Endocrinological and clinical evaluation of exemestane, a new steroidal aromatase inhibitor

Abstract

Summary The androstenedione derivative, exemestane (FCE 24304), is a new orally active irreversible aromatase inhibitor. Fifty-six post-menopausal advanced breast cancer patients entered this study to evaluate the activity of four low exemestane doses in reducing oestrogen levels. The drug's tolerability and clinical efficacy were also assessed. Exemestane was orally administered to four consecutive groups at daily doses of 25, 12.5, 5 and 2.5 mg, and the changes in oestrogen, gonadotrophins, sex-hormone binding globulin and dehydroepiandrosterone sulphate levels were evaluated. Drug selectivity was studied by measuring 17-hydroxycorticosteroid urinary levels. After 7 days of treatment, mean oestrone and oestradiol levels had decreased by respectively 64% and 65% (a decrease which was maintained over time); in the 2.5 mg group, oestrone sulphate levels also decreased by 74%. Gonadotrophin levels were significantly higher, whereas no changes in the other serum hormone levels or any interference with adrenal synthesis were detected. Treatment tolerability was satisfactory: nausea and dyspepsia were reported in 16% of patients. The overall objective response rate was 18%. In conclusion, exemestane is effective in reducing oestrogen levels at all of the tested doses and shows interesting clinical activity.Keywords: exemestane; aromatase inhibitor; breast cancer; advanced disease; post-menopausal patients Aromatase inhibition represents one of the main endocrine treatment options in post-menopausal metastatic breast cancer, and irreversible aromatase inhibitors (steroidal compounds structurally related to the natural substrate androstenedione) have recently been developed.The first of these to be used in clinical practice was formestane (Coombes et al., 1984;Goss et al., 1986; Hoffken et al., 1990;Pickles et al., 1990;Stein et al., 1990) for which, although it has been described as a 'suicide inhibitor' because of its mechanism of action, possible interference with growth factors has also been evaluated (Reed et al., 1992;. In our experience, it has been found to lead to a significant reduction in oestrogen levels and to have good clinical efficacy (Bajetta et al., 1993. The preferred route of administration is parenteral because of the drug's rapid and extensive hepatic metabolism; the oral formulation requires higher doses to be effective (Dowsett et al., 1989). Although local side-effects were mild and infrequent in our experience, other authors have described local pain at the injection site in approximately 14% of patients .In an attempt to identify an aromatase inhibitor with better oral activity than formestane, a new steroidal derivative, exemestane (FCE 24304), has been evaluated (Guidici et al., 1988;di Salle et al., 1990). In animal mammary tumour models, this has been found to be effective in inducing tumour regression when used either orally or by the subcutaneous route (Zaccheo et al., 1989a), and these results have been confirmed in a model of post-menopausal breast cancer in ovariectomised rats bear...

Pharmacokinetics and Dose Finding of a Potent Aromatase Inhibitor, Aromasin (Exemestane), in Young Males

“…The rise in the aromatase substrates, testosterone and androstenedione, is probably secondary to substrate accumulation and/or to the feedback increase in gonadotropins caused by aromatase blockade. The 21% decrease in SHBG concentrations caused by 25 mg exemestane confirms the observation in postmenopausal women (20).…”

NSABP Breast Cancer Clinical Trials: Recent Results and Future Directions

“…Phase I/II studies in patients with advanced breast cancer, it has demonstrated significant antitumor activity and favorable toxicity profile. [52][53][54][55] More importantly, in a phase III study, as second line treatment in patients with advanced breast cancer, exemestane was equivalent to Megace in objective response, but was significantly superior to Megace in duration of overall success, time to progression, time to treatment failure and OS. 38 Eligible patients for the B-33 trial must have completed approximately 5 years of adjuvant tamoxifen therapy, must be postmenopausal, and disease free at the time of randomization.…”

Anastrozole Versus Exemestane in Patients with Postmenopausal Breast Cancer and Visceral Metastases

“…The time to obtain maximal estradiol (E2) suppression is 2-4 days for anastrozole and 7 days for exemestane, 14,15 but both anastrozole and exemestane achieve a steady state drug level by day seven. 16 A comparable inhibition in excess of 90%, of in vivo aromatase activity has been observed with both classes of aromatase inhibitors. While both anastrozole and exemestane are hepatically metabolized unlike anastrozole, exemestane is a major substrate of the CYP3A4 enzyme system in the liver.…”