Clinical Study Results of the New Formulation Leuprorelin Acetate Three-Month Depot for the Treatment of Advanced Prostate Carcinoma

Abstract

Androgen suppression, using gonadotrophin-releasing hormone analogues (leuprorelin), is being developed as an effective treatment of advanced prostate carcinoma. Treatment with leuprorelin acetate 1-month depot is already well established all over the world. In order to increase patients’ acceptability of this treatment, by reducing frequency of administration, a 3-month depot formulation has been developed in Takeda’s research laboratories. A single-shot pharmacokinetic study was conducted to confirm efficacy in terms of hormone suppression and safety of the 3-month depot formulation. Thereafter, a parallel-group, open-labelled, randomized trial was performed to compare clinical efficacy and safety profiles of the 1- and 3-month depot formulations. Patients with a histologically and/or cytologically confirmed advanced prostate carcinoma, without prior hormonal or surgical androgen deprivation, are included. According to 1:2 randomization, patients are treated with either the 1- or 3-month depot for 9 months. To prevent initial flare-up, a concomitant antiandrogen therapy might be administered within 2 weeks prior to first injection and continued for up to 3 weeks. The clinical efficacy of the formulations is assessed by both objective response, EORTC and NPCTG response criteria, and subjective response by using WHO performance status. In addition, the level of prostate-specific antigen is determined every 3 months. The efficacy of the two formulations is also evaluated by determination of serum testosterone, dihydrotestosterone, luteinizing hormone and follicle stimulating hormone. To date, 106 patients have been treated with the 3-month depot and 53 patients with the 1-month depot. Preliminary evaluation shows a satisfying level of testosterone suppression with both the 3- and 1-month depot formulations. Therapeutic equivalence was assumed. The 3-month depot is tolerated as well as the 1-month depot.

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

“…The median PSA reduction achieved with the 1-month and 3-month depot was in a range similar to that reported in the literature for other LH-RH-a [9][10][11] or after bilateral orchiectomy [12]. The response rates obtained, which were virtually identical in the two arms, coincide with the results of previously published experience with both leuprorelin formulations [2,7,13].…”

“…This first human pharmacology trial clearly confirmed the results of the animal experiments. A single administration of 11.25 mg leuprorelin acetate as a 3-month depot again caused adequate suppression of serum testosterone over a minimum of 13 weeks, so that the requirements for clinical trials with multiple dosing were met [7].…”

GnRH agonists and antagonists in prostate cancer

“…Studies comparing one and three months formulations showed no relevant differences concerning effects on testosterone levels and PSA [84][85][86][87]. This was also the case for a comparison of three and six months formulations in a mixed population [88].…”

Leuprorelin Acetate in Prostate Cancer: A European Update

“…This level can be achieved by a one‐month depot injection of 3.75 mg leuprorelin, 9 or by a three‐month depot injection of 11.25 mg (Figure 1). 17,21,22 As with other LHRH analogues, a rise in testosterone levels is seen after the first leuprorelin injection only (see below), but castrate levels are achieved within 2–4 weeks and maintained for the duration of treatment.…”

“…In a randomised open‐label comparative study of the efficacy, safety and tolerability of leuprorelin, one‐month and three‐month depot in patients with advanced prostatic cancer, a single three‐month dose of 11.25 mg has been shown to be therapeutically equivalent to a one‐month dose of 3.75 mg injected three times (Table 1, Figure 1). 17,21,39 This study included 237 patients with locally advanced or metastatic prostate cancer, treated for nine months with either the one‐month 3.75 mg formulation (n=80) or the three‐month 11.25 mg formulation (n=157).…”