Exemestane

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.

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.

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 statistically significant survival advantage was reported for exemestane over megestrol, although too few deaths occurred to draw meaningful conclusions on the long term effects on survival. Exemestane also improved tumour-related signs and symptoms and several aspects of quality of life, compared with megestrol treatment. Benefits of exemestane on subjective measures of pain have also been reported.

Objective responses, lasting a median of 40 and 96 weeks, were reported in 11 and 13% of patients with disease refractory to tamoxifen and megestrol. Responses were similar in previous megestrol responders and nonresponders. Objective response and overall success rates of 6.6 and 24.3% occurred in patients refractory to nonsteroidal aromatase inhibitors who received once daily exemestane 25mg. Importantly, tumour responses (objective response 6.1%, overall success rate 24.7%) were reported in patients who had not responded to their last hormonal treatment.

Tumour responses were elicited by exemestane regardless of disease site. Importantly, exemestane demonstrated efficacy in patients with predominantly visceral or bone disease. In a randomised study involving patients in whom tamoxifen treatment had failed, median times to disease progression and treatment failure with exemestane were only slightly shorter than in patients with visceral metastases compared with the entire patient cohort.

Interim data from a small study indicate that exemestane is effective as first-line treatment of postmenopausal women with advanced breast cancer. Once daily exemestane 25mg elicited objective and overall success rates of 42 and 58%, compared with 16 and 31% for once daily tamoxifen 20mg. Median times to disease progression were 8.9 and 5.2 months in exemestane and tamoxifen groups, respectively.

Exemestane was generally well tolerated in clinical trials at once daily dosages up to 600mg and the maximum tolerated dose was not reached. Withdrawal due to adverse events occurred in 1.7 to 8% of patients.

Androgenic events have been reported in some patients receiving once daily exemestane 200mg, but were rarely reported at the recommended dos age. Symptoms that may have been androgenic in nature and may have been related to exemestane 25mg were reported in 1 study (alopecia 2 patients, acne 1, hypertrichosis 1).

Exemestane is indicated for the treatment of postmenopausal women with advanced breast cancer whose disease has progressed after tamoxifen or other antiestrogen therapy.

The recommended dosage of exemestane is 25mg taken orally once daily after a meal. Treatment should continue until disease progression occurs.

No dosage adjustment is necessary in the elderly or in patients with moderate or severe hepatic or renal impairment.