Non-inferiority of goserelin 10.8 mg given every 12 weeks over 3.6 mg administered every 4 weeks has been demonstrated in premenopausal breast cancer patients with oestrogen receptor (ER)-positive tumours. Suppression of serum oestradiol to postmenopausal level was also confirmed with goserelin given every 12 weeks, according to the results of study presented by Dr Kim HJ of the ASAN Medical Center, Seoul, Korea at 9th European Breast Cancer Conference (EBCC-9) held in Glasgow, Scotland from 19 to 21 March 2014.
Reasons for this study
Ovarian suppression with a gonadotropin releasing hormone agonist (GnRHa) is a well established treatment for premenopausal breast cancer patients with ER-positive tumours, with monthly GnRHa treatment as the standard. However the treatment in men with prostate cancer shows efficacy of a 3-monthly hormonal formulation. Such 3-montly administration is more convenient to patients and associated with cost savings for health system, but its efficacy in women with breast cancer is unclear.
A study (ClinicalTrials.gov identifier NCT00322348), designed to answer such question in breast cancer patients, conducted in Czech Republic, Russian Federation and Ukraine was stopped with recruitment in 2007 due to very slow enrolment.
The study presented at EBCC-9 was designed as a prospective, randomised, non-inferiority study (ClinicalTrials.gov identifier NCT01073865) and performed to compare subcutaneous injection of goserelin (Zoladex®) 10.8 mg and 3.6 mg as a GnRHa in premenopausal patients with advanced or recurrent, ER-positive breast cancer. The patients were randomised in a 1:1 ratio to either of the two treatment groups with goserelin, both given in combination with tamoxifen tablets. Besides recruiting patients in Korea, other study recruiting sites were located in Philippines, India, Japan, Taiwan, and Thailand.
The study endpoints and criteria
The primary outcome measure was the number of patients with progression-free survival (PFS) at 24 weeks, meaning that no progression event was recorded prior to week 24. Overall visit response was foreseen as complete response (CR), partial response (PR) or stable disease (SD) at a tumour assessment at least 24 weeks after randomisation. Overall visit response was assessed according to the RECIST version 1.1.
Secondary outcome measures were the number of responders at 24 weeks after the first dosing. Responders were defined as those patients with a best objective tumour response of CR or PR during the first 24 weeks of therapy. Tumour response was assessed according to the RECIST version 1.1. The overall response rate (ORR) was defined as the proportion of patients who are responders. The researchers also measured oestradiol serum concentrations at 24 weeks after the first dosing.
Study inclusion criteria were pre-menopausal female ≥20 years old. Pre-menopausal status was defined as 1) last menses within 1 year of randomisation, and 2) oestradiol ≥10 pg/mL and FSH ≤ 30 mIU/mL within 4 weeks of randomisation. For patients who have had a hysterectomy, it was acceptable to meet only hormone sensitivity (ER-positive) of primary or secondary tumour tissue and histological/cytological confirmation of breast cancer among patients who are candidates to receive hormonal therapy for advanced breast cancer.
Exclusion criteria were patients who have received tamoxifen or other hormonal therapies as adjuvant therapy for breast cancer within 24 weeks before randomisation and/or who have received prior treatment with hormonal therapies for advanced breast cancer; patients who have received LHRHa as adjuvant therapy for breast cancer within 48 weeks before randomisation; and patients who have relapsed during adjuvant hormonal therapy or within 48 weeks after completion of adjuvant hormonal therapy.
All patients enrolled provided written informed consent and the study was conducted in accordance the applicable local regulatory requirements.
A total of 222 patients were randomised into the study with 109 patients in the goserelin 10.8 mg group and 113 patients in 3.6 mg group. Non-inferiority of goserelin 10.8 mg to goserelin 3.6 mg in terms of the proportion of patients who are progression-free at 24 weeks with the non-inferiority margin of -17.5% was shown. In summary:
- 67 patients (61.5%) in the goserelin 10.8 mg group and 68 patients (60.2%) in the goserelin 3.6 mg group were progression free; 95% CI for the difference: 1.29 (-11.40, 13.90).
- The ORR at 24 weeks was 23.9% in 21 patients in the goserelin 10.8 mg and 26.9% in 25 patients in the goserelin 3.6 mg group (95% CI: −3.02 [−15.47, 9.67]).
- Mean serum oestradiol levels at 24 weeks were similarly suppressed in both groups (20.3 pg/ml for goserelin 10.8 mg vs. 24.8 pg/ml for goserelin 3.6 mg).
- Goserelin 10.8 mg and goserelin 3.6 mg were equally well tolerated.
The researchers concluded that non-inferiority of goserelin 10.8 mg over goserelin 3.6 mg has been demonstrated in their study in premenopausal breast cancer patients with ER-positive tumours. Suppression of serum oestradiol levels to postmenopausal levels was also confirmed with goserelin 10.8 mg.
While the number of patients included in the PRESTIGE study was small, and the results warrant further confirmation in larger group of patients and longer follow-up in term of outcome, the findings are interesting for optimising the current clinical practice and could be considered when evaluating treatment administration time schedules.
The following conflicts of interest were reported by the authors: Shinzaburo Noguchi serves as advisory board member and receives corporate-sponsored research funding from Astrazeneca. In term of other substantive relationships, Eisei Shin is employee and holds stock in AstraZeneca.