The Longstanding Quest for a Better Endocrine Therapy Continues High-Dose Fulvestrant: Have We Found Its Effective Dose, Combination, Setting, or Sequence?

Angela Mae Obermiller, PharmD; and Mehmet Sitki Copur, MD
Published: Tuesday, Mar 15, 2011
While the beginnings of endocrine therapy for breast cancer can be traced to the 19th century, 1 the exact mechanisms of tumor response and resistance to endocrine manipulation still remain to be elucidated. The first truly successful targeted therapy against the estrogen receptor (ER) came with the resurrection of the compound ICI 46474, as tamoxifen, after it was initially abandoned in 1972.2 Although several endocrine therapies, including selective ER modulators, aromatase inhibitors (AIs), progestins, androgens, and luteinizing hormone-releasing hormone (LHRH) agonists, are available today, the quest for a better tamoxifen still continues. Many promising agents in the preclinical setting have not proven nearly as effective as tamoxifen in the clinical setting.3,4

In the early 1990s, a new compound, ICI 182780, a 7 alpha-alkylamide analogue of estradiol with promising preclinical activity, was selected for additional clinical studies under the name of fulvestrant.5 A pure novel antiestrogen, fulvestrant competitively binds to ER and blocks receptor dimerisation. The unstable fulvestrant- ER complex then undergoes accelerated degradation, resulting in downregulation of the ER with subsequent inhibition of ER-DNA binding and abrogation of the expression of genes associated with tumor progression, metastasis, and angiogenesis6,7 Fulvestrant produces dosedependent reductions in the cellular levels of ERs and progesterone receptors (PGRs), resulting in more profound effects in tumors that express both hormonal receptors.8,9 Fulvestrant’s distinct mechanism of action ensures a lack of cross-resistance with other hormonal agents and no known estrogen agonist effects.10 Following a pivotal phase III clinical trial,11 fulvestrant 250 mg by monthly intramuscular injection was approved by the FDA in April 2002 for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.12

Prior to the fulvestrant era, data on the endocrine treatment of breast cancer favored the use of third-generation AIs over progesterone, tamoxifen, and older AIs.13 Preclinical research and early clinical studies of fulvestrant suggested that it would outperform existing endocrine therapies for hormone receptor-positive breast cancer. So far, however, several randomized clinical trials have shown only comparable efficacy but no obvious superiority of fulvestrant to tamoxifen, anastrazole, or exemestane in postmenopausal women with hormone receptor-positive metastatic breast cancer.14-17

There are 3 possible explanations for fulvestrant’s lack of superiority compared to other endocrine therapies: 1) a delay in obtaining steady-state levels, 2) the competitive effect from circulating estrogens, and 3) the inability to reach the maximally effective and tolerated dose.

Delay in Obtaining Steady-State Levels

In most early clinical trials of fulvestrant, the drug was administered as a monthly, slow intramuscular injection of 5 ml of 50 mg/ml solution containing 250 mg of fulvestrant, plus excipients (ethanol 96%, benzyl alcohol, benzyl benzoate, and castor oil). With this so-called approved dose (AD) regimen it can take 3 to 6 months to reach steady-state levels. Early progression of patients on the AD regimen led to the concept of a loading dose (LD) regimen, which consisted of a 500 mg injection on day 1, then 250 mg injections on days 14 and 28, and monthly 250 mg injections of fulvestrant thereafter. The LD regimen produced steady-state plasma fulvestrant concentrations in 28 days as opposed to 3 months with the AD regimen.17 The use of the LD fulvestrant regimen, however, not only failed to prove superior to exemestane in patients who failed prior nonsteroidal AIs, but also was not better than anastrozole monotherapy alone, even when combined with anastrozole.17,18

Competitive Effect from Circulating Estrogens

Fulvestrant competes with estradiol for binding at the ER. Preclinical data show that complete estrogen blockade, by downregulating ER and inhibiting estrogen synthesis, has greater effect on tumor growth than either treatment alone.19,20 Since the major source of estradiol in postmenopausal women is by aromatization of androgens, the combination of AIs with fulvestrant may enhance the efficacy of fulvestrant by reducing plasma estrogen levels.


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