Letrozole (
Femara; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a nonsteroidal inhibitor of
aromatase enzyme complex. It inhibits the peripheral conversion of circulating
androgens to
estrogens. In postmenopausal women,
letrozole decreases plasma concentrations of
estradiol,
estrone, and
estrone sulfate by 75-95% from baseline with maximal suppression achieved within 2-3 days of treatment initiation. Suppression is dose related, with doses of >or=0.5 mg giving
estrone and
estrone sulfate values that were often below assay detection limits. At clinically used dosage,
letrozole does not impair adrenal synthesis of
glucocorticoids or
aldosterone. In 1998,
letrozole was approved by the United States Food and Drug Administration (FDA) for the treatment of advanced
breast cancer in postmenopausal women, with
hormone receptor positive or unknown
breast cancer, who had failed one prior
antiestrogen treatment (i.e., for "second-line" treatment). Approval was based on two randomized trials comparing
tumor RRs of patients receiving 0.5 mg of
letrozole, 2.5 mg of
letrozole, and either
megestrol acetate (MA) or
aminoglutethimide. In the
megestrol trial, 2.5 mg/day
letrozole was superior to 0.5 mg of
letrozole and MA (RRs 24, 13, and 16%, respectively), whereas in the
aminoglutethimide trial, there was no significant difference in 2.5 mg of
letrozole and 0.5 mg of
letrozole RRs (20 and 17%). There was a trend toward RR superiority of 2.5 mg of
letrozole over
aminoglutethimide (P = 0.06).
Letrozole (2.5 mg) was the dose chosen for comparison with
tamoxifen in the first-line setting. In July 2000, a marketing application for first-line
letrozole treatment of postmenopausal women with
hormone receptor positive or
hormone receptor unknown locally advanced or metastatic
breast cancer was submitted to the FDA. A single double-blind, double dummy, randomized, and multicenter trial compared 2.5 mg of
letrozole to 20 mg of
tamoxifen (456 patients/arm).
Letrozole was superior to
tamoxifen with regard to time to progression (
TTP) and objective response rate (RR). The median
TTP for
letrozole treatment was 9.9 months [95% confidence interval (CI) 9.1-12.2] versus 6.2 months (95% CI 5.8-8.5) for
tamoxifen, P = 0.0001, hazard ratio 0.713, (95% CI 0.61-0.84). RR was 32% for
letrozole versus 21% for
tamoxifen (odds ratio 1.74, 95% CI 1.29-2.34, P = 0.0003). Preliminary survival data (survival data are still blinded) indicate that
letrozole is unlikely to be worse than
tamoxifen. Both treatments were similarly tolerated. On the basis of these results, the United States FDA approved
letrozole tablets, 2.5 mg/day, for first-line treatment of postmenopausal women with
hormone receptor-positive or
hormone receptor-unknown locally advanced or metastatic
breast cancer. The manufacturer made a commitment to provide updated information on survival.