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(Drug information on 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(Drug information on anastrozole) (Arimidex), vorozole (Rivizor), and letrozole(Drug information on 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.
Potency and Endocrine Effects
Letrozole is a nonsteroidal triazole derivative. One of the most potent aromatase inhibitors yet developed, letrozole is approximately 10,000 times as potent as aminoglutethimide in vivo, with no evidence of inhibition of other steroid pathways at doses required to inhibit estrogen.[6] In animal models, it achieves almost complete regression of estrogen-dependent, dimethylbenzanthracene-induced mammary tumors.[6]
Endocrine Effects
In a phase I study conducted at the Royal Marsden Hospital, 21 postmenopausal patients were treated with letrozole in three successive groups of seven, receiving 0.1, 0.5, and 2.5 mg/d orally, respectively. Letrozole produced a statistically significant suppression of estradiol(Drug information on estradiol) by 74% from baseline levels and estrone(Drug information on estrone) by 79% (P < .0001). Suppression occurred in all three patient groups, with many patients having serum estradiol and estrone concentrations below the limit of detection of the assays (3 and 10 pM, respectively), corresponding to a maximum measurable estrogen suppression of 86%.[7] Letrozole had no significant effect on serum follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), cortisol, 17-hydroxyprogesterone, androstenedione, or aldosterone.
In a subsequent Royal Marsden phase I trial of letrozole specifically designed to measure aromatase inhibition in vivo (see below), 13 patients were randomly allocated to 0.5 and 2.5 mg/d.[8] Estrone and estradiol levels fell by 82% and 84.1%, respectively, at 0.5 mg/d and by 81% and 68%, respectively, at 2.5 mg/d.
In a nonrandomized comparative phase I clinical efficacy study, Demers et al[9] compared the endocrine-suppressing effects of fadrozole and letrozole using the same high-sensitivity estrogen radioimmunoassay. Letrozole appeared to be the more potent of the two drugs. Fadrozole achieved a 68% suppression of estrone and 70% suppression of estradiol at all of the doses used. Letrozole, at doses of 0.1 to 5 mg/d, suppressed both estrone and estradiol by > 95%, resulting in undetectable levels in many patients.
In Vivo Aromatase Inhibition
At the Royal Marsden, we measured in vivo aromatase inhibition by letrozole in 13 postmenopausal patients with advanced breast cancer randomized to a daily dose of 0.5 or 2.5 mg for at least 6 weeks.[8] After 6 weeks, 0.5 and 2.5 mg/d of letrozole inhibited aromatization by a mean (geometric) of 98.4% (range, 97.3% to > 99.1%) and > 98.9% (98.5% to > 99.1%), respectively. This was a greater degree of aromatase inhibition than had been achieved previously with any other inhibitor.
Phase I and II Studies
In our original phase I study,[7] 7 (33%) of 21 patients achieved an objective response and 5 had stable disease for more than 3 months. All of these patients had received at least one prior endocrine treatment.
In an American phase I trial, 23 heavily pretreated postmenopausal patients with metastatic breast cancer were given letrozole at doses ranging from 0.1 to 5 mg/d. Only two patients (10%) had partial responses, but an additional seven had stable disease.[10]
Better results were achieved in a third phase I Italian trial, in which 14 postmenopausal patients were treated with 0.5 mg/d of letrozole. One patient achieved a complete response and four patients, a partial response, for an overall objective response rate of 36%. No toxic effects relating to letrozole were seen in any patient.[11]
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