Pivotal Trials of Letrozole: A New Aromatase Inhibitor

ABSTRACT: Letrozole (Femara) is a nonsteroidal aromatase inhibitor that is approximately 10,000 times as potent as aminoglutethimide in vivo. Two pivotal multinational phase III trials have compared letrozole (0.5 and 2.5 mg/d) against megestrol acetate and aminoglutethimide, respectively, in patients with locally advanced or metastatic breast cancer. The letrozole vs megestrol acetate trial showed the superiority of letrozole (2.5 mg/d) over megestrol acetate with respect to response rate, response duration, duration of overall clinical benefit (complete response plus partial response plus stable disease ³ 6 months), time to progression, and time to treatment failure. The letrozole-treated patients also showed a nonsignificant trend toward better survival. In the letrozole vs aminoglutethimide trial, letrozole (2.5 mg/d) was significantly superior in terms of duration of overall clinical benefit and survival. There were also strong trends favoring letrozole with regard to objective response rate and duration of response. Unexpectedly, both trials demonstrated a dose-response effect for 2.5 mg of letrozole over 0.5 mg in terms of response and overall survival. This finding raises the possibility that intratumoral aromatase suppression may be more relevant in breast cancer therapy than are plasma estrogen levels.[ONCOLOGY(Suppl 5):41-44, 1998]

Over the last 15 years, inhibitors of aromatase, the enzyme responsible for estrogen biosynthesis, have been found to be active agents in the treatment of breast cancer. Aminoglutethimide, the first aromatase inhibitor, was shown to be an effective, useful agent,[1] with activity at least equivalent to that of tamoxifen (Nolvadex)[2] in advanced breast cancer. Aminoglutethimide was associated with unwanted side effects, however, including somnolence (at higher doses) and rash.[3]

The next step in the clinical development of aromatase inhibitors was 4-hydroxyandrostenedione (formestane), the first steroidal compound to be structurally designed to inhibit aromatase.[4] This agent proved to be more specific than aminoglutethimide and had fewer systemic side effects, but it had poor oral availability and therefore had to be given by intravenous injection.[5]

A third generation of nonsteroidal imidazole aromatase inhibitors has now been developed; these new inhibitors are several orders more potent than aminoglutethimide. The first of the third-generation agents, fadrozole (COS 16949A), initially led the field in clinical trials. It gradually became apparent, however, that fadrozole had minor but unwanted aldosterone-suppressing effects.

Three other important imidazole-type aromatase inhibitors are now in advanced clinical trials or are registered for use in advanced breast cancer: anastrozole (Arimidex), vorozole (Rivizor), and letrozole (Femara). This paper focuses on the clinical development of letrozole, with particular emphasis on the pivotal large phase III clinical trials that led to its approval by the FDA for use in the treatment of advanced breast cancer.

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