In an open, randomized phase II pharmacokinetic study conducted in Germany and Italy, a total of 42 patients with advanced or metastatic prostate cancer (PCa) were treated for 9 months with the luteinizing hormone-releasing hormone analogue (LH-RH-a) leuprorelin acetate depot in two different formulations. Fifteen patients received the 1-month depot and 27 patients received the newly developed 3-month depot, containing 3.75 mg and 11.25 mg, respectively. In both groups, subcutaneous injections of leuprorelin acetate injected monthly or at 3-month intervals produced a complete down-regulation of the pituitary and led to persistent suppression of testosterone and dihydrotestosterone to the castrate range (< or = 50 ng/dl for testosterone) within the first month of treatment, which thereafter could be maintained over the entire observation period of 9 months. In 10 patients, pretreatment with an antiandrogen for the prevention of clinical flare-up resulted in a slightly more profound and earlier drop in serum testosterone. The 3-month depot showed a higher median peak serum concentration (Cmax) of leuprorelin at 20.8 ng/ml than the 1-month depot at 10.7 ng/ml but, conversely, this did not influence the rise in serum testosterone levels. Cmax occurred at 3 h for the 3-month and at 1 h for the 1-month depot formulation. During the steady state, constant release could be detected, starting on day 3 and day 7 for the 1-month and 3-month depot, respectively. A marked decrease in median prostate-specific antigen levels of 97.8% (1-month depot) and 96.6% (3-month depot) compared with baseline was observed, indicating an objective clinical response for more than 80% of all patients in both arms. Based on European Organization for Research and Treatment of Cancer criteria, the best response in terms of complete/partial remissions and stabilization was comparable in the two arms at 86.7% (1-month depot) and 85.2% (3-month depot). 6.7% in the 1-month group and 3% in the 3-month depot group showed progression of the disease. The most common side effects in both treatment groups were related to hormone deprivation. Both formulations of the potent LH-RH-a leuprorelin acetate were highly effective in the treatment of advanced PCa and led to comparable endocrine and clinical effects.