Flutamide

Summary

Synopsis

Flutamide is a non-steroidal antiandrogenic drug devoid of hormonal agonist activity. Flutamide appears to be a specific antiandrogen only at androgen-dependent accessory genital organs. Its pharmacological activity is due substantially to the principal metabolite, 2-hydroxyflutamide. In comparative trials involving small numbers of patients with previously untreated advanced prostatic cancer, flutamide 750mg daily is comparable with stilboestrol 1 or 3mg daily and with estramustine 560 or 840mg daily. Treatment of newly diagnosed advanced prostatic cancer with flutamide plus a luteinising hormone releasing hormone (LHRH) agonist has produced very promising results, and appears to prolong survival relative to that achieved with leuprolide alone. However, these results require confirmation in suitably designed prospective studies. In previously treated patients refractory to castration, flutamide 750mg daily appears comparable in efficacy to estramustine phosphate 600 mg/m² daily. Apart from a high incidence (34 to 100%) of gynaecomastia flutamide monotherapy is usually well tolerated, and has the advantage of preserving libido and sexual potency in at least 80% of patients. Gynaecomastia is infrequent, however, when flutamide is used in conjunction with surgical castration or an LHRH agonist. Thus, flutamide is a suitable alternative to other systemic treatment in patients with advanced prostatic cancer who wish to preserve sexual potency. In combination with an LHRH agonist flutamide may become a first-line agent for previously untreated patients with cancer of the prostate.

Pharmacodynamic Properties

Flutamide is a non-steroidal antiandrogenic drug devoid of hormone agonist activity. In animal studies flutamide has been shown to be a specific antagonist at the androgen-dependent seminal vesicles and ventral prostate. Androgen receptor binding studies using human benign prostatic tissue demonstrated that the hydroxylated metabolite was more active than flutamide itself in suppressing the nuclear uptake of ³H-testosterone, as was cyproterone acetate. Intraprostatic levels of androgen receptors and testosterone were depressed more following treatment with flutamide plus castration than with surgical castration alone. Administration of flutamide to patients with benign prostatic hypertrophy caused a significant increase in mean serum concentrations of testosterone, oestradiol and luteinising hormone (LH) due to simulation of an androgen deficit resulting in increased release of gonadotrophin, while cyproterone acetate, which possesses antigona-dotrophin activity, depressed mean plasma concentrations of testosterone, oestradiol, LH and follicle stimulating hormone (FSH). Flutamide also increased serum concentrations of LH and FSH in surgically castrated patients. These increases are prevented by the concomitant administration of a luteinising hormone releasing hormone (LHRH) agonist and such a combination forms the basis of ’complete androgen blockade’ therapy, advocated by some investigators as initial treatment in patients with newly diagnosed advanced prostatic cancer (see below). Administration of flutamide to postmenopausal women with metastatic breast cancer depressed levels of the main C-19 steroid precursor. Decreases in markers of C-19 steroid metabolism in castrated males suggested that flutamide increased the metabolism of adrenal C-19 steroids into inactive steroid glucuronides.

During administration of flutamide plus an LHRH agonist plasma concentrations of very low density lipoprotein (VLDL)-cholesterol and apolipoprotein B were significantly lower than previously recorded with castration or oestrogen therapy or in untreated patients. LDL-cholesterol and apolipoprotein B levels were higher with flutamide plus an LHRH agonist than with oestrogen, while the high density lipoprotein (HDL) apolipoprotein AII was lower during the combined regimen than during oestrogen therapy. Thus, the profile of changes in plasma lipoproteins with flutamide/LHRH agonist therapy relative to oestrogen treatment requires further clarification.

Mechanism of Action

The exact mechanism of action of flutamide has yet to be established conclusively. Flutamide appears to exert its antiandrogenic effects on male secondary sex structures by inhibition of androgen uptake and/or inhibition of nuclear binding of androgens in target tissues where it appears to form inactive complexes with nuclear androgen receptors. Flutamide did not appreciably influence conversion of testosterone to dihydrotestosterone or other metabolic products. The lesser antiandrogenic effect in vitro than in vivo suggested involvement of an active metabolite. The hydroxylated metabolite is present in human plasma at much higher concentrations than unchanged flutamide and has antiandrogenic properties. Pure antiandrogens such as flutamide are more active in androgen-treated castrates than in intact animals; thus, the relative antiandrogenic activity of flutamide and cyproterone acetate depends upon the animal model. The antiandrogenic activity of flutamide is enhanced by the addition of an antigonadotrophic steroid.

Pharmacokinetic Properties

Maximum plasma concentrations of unchanged flutamide of 10 to 20 μg/L have been attained within 1 hour of oral administration of a single 250mg dose. In contrast, maximum concentrations of the active metabolite, 2-hydroxyflutamide, were 1290 to 1320 μg/L after the same dose, and mean steady-state concentrations of 940 μg/L were attained within 2 to 4 days. After repeated doses of flutamide 250mg, mean maximum plasma concentrations were 4- to 5-fold higher than after the first dose. In humans, flutamide is rapidly metabolised following oral administration to at least 10 plasma metabolites, although not all have been identified. The principal metabolite, 2-hydroxyflutamide, appears to be largely responsible for the antiandrogenic activity of flutamide. After single-dose oral administration of ³H-flutamide 200mg, 48.5% of the dose was recovered in the urine within 72 hours. Faecal recovery was 4.2% over the same period. Elimination half-life of the hydroxylated metabolite was 4 to 6.6 hours and 8 to 22 hours after 250 and 500mg, respectively.

Therapeutic Trials

Trials of flutamide alone and in conjunction with an LHRH agonist have been conducted in generally small groups of patients with advanced prostatic cancer. Because most studies used different objective assessment criteria, meaningful comparisons of results among studies are not possible. However, using fairly rigid criteria some promising results have been achieved using flutamide alone and in conjunction with an LHRH agonist in newly diagnosed patients with metastatic cancer of the prostate. Using the assessment criteria of the European Organisation for the Research of the Treatment of Cancer (EORTC), a complete or partial response has been noted in up to 82% of patients treated with flutamide 750mg daily alone. Similar results were reported in other studies using less rigorous criteria. With flutamide, as with other systemic treatments, the response rates in patients whose disease was refractory to hormonal manipulation were less satisfactory. Although up to 40% of patients with refractory cancer exhibited a positive response, the duration of response was generally short. One group of investigators has advocated treatment of previously untreated advanced prostatic cancer by ‘complete’ androgen blockade using flutamide plus an LHRH agonist or orchidectomy. These workers have reported that such a regimen produced a complete or partial response, according to rigid criteria of the United States National Prostatic Cancer Project (USNPCP), in 56% of patients, and stabilisation of the disease in a further 37%. A retrospective analysis of mortality in this study relative to that in studies of surgical castration or oestrogens alone, suggested improved survival in patents treated with flutamide plus an LHRH agonist. Confirmation of these results is needed and a suitably designed trial is in progress. Flutamide plus an LHRH agonist has also produced promising results in patients refractory to oestrogen therapy, with a positive response being achieved in about one-third of patients (USNPCP criteria).

Most of the few studies comparing flutamide with oestrogen therapy or estramustine phosphate have involved previously untreated patients. In generally small numbers of such patients, flutamide 750mg daily was similar in efficacy to stilboestrol 1 or 3mg daily. In comparisons with estramustine phosphate in newly diagnosed patients response to either drug was similar, but in one small study flutamide-treated patients relapsed significantly sooner than those treated with estramustine. In a larger group of patients who failed to respond to orchidectomy or whose disease progressed after an initial response, the initial response rate and 1-year survival were similar with flutamide 750mg and estramustine phosphate 600 mg/m2 daily.

Adverse Effects

Apart from a high incidence of gynaecomastia and some gastrointestinal discomfort flutamide has usually been well tolerated. Gynaecomastia, often mild to moderate, has occurred in 34 to 100% of non-castrated patients treated with flutamide alone, but was less pronounced and developed later than in patients treated with stilboestrol, and is infrequent when flutamide is used in conjunction with orchidectomy or an LHRH agonist. Elevation of plasma concentrations of alanine aminotransferase has been noted in many studies and in up to 32% of patients, but values have returned to normal without dosage modification in some patients. Some cases of severe toxic hepatitis have been reported, but in all patients liver function returned to normal after cessation of flutamide. Hot flushes have occurred in 50% of patients treated with flutamide plus an LHRH agonist. A favourable feature of flutamide therapy has been its lesser effect on libido and sexual potency; fewer than 20% of patients treated with flutamide alone reported such changes. In contrast, nearly all patients treated with oestrogens or estramustine phosphate reported loss of sexual potency.

Dosage

Flutamide is administered orally at a dosage of 250mg 3 times daily (with or without castration) in both newly diagnosed patients and those whose disease is refractory to hormonal manipulation.