Exemestane

Exemestane (Aromasin®) is an orally active steroidal irreversible inactivator of the aromatase enzyme indicated as an adjuvant treatment in postmenopausal women with estrogen receptor-positive early-stage breast cancer following 2–3 years of adjuvant treatment with tamoxifen, and for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen or other antiestrogen therapy.

Exemestane is effective for the treatment of postmenopausal women with early-stage or advanced breast cancer. In early-stage disease, switching to exemestane for 2–3 years after 2–3 years of adjuvant tamoxifen treatment was more effective in prolonging disease-free survival than continuing tamoxifen therapy, although it was not associated with an overall survival benefit, except in those with estrogen receptor-positive or unknown receptor status disease when nodal status, hormone replacement therapy (HRT) and chemotherapy use were adjusted for. Moreover, preliminary data suggest that the efficacy of exemestane is generally no different to that of tamoxifen in the primary adjuvant treatment of early-stage breast cancer, although exemestane may be better in prolonging the time to distant recurrence. In advanced disease, exemestane showed equivalent efficacy to megestrol in patients with disease refractory to tamoxifen and an efficacy not significantly different from that of fulvestrant in those refractory to a nonsteroidal aromatase inhibitor. Available data, some of which are limited, suggest exemestane is also effective in the first-line hormonal treatment of advanced breast cancer in postmenopausal women. Exemestane is generally well tolerated, although the potential bone fracture risk of the drug requires further investigation. Results from directly comparative trials indicating the efficacy, tolerability and bone fracture risk of exemestane relative to third-generation aromatase inhibitors and other agents in both early-stage and advanced disease, as well as the optimal sequence of endocrine therapies, are awaited with interest. In the meantime, switching to exemestane should be considered in postmenopausal women who have received 2–3 years of adjuvant tamoxifen treatment for early-stage breast cancer, and is an emerging treatment option for postmenopausal women with advanced breast cancer refractory to one or more antiestrogen therapies.

Exemestane acts by irreversibly binding to the aromatase active site, resulting in potent suppression of whole body aromatization and estrogen synthesis, without any marked or clinically relevant effect on levels of other steroid hormones. The drug may affect lipid levels and increase levels of homocysteine, but does not appear to have long-term effects on coagulation parameters. A switch from tamoxifen to exemestane may also reverse the endometrial thickening associated with tamoxifen. Exemestane is generally associated with a loss of bone mineral density and increases in serum or urinary levels of markers of bone turnover in postmenopausal women.

The absorption of exemestane is rapid after oral administration, with maximum plasma concentrations reached within 2 hours of a single 25 mg dose. The drug is 90% plasma protein bound and is extensively distributed into tissues. Exemestane undergoes extensive metabolism, primarily via cytochrome P450 3A4, as well as via aldoketoreductases, to metabolites that are inactive or have less activity than the parent drug. Exemestane is excreted mainly via urine and faeces and has a mean terminal elimination half-life of ≈24 hours.

Oral exemestane 25 mg/day for 2–3 years after 2–3 years of adjuvant tamoxifen was generally more effective than 5 years of continuous adjuvant tamoxifen in the treatment of postmenopausal women with early-stage estrogen receptor-positive/unknown receptor status breast cancer in a large well designed trial (IES). Switching from tamoxifen to exemestane was consistently associated with a significantly lower risk of experiencing one of the events (recurrence, contralateral breast cancer or death without recurrence) in the primary combined endpoint of disease-free survival than continued tamoxifen at median follow-ups of 30.6 and 55.7 months. The exemestane regimen was also more effective with regard to other endpoints, including the risk of contralateral breast cancer and breast cancer-free survival. There was generally no overall survival benefit in switching to exemestane, except in patients with estrogen receptor-positive or unknown receptor status disease at the median 55.7-month follow-up, when nodal status, HRT and chemotherapy use were adjusted for.

Moreover, preliminary data from the large, randomized, open-label, phase III, TEAM trial comparing exemestane with tamoxifen indicate that exemestane 25 mg/day is also effective in the primary adjuvant treatment of early-stage breast cancer in postmenopausal women. Disease-free survival (primary endpoint) did not significantly differ between exemestane and tamoxifen recipients. There was also no difference between the treatments in terms of relapse-free survival; however, exemestane was more effective in terms of the risk of distant metastases.

Exemestane 25 mg/day has also demonstrated efficacy in the treatment of postmenopausal women with advanced breast cancer refractory to one or more antiestrogen therapies in two large, well designed, phase III studies. In one of these studies, exemestane provided similar efficacy to megestrol in terms of objective response rate (primary endpoint) in postmenopausal women with advanced breast cancer refractory to tamoxifen. Although there was also no significant difference between the treatments in the median duration of objective response or the rate of overall success, exemestane recipients had a significantly longer median duration of overall success, time to disease progression and time to treatment failure than megestrol recipients. In the other trial, exemestane demonstrated efficacy not significantly different from that of intramuscular fulvestrant in patients with advanced breast cancer refractory to a nonsteroidal aromatase inhibitor, with no significant between-group difference in the time to disease progression (primary end-point) or other endpoints, including objective response rate, clinical benefit rate or overall survival.

Data, some of which are limited, from randomized, open-label, phase II or III studies comparing exemestane with anastrozole or tamoxifen, respectively, suggest that exemestane is an effective first-line hormonal treatment in postmenopausal women with advanced breast cancer. There were generally no differences between exemestane and these agents in terms of efficacy, although a significantly higher objective response rate was seen with exemestane than with tamoxifen in the largest phase III study.

Exemestane was generally well tolerated in postmenopausal women with early-stage or advanced breast cancer, with adverse events generally being mild to moderate in severity and of a similar nature irrespective of the stage of disease. Overall, hot flashes were the most common adverse event considered to be drug-related or of indeterminate cause experienced by exemestane recipients in active comparator-controlled trials.

In the large IES, at a median 55.7-month follow-up, patients with early-stage breast cancer switched to exemestane had significantly fewer serious gynaecological events, endometrial hyperplasia, uterine polyps/fibroids, venous thrombolytic events and muscle cramp than those who continued tamoxifen treatment. In contrast, exemestane was associated with a significantly higher incidence of musculoskeletal pain, arthralgia, diarrhoea, carpal tunnel syndrome, paraesthesia and joint stiffness than tamoxifen. There were no between-group differences in the incidences of the most common adverse events: menopausal symptoms (e.g. hot flashes), hypertension and fatigue. Moreover, a switch to exemestane was associated with a significantly lower incidence of abnormal endometrial thickening than continued tamoxifen. Preliminary data from the TEAM study after 2.75 years’ treatment indicated that the tolerability profile of exemestane versus tamoxifen in the primary adjuvant treatment of early-stage breast cancer was generally consistent with the findings of the IES. The incidence of fractures did not significantly differ between exemestane and tamoxifen recipients in the TEAM trial or in an on-treatment analysis of the IES, although it was significantly greater in exemestane than tamoxifen recipients in the IES when post-treatment adverse events were included.

Exemestane also had a generally similar tolerability profile to that of tamoxifen when used as a first-line hormonal treatment in postmenopausal women with advanced breast cancer, although it appeared to be more favourable than tamoxifen in terms of anaemia, thrombocytopenia and vaginal discharge, and less favourable in terms of weight gain, arthralgias, hypertension and diarrhoea (all between-group differences in incidence ≥5%). Postmenopausal women with advanced breast cancer who received exemestane were less likely to experience dyspnoea or moderate to severe gains in body-weight than those who received megestrol, although they were more likely to experience hot flashes, nausea and vomiting. The tolerability profile of exemestane was broadly similar to that of fulvestrant in postmenopausal women with advanced breast cancer.

In modelled cost-utility analyses that incorporated data from the IES and direct medical costs, switching to exemestane after 2–3 years of tamoxifen was generally predicted to be cost effective with regard to the cost per quality-adjusted life-year (QALY) gained relative to continuing tamoxifen treatment in postmenopausal women with early-stage breast cancer in a number of countries over 10-year, 20-year and/or lifetime time horizons. Using data from trials that did not directly compare the regimens, analyses in Canada and Belgium suggested that switching from tamoxifen to exemestane was cost saving in terms of the cost per QALY gained relative to primary adjuvant anastrozole or extended adjuvant therapy with tamoxifen followed by letrozole in postmenopausal women with early-stage breast cancer over a time horizon of 20 years.