Dose-escalated abarelix in androgen-independent prostate cancer: a phase I study

Follicle-stimulating hormone has been shown to be a mitogen in preclinical models of androgen-independent prostate cancer and abarelix has been previously shown to significantly reduce follicle-stimulating hormone levels in patients when administered monthly. Consequently, we evaluated the safety of more frequent (biweekly) dosing of abarelix and characterized the effect of this dosing schedule on serum follicle-stimulating hormone levels in men with prostate cancer that is progressing despite luteinizing hormone-releasing hormone agonist therapy. Twenty-one patients with prostate cancer progressing on gonadotropin-releasing hormone agonist therapy discontinued the gonadotropin-releasing hormone agonist and received abarelix-depot 100 mg by intramuscular injection every 2 weeks for up to 12 weeks. Safety profile and effect on serum follicle-stimulating hormone were the primary end-points, while prostate-specific antigen response was a secondary end-point. Abarelix therapy was generally well tolerated. One patient experienced an acute immediate allergic reaction. The mean follicle-stimulating hormone serum concentration declined from 3.5 mIU/ml (95% confidence interval: 2.7-4.3) to 2.0 mIU/ml (95% confidence interval: 1.3-2.6) on day 57 and to 2.0 mIU/ml (95% confidence interval: 0.9-3.0) on day 85 (P=0.008 in a Kruskal-Wallis test), but no patient's follicle-stimulating hormone has reached the lower limit of quantitation (below 0.15 mIU/ml). No patient met criteria for prostate-specific antigen response. At the end of 12 weeks of therapy, three (14.3%) patients had no change in prostate-specific antigen levels on days 57 and 85 compared with baseline. Twelve patients (57%) had stable disease throughout treatment defined as percent change from baseline within -50 to 50% at a given time-point confirmed by a second measurement at least 4 weeks later. Treatment with biweekly abarelix in patients with androgen-independent prostate cancer is feasible with no unexpected toxicity, but fails to completely suppress serum follicle-stimulating hormone levels or produce prostate-specific antigen responses.