Comparison of LH-RH Analogue 1-Month Depot and 3-Month Depot by Their Hormone Levels and Pharmacokinetic Profile in Patients with Advanced Prostate Cancer

Abstract

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 (≤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 (C_max) 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. C_max 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.

Safety and clinical efficacy of a new 6-month depot formulation of leuprorelin acetate in patients with prostate cancer in Europe

“…These results are consistent with other study results published with the well-established 3M depot of leuprorelin acetate showing clinical response rates of 76, 72, 84 and 85%. 3,[6][7][8] Objective progression rate at any time point during the study was slightly higher, but not statistically significant, in the 6M depot group, which may be due to more advanced tumour stages in this group, that is more distant metastases, more lymph node involvement, higher tumour grade, higher Gleason Scores and longer time since first diagnosis. By final examination at month 12, more than 90% of patients in both groups showed no progression.…”

Preparation, characterization, and biodistribution study of technetium-99m-labeled leuprolide acetate-loaded liposomes in ehrlich ascites tumor-bearing mice

“…[1][2][3][4][5][6][7] GnRH agonists induce cell cycle arrest in the Go/G1 phase, but the detailed molecular mechanism is unknown. One of the proposed mechanisms of the antitumor effect of GnRH agonists is the downregulation of GnRH receptor (GnRH-R) activity in the pituitary gland that results in inhibition of sex steroid secretion in patients with premenopausal breast cancer or prostate cancer.…”

Androgen deprivation decreases prostate specific antigen in the absence of tumor: implications for interpretation of PSA results

“…In patients with prostate cancer the decline in PSA after therapy with LHRH analogs is regarded as a sign of disease regression [22,23]. This was the first trial to prospectively examine the influence of an LHRH analog on PSA levels.…”