Formestane

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Abstract
Formestane (4-hydroxyandrostenedione) is an aromatase inhibitor which significantly reduces plasma levels of estrogen and has shown antitumour activity in postmenopausal women with breast cancer. Objective response rates in heavily pretreated patients with advanced breast cancer generally range between 20 and 30% during treatment with intramuscular formestane 250 or 500mg once every 2 weeks, and a further 20 to 30% of patients experience disease stabilisation. The median duration of response is between 8 and 14 months. Highest response rates are observed in soft tissue metastases, in patients with estrogen-responsive tumours and in those showing a response to previous endocrine therapy. Furthermore, there is some evidence to suggest that higher response rates are achieved with formestane 500 versus 250mg once every 2 weeks. In comparative studies, the clinical efficacy of intramuscular formestane 250mg did not differ significantly from that of oral megestrol when administered as second-line endocrine therapy to patients with advanced disease in whom previous tamoxifen therapy had failed. In addition, formestane produced a response rate, duration of response and overall survival rate that was not significantly different from that of oral tamoxifen when administered as first-line endocrine therapy to patients with advanced disease, but tamoxifen was superior in some measures. Further investigation of these 2 agents, including the higher dosage of formestane (500mg), is necessary to confirm their relative efficacies. Formestane is well tolerated by the majority of patients; adverse events rarely necessitate cessation of therapy. The most common adverse events are local reactions at the injection site and systemic events usually related to the effect of the drug on the hormonal milieu. The systemic tolerability of formestane is similar to that of tamoxifen but better than that of megestrol. Thus, formestane is effective and well tolerated as first-line endocrine therapy for advanced disease. However, at present, it is unlikely to challenge tamoxifen in this indication, based on recent findings from a large comparative study and the fact that formestane requires intramuscular administration. Nonetheless, formestane, which appears to have a better tolerability profile than other currently available second-line agents (including megestrol and the aromatase inhibitor aminoglutethimide), is a valuable drug for the second-line treatment of postmenopausal women with advanced breast cancer. Aromatase is responsible for the conversion of androgens to estrone and estradiol (the major source of estrogen production in postmenopausal women). Formestane (4-hydroxyandrostenedione) competes with androstenedione for the substrate binding site of aromatase and, upon binding, causes irreversible inhibition of the enzyme. Formestane inhibited aromatase activity in several in vitro models including breast tumour biopsy samples, in which it showed significantly more powerful inhibition of aromatase than either aminoglutethimide or testolactone. Plasma estradiol levels in postmenopausal women with breast cancer were significantly reduced during treatment with formestane 250 or 500mg for up to 7 months (generally by about 50 to 70% from baseline). Reductions were observed within 24 hours of intramuscular administration. Estradiol levels were more variable in patients treated with the lower dose of formestane compared with the higher dose, and one study reported significantly greater maximal suppression of estradiol levels with formestane 500 versus 250mg (67 vs 58%). Formestane did not have any significant effect on other endocrine variables in postmenopausal women. Plasma levels of luteinising hormone, follicle stimulating hormone, sex hormone binding globulin and androgenic precursors were usually unchanged. The antitumour activity of formestane has been demonstrated in rats bearing chemically induced mammary tumours. Tumour regression was evident in 90 to 100% of animals treated with formestane, a higher regression rate than that observed in animals treated with aminoglutethimide, tamoxifen or combined treatment with formestane plus either of these agents. Studies in nude mice bearing human mammary tumours also showed significant inhibition of tumour growth in animals treated with formestane compared with untreated controls. Formestane is slowly absorbed into the circulation from a depot of the drug which is formed after intramuscular injection. Peak plasma concentrations are achieved 1 to 2 days after injection and steady-state concentrations are reached after the third or fourth dose. The mean serum concentration after a single 250mg intramuscular dose is 2.4 μg/L, compared with 4.5 μg/L at steady-state during 2-weekly injections of formestane 250mg. Formestane concentrations in malignant breast tissue exceed those in normal breast tissue (≈2-fold) and in plasma (>5-fold). Formestane is rapidly and extensively metabolised; the main metabolite after oral administration is the glucuronide conjugate of the parent drug. Metabolism after intramuscular administration is unknown at present. Plasma elimination of intramuscular formestane is biphasic: initial elimination half-life (t½) is 2 to 4 days and terminal t½ is up to 10 days. Intramuscular formestane 250 or 500mg once every 2 weeks generally produced objective responses (complete plus partial) in about 20 to 30% of heavily pretreated postmenopausal women with advanced breast cancer in phase I and II clinical trials. Responses were maintained for a median of 8 to 14 months and a further 20 to 30% of patients experienced disease stabilisation. The response rate was higher in patients treated with formestane 500mg than in those receiving the lower dosage of 250mg (46 vs 28% in one study) as second-line therapy. Metastases varied in their response to formestane therapy, with soft tissue generally responding better than visceral or bone metastases. In addition, higher response rates were observed in patients whose tumours expressed the estrogen receptor, in older patients (>70 years), and in patients who had responded to prior endocrine therapy. The clinical efficacy of intramuscular formestane 250mg once every 2 weeks did not differ significantly from that of oral megestrol 160 mg/day as second-line endocrine therapy in patients with advanced breast cancer in whom previous tamoxifen therapy had failed. In the largest study, response rates were 18.6 and 23.2%, the median duration of response was 388 and 393 days and the time to disease progression was 175 and 191 days, respectively, in evaluable formestane and megestrol recipients. When formestane was administered as first-line endocrine therapy to patients with advanced breast cancer, the efficacy of an intramuscular 250mg dose once every 2 weeks was similar to that of oral tamoxifen 30 mg/day for most measures in a large nonblind randomised multicentre trial. Response rates were 33 versus 37% and the median duration of response was 458 versus 604 days. Although there was no significant difference in median survival between treatment groups, the median time to disease progression and time to treatment failure were significantly longer in tamoxifen recipients. However, recent findings indicate that higher response rates are achieved with formestane 500mg versus the 250mg dosage as first-line therapy (39 vs 26.5%). Formestane 250mg once every 2 weeks caused tumour regression in 12 of 34 patients (35%) with primary invasive breast cancer when administered for 3 months prior to surgery. Similar response rates were observed in another trial in which patients received neoadjuvant formestane, tamoxifen or aminoglutethimide. Intramuscular formestane 250 or 500mg once every 2 weeks is well tolerated by the majority of postmenopausal women with breast cancer. Local and systemic adverse events were usually mild and cessation of treatment due to intolerable adverse events was rarely necessary. Local reactions at the injection site (usually mild inflammation or pain) occurred in 7.2 and 7% of patients in 2 large multicentre studies. Systemic events occurred in 17.1 and 19% of patients in these 2 studies, the most common events being hot flushes. Other common adverse events included nausea and vomiting, lethargy, dizziness, asthenia and skin rash or itching. The systemic tolerability of intramuscular formestane 250mg was similar to that of oral tamoxifen 30 mg/day but superior to that of oral megestrol 160 mg/day, the latter being associated with a higher incidence of cardiovascular events, vaginal haemorrhage, increased sweating, weight increase, oedema, dyspnoea and dyspepsia. Indirect comparisons show formestane to have better tolerability than the aromatase inhibitor aminoglutethimide. For the treatment of postmenopausal women with advanced breast cancer, the current recommended dosage of formestane is 250mg administered by intramuscular injection once every 2 weeks. Treatment should be continued until there is evidence of disease progression.