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Breast Cancer

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

Professorial Unit of Surgery, Nottingham City Hospital, Nottingham, United Kingdom

Key Words. Breast cancer • Dose–response relationship • Drug • Estrogen receptor • Fulvestrant • Pharmacokinetics

Correspondence: Correspondence: John F. R. Robertson, M.D., Professorial Unit of Surgery, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, United Kingdom. Telephone: 44-0115-8231876; Fax: 44-0115-8231877; e-mail: john.robertson{at}nottingham.ac.uk

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.

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