Fulvestrant (Faslodex) -- how to make a good drug better

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.