Clinical Trials in the Second Line Post Tamoxifen Setting

The clinical efficacy of fulvestrant as a second-line agent was established by two phase III trials (Trials 0020 and 0021) (24,25). Trial 0020 was an open-label trial that recruited patients in Europe, Australia, and South Africa (25). Trial 0021 was a double-blind, double-placebo trial conducted in North America (24). Although the two trials differed in geography and in blinding status, they were designed to run concurrently and to be analyzed with individual as well as pooled data.

By the time fulvestrant was ready for phase III testing, the third generation aromatase inhibitors (AIs) were regarded as the standard second-line treatment for tamoxifen-resistant breast cancer in postmenopausal women (28-34). Therefore, anastrozole was the comparative agent.

Both trials were large, multi-center, parallel group trials of postmenopausal women, with locally advanced or metastatic breast cancer, who failed prior endocrine therapy (adjuvant or first-line for advanced disease). All patients had either documented prior response to endocrine therapy or positive ER and/or PgR. The trials were powered to show superiority of fulvestrant over anastrozole, and patients were followed until death (24,25).

Patients were initially randomized to fulvestrant (either 250 or 125 mg IM) or to anastrozole 1 mg PO (24,25). In a planned preliminary interim analysis, fulvestrant 125 mg did not demonstrate clinical activity and recruitment to this arm was stopped (24,25). The final protocol for both trials compared fulvestrant 250 mg (1 x 5 mL or 2 x 2.5 mL monthly IM injections) with anastrozole 1 mg PO daily given until disease progression or withdrawal. The primary endpoint was TTP. Secondary endpoints included objective response (OR), clinical benefit (CB) (complete responders + partial responders + those with SD >24 weeks), and DOR.

Trial 0020

In the European trial (n = 451, median follow-up = 14.4 months), there was no difference in TTP for fulvestrant and anastrozole [HR, 0.98; 95.14% confidence interval (CI), 0.80-1.21; P = 0.84] (25). The median TTP was 5.5 months for fulvestrant and 5.1 months for anastrozole, with a similar CB in both arms (44.6% and 45.0%, respectively).

The data suggested an advantage for fulvestrant for some secondary endpoints. Fulvestrant had a numerically superior OR, compared with anastrozole: OR = 20.7% and 15.7%, respectively (odds ratio, 1.38; 95.14% CI, 0.84-2.29; P = 0.20) (25). In addition, the DOR was significantly greater for fulvestrant than for anastrozole (ratio of average response durations, 1.27; 95% CI, 1.05-1.55; P = 0.01). For responders, the median DOR was 15 months for fulvestrant (n = 48) and 14.5 months for anastrozole (n = 39) (25).

Trial 0021

The results of the North American trial (n = 400, median follow-up = 16.8 months) were similar to those of Trial 0020 (24). There was no difference in the TTP between fulvestrant and anastrozole (HR, 0.92; 95.14% CI, 0.74-1.14; P = 0.43) (24). The median TTP was 5.4 months for fulvestrant and 3.4 months for anastrozole, with a CB of 42.2% and 36.1%, respectively.

In contrast to the European trial, the OR rate did not show a numerical advantage for fulvestrant (OR = 17.5% in both arms). However, the DOR was significantly greater for fulvestrant than for anastrozole [ratio of average DOR, 1.35 (95% CI, 1.10-1.67; P < 0.01)] (24). For responders, the median DOR was 19.0 months for fulvestrant (n = 36) and 10.8 months for anastrozole (n = 34) (24). The difference in the DOR for responders was larger than that observed in Trial 0020.

Updated Combined Analysis of Trials 0020 and 0021

The updated combined analysis of Trials 0020 and 0021 (n = 821) was prospectively planned and the results were comparable with those from the individual trials (24,25,35,36). The prior treatment exposure for patients in both trials was similar, with the majority of women in each arm receiving prior tamoxifen (>96%) and prior chemotherapy (>52%) (36). The treatment groups were generally well matched in terms of other patient characteristics (36). At an extended median follow-up of 15.1 months, there was no difference for combined TTP, OR, or CB (36).

At a median follow-up of 27.0 months (range 0-66.9 months), there was no difference between fulvestrant and anastrozole for the combined median overall survival: 27.4 and 27.7 months, respectively (HR, 0.98; 95% CI, 0.84-1.15; P = 0.809) (35). Because the upper CI was <1.25, fulvestrant was described as noninferior to anastro-zle for overall survival (35). On the basis of this phase III data, fulvestrant 250 mg IM injection gained approval by the United States Food and Drug Administration in April 2002 (37) and received marketing approval for the European Union in March 2004 (10). Fulvestrant is presently indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy (37). The monthly dose may be given as a single 5 mL IM injection or as two 2.5 mL injections into each buttock (37).

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