Exemestane

Publisher Website
Google Scholar
Abstract
Exemestane is an orally active irreversible steroidal aromatase inactivator that effectively suppresses in vivo aromatase activity and circulating estrogen levels in postmenopausal women with advanced breast cancer. In clinical trials, tumour responses were elicited by exemestane regardless of disease site, importantly, in patients with visceral disease. In patients with disease refractory to tamoxifen, once daily exemestane 25mg produced objective response rates of 15 to 28% that were sustained for a median duration of 69 to 76 weeks. In a large comparative study, exemestane and megestrol showed similar clinical efficacy according to objective response and overall success rates. However, the duration of overall success and times to disease progression and treatment failure were significantly prolonged with exemestane compared with megestrol. Additionally, a significant survival advantage for exemestane over megestrol was reported. Exemestane retains efficacy in patients refractory to multiple hormonal therapies. In patients whose disease had progressed after tamoxifen and megestrol, objective response rates of 11 and 13% were reported, and responses were similar regardless of whether megestrol resistance was de novo or acquired. Objective responses also occurred in studies that explored sequential use of exemestane after failure of aminoglutethimide (26% with exemestane 200 mg/day) or other nonsteroidal aromatase inhibitors (6.6% with exemestane 25 mg/day). Additionally, tumour responses (objective response 6.1%, overall success rate 24.7%) were reported in patients who had not responded to their last hormonal treatment. As first-line treatment, once daily exemestane 25mg elicited objective and overall success rates of 42 and 58%, compared with 16 and 31% for once daily tamoxifen 20mg. Exemestane was generally well tolerated in clinical trials at once daily dosages up to 600mg. At the 25mg recommended once daily dosage, the most commonly occurring adverse events were nausea, hot flushes, fatigue, increased sweating and dizziness. Weight gain occurred in significantly more patients receiving megestrol than among those treated with exemestane. Androgenic events have been reported in a small number of patients receiving once daily exemestane 200mg, but were rarely reported at the recommended dosage. Conclusions: Exemestane is effective in postmenopausal patients with tamoxifen-refractory advanced breast cancer, prolonging time to disease progression and treatment failure and improving survival compared with megestrol treatment. Moreover, exemestane has an acceptable tolerability profile and a convenient once daily oral dosage regimen. Available data indicate that exemestane maintains its efficacy in patients with visceral metastases and does not show cross-resistance with nonsteroidal aromatase inhibitors. Preliminary data indicate that exemestane is also effective as first-line therapy for advanced breast cancer. Exemestane irreversibly inhibits conversion of androgens to estrogens and exhibits specificity for the aromatase enzyme. No significant suppression of other steroid synthetic pathways was reported during clinical endocrinological studies of exemestane. In postmenopausal women with advanced breast cancer, slight decreases of 9% and 7% in circulating sex hormone binding globulin levels were apparent after 8 and 16 weeks’ treatment with once daily exemestane 25mg. Concentrations of exemestane required to inhibit 50% of human aromatase activity in vitro range from 5 to 30 nmol/L. In postmenopausal women with advanced breast cancer, once daily exemestane 25mg effectively suppressed in vivo aromatase activity by 97.9%. Consistent with this effect on whole body aromatisation, circulating estrone, estrone sulphate and estradiol levels were reduced by >85% during once daily treatment with exemestane 25mg. Exemestane demonstrated antitumour efficacy in a rodent model of postmenopausal breast cancer. Tumour regression was induced in 76% of animals receiving 4 weeks’ treatment with oral exemestane 10 mg/kg/day. In comparison, 52% regression occurred in control rats. Exemestane is rapidly absorbed after oral administration, reaching peak plasma concentrations of 17 μg/L within 1 to 2 hours after a single dose of 25mg in postmenopausal volunteers. Steady state is reached within 7 days of repeated administration. Exemestane is extensively metabolised by cytochrome P450 3A4 and aldoketoreductases. The metabolites are either inactive or inhibit aromatase activity with lower potency than the parent drug. The metabolites are excreted in urine and faeces in equal proportions. Exemestane has a total clearance of 517 L/h (assuming 100% absorption) and a terminal elimination half-life of 27 hours. In clinical studies of hormonal therapies for advanced breast cancer, stable disease of ≥24 weeks’ duration plus objective response (overall success) equates to clinical benefit. The efficacy of exemestane has been investigated in the treatment of postmenopausal women with advanced breast cancer refractory to tamoxifen and in patients who experienced failure of multiple hormonal therapies. Exemestane, generally at a dose of 25mg, was administered as an oral once daily regimen until disease progression. In a large randomised comparative study in patients with tamoxifen-refractory disease, objective response and overall success rates were similar in patients receiving exemestane 25mg once daily (15.0 and 37.4%) and megestrol 40mg 4 times daily (12.4 and 34.6%). Patients in the exemestane group experienced a longer duration of overall success (60.1 vs 49.1 weeks, p = 0.025) and greater (p < 0.05) times to disease progression (20.3 vs 16.6 weeks) and treatment failure (16.3 vs 15.7 weeks) than those receiving megestrol. However, the objective response duration was not statistically different between groups. Importantly, a...