Fulvestrant revisited: efficacy and safety of the 500-mg dose

Postmenopausal women with hormone receptor-positive advanced breast cancer are candidates for endocrine therapy. As the disease will eventually progress in most patients, it is important to investigate agents with novel modes of action to reduce the likelihood of treatment cross-resistance. Fulvestrant is an estrogen receptor antagonist with no known agonist effects that has been shown to be as effective as anastrozole following failure on tamoxifen, at the approved dose of 250 mg/mo. However, pharmacokinetic modelling and evidence of clinical efficacy in early trials, together with the favorable tolerability profile of fulvestrant 250 mg, led to suggestions that increasing the fulvestrant dose would lead to an improved benefit-risk profile. This review describes the rationale behind the development of a 500 mg/mo higher dose of fulvestrant and details relevant clinical trials, including the pivotal phase III COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) study. CONFIRM demonstrated a significant improvement in progression-free survival for fulvestrant 500 mg versus 250 mg in postmenopausal patients who had progressed on previous endocrine therapy. Here, we present and discuss a pooled safety analysis of CONFIRM and three further clinical studies demonstrating fulvestrant 500 mg to be well-tolerated with no evidence of dose-related adverse events. Overall, these data indicate an improved benefit-risk profile for fulvestrant 500 mg versus 250 mg following failure on prior endocrine therapy, and suggest that fulvestrant 500 mg may be considered in future as initial endocrine treatment for advanced breast cancer.