Fulvestrant (Faslodex®)—How to Make a Good Drug Better

• Published in: The oncologist (Dayton, Ohio) Vol. 12; no. 7; pp. 774 - 784
• Main Author: Robertson, John F. R.
• Format: Journal Article
• Language: English
• Published: Durham, NC, USA AlphaMed Press 01.07.2007
• Subjects: Antineoplastic Agents, Hormonal - administration & dosage; Antineoplastic Agents, Hormonal - adverse effects; Antineoplastic Combined Chemotherapy Protocols; Breast cancer; Breast Neoplasms - drug therapy; Dose–response relationship; Drug; Estradiol - administration & dosage; Estradiol - adverse effects; Estradiol - analogs & derivatives; Estrogen receptor; Estrogen Receptor Modulators - administration & dosage; Estrogen Receptor Modulators - adverse effects; Female; Fulvestrant; Humans; Pharmacokinetics; Postmenopause; Randomized Controlled Trials as Topic; Treatment Outcome
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.12-7-774

Fulvestrant (Faslodex®; AstraZeneca Pharmaceuticals, Wilmington, DE) is an estrogen receptor (ER) antagonist with a novel mode of action; it binds, blocks, and increases degradation of ER. Fulvestrant (at the approved dose [250 mg/month]) is at least as effective as anastrozole (1 mg/day) in the treatment of postmenopausal women with hormone receptor–positive advanced breast cancer (HR+ ABC) progressing or recurring on antiestrogen therapy, and is also an active first‐line treatment. Although fulvestrant (250 mg/month) is clearly effective, it takes 3–6 months to achieve steady‐state plasma levels. Steady‐state concentrations are approximately twofold higher than those achieved with a single dose; reaching this earlier, for example, via a loading‐dose (LD) regimen (250 mg/month plus 500 mg on day 0 and 250 mg on day 14 of month 1), may allow responses to be achieved more quickly and limit the possibility of early relapse. Fulvestrant high‐dose (HD) regimens (500 mg/month) offer the possibility of greater antitumor activity, because (a) ER downregulation is a dose‐dependent process (an approximately 70% reduction is observed with a single 250 mg dose of fulvestrant) and (b) evidence correlates greater ER downregulation with superior efficacy. A fulvestrant HD regimen offers the potential of achieving near 100% ER downregulation. There is also potential to increase fulvestrant–ER binding by reducing plasma estrogen levels, for example, with concomitant aromatase inhibitor treatment. Several ongoing trials use LD, HD, and combination regimens; results from these studies are awaited with interest. Meanwhile, fulvestrant (250 mg/month) remains a valuable additional endocrine treatment for postmenopausal women with HR+ ABC recurring or progressing on antiestrogen therapy. Disclosure of potential conflicts of interest is found at the end of this article.