The Oncologist, Vol. 7, No. 6, 477–480,
December 2002
© 2002 AlphaMed Press
FDA Drug Approval Summaries: Fulvestrant
Peter F. Bross,
Martin H. Cohen,
Grant A. Williams,
Richard Pazdur
Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, USA
Peter F. Bross, M.D., Food and Drug Administration, HFD-150, 5600 Fishers Lane, Rockville, Maryland 20857, USA. Telephone: 301-594-5768; Fax: 301-594-0499; e-mail: brossp{at}cder.fda.gov
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ABSTRACT
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Patients with hormone-sensitive breast cancer who have responded to tamoxifen may receive additional benefit from a second endocrine agent following progression or relapse after tamoxifen therapy. Fulvestrant (Faslodex®, ICI 182780, AstraZeneca Pharmaceuticals; Wilmington, Delaware) is a selective antagonist of estrogen designed to have no estrogenic effects. Lack of aqueous solubility led to the development of a parenteral formulation for monthly intramuscular administration. Fulvestrant has been shown to inhibit the proliferative effects of estrogen on sensitive tissues in vitro and in vivo, and is without apparent measurable estrogenic activity. The data upon which marketing approval for fulvestrant was based are summarized below. Eight hundred fifty-one postmenopausal women with advanced breast cancer were enrolled in two phase III studies, 400 in a North American double-blind study and 451 in a European open-label study, comparing the efficacy and safety of fulvestrant with anastrozole. Four hundred twenty-eight patients were randomized to receive fulvestrant 250 mg monthly by intramuscular injection and 423 patients were to receive anastrozole 1 mg daily. Patients were considered hormone sensitive either by receptor status or previous response to endocrine therapy. Over 96% of patients had previously received tamoxifen, either in the adjuvant setting or as treatment for metastatic disease. The primary study end points were response rate and time to progression. Response rates for patients treated with fulvestrant were 17% and 20% in the North American and European trials, respectively, compared with 17% and 15% in the anastrozole treatment arms. There were no statistically significant differences in response rates, time to progression, or survival between treatment arms in either study. The most common adverse events attributed to the treatment (>10%) were injection-site reactions and hot flashes. Common events (1%-10%) included asthenia, headache, and gastrointestinal disturbances (nausea, vomiting, and diarrhea), as well as rash and urinary tract infections. A small increase in joint disorders was reported in the anastrozole-treated patients. On April 25, 2002, fulvestrant 250 mg by monthly intramuscular injection was approved by the U.S. Food and Drug Administration for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Approval was based on similarity of response rates and time to progression between fulvestrant and anastrozole.
Key Words. Fulvestrant • Breast cancer • Metastatic • Hormone therapy
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FASLODEX® (FULVESTRANT) INJECTION
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Fulvestrant is indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. The recommended dose and schedule is 250 mg as either a single 5-ml injection or two concurrent 2.5-ml injections to be administered intramuscularly into the buttock at intervals of 1 month.
Hormonal therapy is generally the first treatment option for patients with estrogen receptor (ER)-positive locally advanced or metastatic breast cancer. If a patient’s tumor initially responds to an endocrine agent or if a patient has received adjuvant endocrine therapy, a second endocrine agent may provide additional benefit at the time of tumor progression or recurrence [1]. The antiestrogen tamoxifen is the most widely used endocrine treatment for hormone receptor-positive breast cancer [2]. Tamoxifen possesses some estrogenic activity, and is thus considered to be a partial estrogen agonist. Partial estrogen agonists such as tamoxifen may have such beneficial effects as delaying or preventing osteoporosis but they have also demonstrated estrogenic side effects. Estrogenic activity may cause endometrial hyperplasia or carcinoma and may also predispose patients to thrombosis. Agonists also may produce withdrawal responses in the treatment of patients with breast cancer. Fulvestrant is an estrogen receptor antagonist designed to be devoid of agonist activity [3]. The low aqueous solubility of this compound necessitated the development of a long-acting intramuscular depot formulation containing benzyl alcohol and castor oil as solvents.
Intramuscular fulvestrant was compared with oral anastrozole in two randomized, controlled clinical trials (a North American double-blinded study and a European open-label study) in postmenopausal women with locally advanced or metastatic breast cancer. Subjects were previously treated with adjuvant endocrine therapy or had tumors initially responding to endocrine therapy in the metastatic setting. A total of 851 patients were enrolled, with 428 randomized to receive fulvestrant 250 mg monthly by intramuscular injection and 423 patients to receive anastrozole 1 mg daily . The study population was predominantly Caucasian, with a median age of 63 years and good World Health Organization performance status (90% 0/1). Approximately 75% of the patients had documented ER-positive tumors (Table 1
), and the remainder of the patients showed clinical evidence of hormone sensitivity. Sensitivity was defined as at least 12 months of adjuvant hormonal treatment, or in the advanced disease setting, hormone-induced tumor remission or tumor stabilization lasting at least 3 months. Over 96% of patients had previously received tamoxifen either in the adjuvant setting or as treatment for metastatic disease. Sixty-two percent of patients on the North American trial and 42% of patients on the European trial had previously received chemotherapy. While some of the 423 subjects treated with fulvestrant in the two pivotal trials were treated for up to 3 years, the median exposure to fulvestrant was about 6 months.
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RESULTS
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Fulvestrant response rates were 17% and 20% in the North American and European trials, respectively, compared with 17% and 15% in the anastrozole treatment arms (Table 2). Differences were not statistically significant. For each of the trials, analysis of the response rates ruled out a difference in response >10% with respect to anastrozole using two-sided 95.4% confidence intervals, thus satisfying criteria used by the Food and Drug Administration (FDA) as the basis of approval of previous hormonal treatments for breast cancer. There were no statistically significant differences in time to progression or survival between the two treatment arms in either trial.
Investigators identified relatively few drug-related serious adverse events in either treatment group. The most common drug-related events (>10%) were injection-site reactions and hot flashes (Table 3). Common events (1%-10%) included asthenia, headache, and gastrointestinal disturbances such as nausea, vomiting, and diarrhea. Rash and urinary tract infections were also reported. A small increase in joint disorders was reported in anastrozole-treated patients.
On April 25, 2002, the FDA approved fulvestrant 250 mg monthly injections for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Approval was based on a comparison with anastrozole, which has a well-described treatment effect and safety profile [4, 5].
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ACKNOWLEDGMENT
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The views expressed are the result of independent work and do not necessarily represent the views and findings of the U.S. FDA.
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REFERENCES
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- Buzdar AU. Endocrine therapy in the treatment of metastatic breast cancer. Semin Oncol 2001;28:291–304.[CrossRef][Medline]
- Buzdar A. Tamoxifen’s clinical applications: old and new. Arch Family Med 2000;9:906–912.[Abstract/Free Full Text]
- Howell A, Osborne CK, Morris C et al. ICI 182,780 (Faslodex): development of a novel, "pure" antiestrogen. Cancer 2000;89:817–825.[CrossRef][Medline]
- Buzdar A, Jonat W, Howell A et al. Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. J Clin Oncol 1996;14:2000–2011.[Abstract/Free Full Text]
- Buzdar AU, Jonat W, Howell A et al. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Cancer 1998;83:1142–1152.[CrossRef][Medline]
Received July 31, 2002;
accepted for publication August 27, 2002.
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Abstract
Faslodex(R) (Fulvestrant)...
