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The clinical results in phase III for Abarelix are outstanding. The following should help explain:
Standard and Newer Hormonal Therapies
In treating patients with advanced prostate cancer, one must decide whom to treat, how to treat, and when to treat. Dr. John Trachtenberg, Professor of Surgery and Medical Imaging at the University of Toronto and Director of the Prostate Center at the Princess Margaret Hospital discussed in his presentation the "how" and "when" of treatment.
Luteinizing Hormone-Releasing Hormone Antagonists
Standard "how" began after androgen ablation therapy was introduced by Drs. Huggins and Hodges in 1941 as reported in the Archives of Surgery.[21] The equivalency of surgical castration to estrogen administration was established, leading to marked tumor volume regression and palliation of symptoms. More than 40 years later, luteinizing hormone-releasing hormone (LH-RH) analogue agonists, such as leuprolide acetate, were introduced, providing similar efficacy, with improved safety and decreased adverse effects compared with estrogen therapy.[22]
Kaisary and associates[23] showed in a randomized clinical trial that the LH-RH analogue goserelin was as effective in lowering serum testosterone concentrations in patients with previously untreated metastatic prostate carcinoma as surgical castration. It induced equivalent subjective and objective response rates with equivalent times to treatment failure and equivalent overall survival of 20 to 30 months. Since their introduction, these agents have come to be regarded as standard therapy for advanced prostate cancer in lieu of estrogens.
In an effort to improve on the short survival times afforded by LH-RH agonists, investigators proposed that maximal androgen blockade be used to prevent the development of androgen-insensitive or androgen-resistant prostate cancer clones, originally brought about by incomplete androgen blockade. The adrenal glands were targeted as the significant independent source of such androgen production. The combination of antiandrogen blockade with LH-RH analogues predictably reduced the flare response seen in the first 7 to 10 days after LH-RH analogue injection. However, when 26 randomized clinical trials with a combined enrollment of more than 8000 patients were analyzed, most failed to show improvement in either time to response or overall survival.[24] A meta-analysis of 22 randomized trials, including 5710 patients with advanced prostate cancer, showed a statistically insignificant 3% to 5% improvement in 5-year survival rates when patients received maximal androgen blockade vs those who underwent surgical castration alone.[25]
Gonadotropin-Releasing Hormone Antagonists
Peptide antagonists of gonadotropin-releasing hormone (GnRH), such as abarelix, are now being tested in phase 3 trials, having been shown previously to rapidly decrease serum testosterone levels without producing a flare reaction.[26] Two dose formulations have been studied, a continuous subcutaneous infusion and a recently developed sustained-release formulation (abarelix-depot), which allows for intramuscular or subcutaneous injection once every 28 days. In one study, in 26 patients with stage D1 or D2 prostate cancer or with rising PSA levels following radiation therapy, radical prostatectomy, or other local therapy, continuous subcutaneous infusion of abarelix in doses up to 50 mcg/kg daily produced castrate levels of testosterone in 100% of patients within 48 hours. These castrate levels were sustained throughout the 28-day treatment period. A dose-related PSA reduction of greater than 85% from baseline was also observed.
In a second study, prostate gland volume declined by 22% in 36 patients with stage T1c to T3 disease who were treated with daily continuous infusion of abarelix for up to 85 days before brachytherapy or external beam radiation. Overall reduction in prostate volume was 35%, although a 43% reduction was observed in patients with baseline gland volumes greater than or equal to 42 cm3. Castrate levels of testosterone were achieved in 35 of 36 patients within 2 weeks of infusion initiation, and all patients achieved castrate levels within 4 weeks.
A third study compared gonadotropin and androgen levels following abarelix-D vs leuprolide and goserelin use for 12 weeks.[27] Testosterone was reduced to castrate levels in 159 (76%) of 209 patients at the end of week 1 in patients treated with abarelix-D as opposed to leuprolide or goserelin, both of which produced comparable castrate levels only by week 4. Ten of 11 patients with stage D2 prostate cancer achieved objective responses at week 12 following treatment with abarelix-D (1 complete remission, 2 partial remissions, 7 stable disease). At a dose of 50 mg intramuscularly once a month, abarelix-D caused few if any adverse effects. PSA levels also declined much more rapidly in those patients treated with abarelix-D vs patients treated with leuprolide or goserelin.[27] A 50% PSA reduction was achieved in 79% of the patients treated with abarelix-D at the end of 1 month vs 55% in the leuprolide and goserelin-treated cohort (P=.02).
Both injection of abarelix solution and abarelix-D induced rapid decreases in androgen, gonadotropin, and PSA levels in patients with locally advanced prostate cancer, producing a readily maintained medical castration. Additional phase 3 data presented at the 36th Annual Meeting of the American Society of Clinical Oncology confirmed that abarelix induced medical castration more rapidly than leuprolide[28] or leuprolide plus bicalutamide[29] without evidence of the initial testosterone surge characteristic of GnRH superagonists.
These agents represent distinct alternatives to surgical and other medical forms of castration, with no significant toxic effects observed. It will be interesting to see how abarelix is incorporated into future clinical regimens, whether as a single agent or in combination with other hormonal or cytotoxic agents. |
