Anastrozole

Anastrozole (Arimidex®) is an aromatase inhibitor approved in the EU, the US and in other countries worldwide for use as an adjuvant treatment in postmenopausal women with early-stage, hormone receptor-positive breast cancer. It is also approved in the EU and other countries worldwide for continuing adjuvant treatment in women who have already had 2–3 years of adjuvant tamoxifen treatment for breast cancer.

Anastrozole is an effective primary adjuvant treatment for postmenopausal women with early-stage breast cancer. In patients with hormone receptor-positive tumours, 5 years of anastrozole treatment was more efficacious in reducing breast cancer recurrence than 5 years of tamoxifen, both in a head-to-head comparison and in switching trials when given after 2–3 years of tamoxifen treatment. The treatment benefits have now been shown to extend to 100 months following breast surgery. To date, overall survival was better in anastrozole than tamoxifen recipients in one switching trial and in a meta-analysis of three switching trials. There was no increased benefit in health-related quality of life with anastrozoleover tamoxifen. In women who had received 5 years of tamoxifen treatment, continuation of treatment with anastrozole further reduced the risk of breast cancer recurrence. Ongoing head-to-head trials against other third-generation aromatase inhibitors will provide data as to its relative efficacy against these agents.

Anastrozole is a generally well tolerated treatment for early-stage breast cancer. Like other aromatase inhibitors, its most important adverse effect was an increased risk of bone fractures, which for anastrozole was restricted to the treatment period. It is still unclear whether primary adjuvant treatment extended beyond 5 years is of benefit and whether primary adjuvant treatment with anastrozole for 5 years is preferable to switching to anastrozole after 2–3 years of tamoxifen treatment. However, the evidence to date establishes anastrozole as a valuable adjuvant and extended adjuvant treatment for postmenopausal women with hormone receptor-positive, early-stage breast cancer.

Anastrozole is a benzyltriazole derivative that reduces estrogen synthesis by binding competitively to the haem group of the cytochrome P450 unit of aromatase. It is a potent, selective aromatase inhibitor and has minimal or no effects on adrenal steroid hormones. In healthy postmenopausal women, multiple doses of anastrozole 1 mg/day led to prolonged suppression of plasma estradiol by ≥80% from baseline levels. In postmenopausal women with advanced breast cancer, plasma and tumour tissue estradiol levels were reduced from baseline levels by ≈90%. In a large clinical trial, after 12 and 24 months of follow-up, anastrozole was associated with decreased hip and lumbar spine bone mineral density, and an increase in serum cholesterol levels. In contrast with tamoxifen, after 5 years’ treatment there was no increase in endometrial thickening with anastrozole.

The ATAC (Arimidex®, Tamoxifen, Alone or in Combination) randomized, double-blind trial compared the efficacy of anastrozole as a primary adjuvant treatment for early-stage breast cancer in postmenopausal women with that of tamoxifen. Anastrozole was consistently more efficacious than tamoxifen according to both primary and secondary endpoints at 3-year, 5-year and 100-month (median) follow-ups. At the 100-month follow-up, for disease-free survival (primary endpoint), the hazard ratio for anastrozole versus tamoxifen was 0.85 (95% CI 0.76, 0.94) in the hormone receptor-positive population, representing a 4.1% absolute difference in the event rate. Three randomized, open-label, multicentre trials evaluated continuous adjuvant tamoxifen treatment for 5 years versus switching from tamoxifen to anastrozole after 2–3 years of tamoxifen treatment. In patients who were switched to anastrozole, the odds of experiencing breast cancer recurrence, cancer in the contralateral breast or death were approximately one-third lower than for those continuing tamoxifen. In a separate trial designed to evaluate 5 years of tamoxifen treatment followed by extended treatment with anastrozole 1 mg/day versus no extended treatment, patients receiving extended anastrozole treatment had fewer recurrences than patients who received no extended treatment. The greatest benefit was a significant reduction in the incidence of distant recurrences (4.1% vs 7.5%).

In the ATAC trial, anastrozole was generally well tolerated when used as the primary adjuvant treatment in early-stage breast cancer. Patients in the anastrozole group had significantly fewer treatment-related adverse events, serious treatment-related adverse events and withdrawals from treatment because of adverse events than tamoxifen recipients. In anastrozole recipients, osteopenia/osteoporosis, arthralgia, fractures, hypertension, hypercholesterolaemia, diarrhoea and paraesthesiae were significantly more common than in tamoxifen recipients. Gynaecological events, such as hot flushes, vaginal discharge, vaginal bleeding, endometrial cancer and hysterectomy, were significantly more common with tamoxifen, as were urinary tract infections, muscle cramps, anaemia, venous thrombosis, deep vein thrombosis and ischaemic cerebrovascular events. Tolerability findings from the switching trials were consistent with these findings from the ATAC trial.

Several studies have used the ATAC trial data to estimate the cost utility of anastrozole. When compared with tamoxifen, from the perspective of the health-funding systems from four countries, anastrozole was a cost-effective treatment for early-stage, hormone receptor-positive breast cancer. Incremental costs per quality-adjusted life-year gained were well below accepted cost-effectiveness thresholds for each economic environment when costs and outcomes were modelled over ≥20-year time horizons.