Pharmacotherapeutic group: Gonadotropin releasing hormone analogues. ATC code: L02AE03.
Pharmacology: Pharmacodynamics: Zoladex (D-Ser(But)6 Azgly10 LHRH) is a synthetic analogue of naturally occurring luteinising hormone releasing hormone (LHRH). On chronic administration Zoladex LA results in inhibition of pituitary LH secretion leading to a fall in serum testosterone concentrations in men and serum oestradiol concentrations in women. Initially, Zoladex LA, like other LHRH agonists, may transiently increases serum testosterone concentration in men and serum oestradiol concentration in women.
In men by around 21 days after the first depot injection testosterone concentrations have fallen to within the castrate range and remain suppressed with treatment every 12 weeks.
In women, serum oestradiol concentrations are suppressed by around 4 weeks after the first depot injection and remain suppressed until the end of the treatment period at levels comparable with those observed in postmenopausal women. Suppression of oestradiol is associated with a response in breast cancer in premenopausal women and will result in amenorrhoea in the majority of patients.
During early treatment with Zoladex some women may experience vaginal bleeding of variable duration and intensity. Such bleeding probably represents oestrogen withdrawal bleeding and is expected to stop spontaneously.
During treatment with LHRH analogues patients may enter the natural menopause. Rarely, some women do not resume menses on cessation of therapy.
Prostate cancer: In the management of patients with metastatic prostate cancer, Zoladex has been shown in comparative clinical trials to give similar survival outcomes to those obtained with surgical castrations.
In a combined analysis of 2 randomised controlled trials comparing bicalutamide 150 mg monotherapy versus castration (predominantly in the form of Zoladex), there was no significant difference in overall survival between bicalutamide-treated patients and castration-treated patients (hazard ratio = 1.05 [CI 0.81 to 1.36]) with locally advanced prostate cancer. However, equivalence of the two treatments could not be concluded statistically.
In comparative trials, Zoladex has been shown to improve disease-free survival and overall survival when used as an adjuvant therapy to radiotherapy in patients with high-risk localised (T1-T2 and PSA of at least 10 ng/mL or a Gleason score of at least 7), or locally advanced (T3-T4) prostate cancer. The optimum duration of adjuvant therapy has not been established; a comparative trial has shown that 3 years of adjuvant Zoladex gives significant survival improvement compared with radiotherapy alone. Neo-adjuvant Zoladex prior to radiotherapy has been shown to improve disease-free survival in patients with high risk localised or locally advanced prostate cancer.
After prostatectomy, in patients found to have extra-prostatic tumour spread, adjuvant Zoladex may improve disease-free survival periods, but there is no significant survival improvement unless patients have evidence of nodal involvement at time of surgery. Patients with pathologically staged locally advanced disease should have additional risk factors such as PSA of at least 10 ng/mL or a Gleason score of at least 7 before adjuvant Zoladex should be considered. There is no evidence of improved clinical outcomes with use of neoadjuvant Zoladex before radical prostatectomy.
Breast Cancer: Japanese Phase II study: Disease free survival following subcutaneous administration of Zoladex LA 10.8mg once every 12 weeks as adjuvant therapy to premenopausal women with estrogen-receptor-positive breast cancer who underwent radical surgery was assessed in comparison with Zoladex 3.6 mg, both in combination with tamoxifen citrate (the duration of treatment was 96 weeks). Four (4.7%) and 1 (1.2%) events were observed in the Zoladex LA 10.8mg group and Zoladex 3.6 mg group, respectively, with median (min, max) disease free survival of 675.0 days (142 days, 687 days) and 675.5 days (160 days, 685 days) in the Zoladex LA 10.8mg group and Zoladex 3.6 mg group, respectively.
Asian multinational Phase III study: The efficacy and safety of subcutaneous administration of Zoladex LA 10.8mg once every 12 weeks to premenopausal women with estrogen-receptor-positive advanced/recurrent breast cancer were assessed in comparison with Zoladex 3.6 mg, both in combination with tamoxifen citrate (the duration of treatment was 24 weeks). The proportion of patients with progression free survival (%PFS) at Week 24, the primary endpoint, were 67/109 (61.5%) in the Zoladex LA 10.8mg and 68/113 (60.2%) in the Zoladex 3.6 mg with the difference [95% CI] of 1.29% [-11.40 - 13.90], which met the pre-specified non-inferiority criterion.
Pharmacokinetics: Administration of Zoladex LA every 12 weeks ensures that exposure to goserelin is maintained with no clinically significant accumulation. Zoladex is poorly protein bound and has a serum elimination half-life of two to four hours in subjects with normal renal function. The half-life is increased in patients with impaired renal function. For the compound given in a 10.8 mg depot formulation every 12 weeks, this change will not lead to any accumulation. Hence, no change in dosing is necessary in these patients. There is no significant change in pharmacokinetics in patients with hepatic failure.
Following subcutaneous administration of this drug to premenopausal patients with breast cancer, plasma goserelin concentrations reached Cmax 2 hours at-post dose (mean value of 4.5 ng/mL). Subsequently, plasma goserelin levels decreased promptly until 48 hours postdose, and thereafter it eliminated gradually and maintained around the lower limit of quantitation (0.1 ng/mL) at Week 10 and 12.
Toxicology: Preclincal Safety Data: Following long-term repeated dosing with Zoladex, an increased incidence of benign pituitary tumours has been observed in male rats. Whilst this finding is similar to that previously noted in this species following surgical castration, any relevance to humans has not been established.
In mice, long term repeated dosing with multiples of the human dose produced histological changes in some regions of the digestive system. This is manifested by pancreatic islet cell hyperplasia and a benign proliferative condition in the pyloric region of the stomach, also reported as a spontaneous lesion in this species. The clinical relevance of these findings is unknown.