Abstract: We included nine studies randomising 4514 women for meta-analysis and review. Overall results for the primary endpoint of PFS indicated that women receiving fulvestrant did at least as well as the control groups (hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.89 to 1.02; P = 0.18, I2= 56%, 4258 women, 9 studies, high-quality evidence). In the one high-quality study that tested fulvestrant at the currently approved and now standard dose of 500 mg against anastrozole, women treated with fulvestrant 500 mg did better than anastrozole, with a HR for TTP of 0.66 (95% CI 0.47 to 0.93; 205 women) and a HR for overall survival of 0.70 (95% CI 0.50 to 0.98; 205 women). There was no difference in PFS whether fulvestrant was used in combination with another endocrine therapy or in the first- or second-line setting, when compared to control treatments: for monotherapy HR 0.97 (95% CI 0.90 to 1.04) versus HR 0.87 (95% CI 0.77 to 0.99) for combination therapy when compared to control, and HR 0.93 (95% CI 0.84 to 1.03) in the first-line setting and HR 0.96 (95% CI 0.88 to 1.04) in the second-line setting. Overall, there was no difference between fulvestrant and control treatments in clinical benefit rate (risk ratio (RR) 1.03, 95% CI 0.97 to 1.10; P = 0.29, I2 = 24%, 4105 women, 9 studies, high-quality evidence) or overall survival (HR 0.97, 95% CI 0.87 to 1.09, P = 0.62, I2 = 66%, 2480 women, 5 studies, high-quality evidence). There was no significant difference in vasomotor toxicity (RR 1.02, 95% CI 0.89 to 1.18, 3544 women, 8 studies, high-quality evidence), arthralgia (RR 0.96, 95% CI 0.86 to 1.09, 3244 women, 7 studies, high-quality evidence), and gynaecological toxicities (RR 1.22, 95% CI 0.94 to 1.57, 2848 women, 6 studies, high-quality evidence). Four studies reported quality of life, none of which reported a difference between the fulvestrant and control arms, though specific data were not presented. For postmenopausal women with advanced hormone-sensitive breast cancer, fulvestrant is at least as effective and safe as the comparator endocrine therapies in the included studies. However, fulvestrant may be potentially more effective than current therapies when given at 500 mg, though this higher dosage was used in only one of the nine studies included in the review. We saw no advantage with combination therapy, and fulvestrant was equally as effective as control therapies in both the first- and second-line setting. Our review demonstrates that fulvestrant is a safe and effective systemic therapy and can be considered as a valid option in the sequence of treatments for postmenopausal women with hormone-sensitive advanced breast cancer.

Plain-language summary: The evidence is current to 7 July 2015. Our review identified nine clinical trials that compared the effectiveness and safety of fulvestrant against other standard treatments for advanced hormone-sensitive breast cancer and pooled the data from these trials to analyse all the data together. Three different endocrine therapies were analysed as comparator drugs against fulvestrant. Two of these drugs were the aromatase inhibitors anastrozole and exemestane, which lower oestrogen levels in postmenopausal women, and the third was tamoxifen, which works by blocking oestrogen. Four of the studies were in the first-line setting, meaning that fulvestrant was tested against these endocrine therapies as the initial treatment for advanced disease. Five of the studies tested fulvestrant in the second-line or more setting, meaning after the women had progressed on a prior initial treatment for advanced disease. Two studies examined fulvestrant in combination with anastrozole against anastrozole alone, and the other seven studies compared fulvestrant alone with other comparator drugs. We found that fulvestrant was at least as effective as the other three standard endocrine therapies used in the treatment of advanced hormone-sensitive breast cancer and is possibly more effective at the new standard dose of 500 mg, rather than the lower dose of 250 mg, which was previously used and tested in all but one of the included studies. We also found that combining fulvestrant with an aromatase inhibitor did not improve effectiveness, and neither was effectiveness influenced by whether fulvestrant was used as the first treatment upon diagnosis of advanced disease or after another endocrine therapy. This was evident in the pooled data analysis for both survival time without progression of cancer and the rate of tumour shrinkage or stabilisation due to fulvestrant as compared with the other endocrine therapies. In addition, fulvestrant-treated women did not experience worse side effects than those receiving the comparator endocrine therapies, and quality of life was equivalent in both fulvestrant-treated women and women treated with the other endocrine therapies. Fulvestrant can therefore be considered an effective and safe treatment for postmenopausal women with advanced hormone-sensitive breast cancer, when treatment with endocrine therapy is indicated. All studies were of high quality.