelix groups where levels declined by 64% (80 mg) and 65% (160 mg) vs. 18% in patients receiving leuprolide. Long-term serum testosterone levels <u><</u>0.5 ng/mL were achieved in 97.2% and 98.3% of degarelix-treated patients and in 96.4% of the leuprolide cohort. Testosterone suppression occurred significantly faster in patients receiving degarelix, with 96% and 95.5% of patients responding by day 3 vs. no patients in the leuprolide group. A testosterone surge (i.e. an increase of <u>></u>15% in testosterone at two measurements during the first two weeks of treatment) with a median 65% increase in levels on day 3 was observed in 161 patients receiving leuprolide vs. no patients receiving degarelix. Microsurges were also recorded in eight patients in the leuprolide group; in four patients, these surges reached values above 0.5 ng/mL (the cutoff for treatment response). There were no microsurges in the degarelix group.

“Its mechanism of action clearly avoids testosterone surge and microsurge which can be especially important in advanced disease,” Dr. Shore explained, adding, “After a decision has been made to start ADT, it seems theoretically inappropriate to risk any testosterone surge; hence, degarelix should be applicable to all patients appropriate for ADT therapy.”

Adverse Events

Previous studies have shown that GnRH antagonists can provoke allergic reactions that prove intolerable to many patients. However, in clinical trials of degarelix, “no allergic reactions were seen in all trials combined,” stated Dr. Shore.

In the phase III trial, both degarelix and leuprolide were well tolerated, with no serious adverse events related to treatment reported. The most frequently occurring adverse event with both agents was injection-site reactions. This was experienced more often with degarelix, and the most frequently reported symptoms of pain, erythema and swelling at the site could be treated with analgesics or cold packs.

While s.c. administration is convenient, according to Dr. Shore, a three-month depot formulation of degarelix is in late-stage development with clinical trials planned for early 2009.

Clinical Implications

GnRH agonists such as leuprolide suppress release of luteinizing hormone (LH) through downregulation. There is an initial stimulation effect or surge that can last for days and sometimes weeks followed by decreased LH and GnRH levels once endogenous production ceases.

The investigator in charge of one of two Canadian trial sites, Dr. Laurence Klotz, Chief of Urology, Sunnybrook Health Sciences Centre, and Professor of Surgery, University of Toronto, Ontario, described the clinical implications of the phase III study. With agonists, “There’s a sharp rise in testosterone that occurs within a few days of administration of the drug. It peaks around 10 to 14 days and it takes about a month to resolve,” Dr. Klotz explained. “Some people have also shown that each time the drug is administered [in maintenance therapy], you can get a little “mini flare” of testosterone.” In contrast, with degarelix and other agents in the new class of antagonists, “there’s a sharp fall in testosterone and you don’t get a flare,” he noted. This is because GnRH antagonists act directly and immediately to shut down GnRH production by occupying the GnRH receptor.

“The major difference between the two drugs is what happens in the first month,” Dr. Klotz commented. “Initially, there’s a big difference in testosterone and also in PSA; the PSA falls much more precipitously with the antagonist than it does with the agonist.” Of utmost concern is the need to prevent testosterone flare in patients that have advanced disease. “If someone has a spinal vertebral metastasis and you stimulate it, then in theory, you could develop a cord compression which might not otherwise happen if they didn’t have that initial flare.”

Typically, the majority of patients requiring ADT therapy do not have extensive bone metastasis with a vertebral mass, but in such patients, GnRH antagonist therapy “is palliative,” Dr. Klotz stated, “but patients live for many years with this type of treatment approach.”

Overall, in prostate cancer patients with rising PSA following localized treatment, the median survival has climbed to eight to 10 years. According to Dr. Klotz, degarelix should be explored in intermittent therapy protocols and possibly as an adjuvant treatment with radiation. Dr. Shore concurred that patients with localized treatment failure and rising PSA might be well suited for an intermittent ADT protocol, and a trial has been designed for this treatment group that is expected to begin in 2009.

Summary

In patients with advanced prostate cancer and/or known metastasis, a testosterone surge may lead to complications. A phase III trial has shown degarelix to be as safe and effective as leuprolide for androgen suppression with the advantage of immediate action and no testosterone flare. Thus, patients do not require supplemental antiandrogens. In the clinical development programme involving over 2000 patients administered degarelix, no immediate or late-onset allergic reactions were reported. This novel GnRH antagonist shows promise in altering the current standard of ADT treatment for advanced prostate cancer.