Flutamide

Abstract

Flutamide, a nonsteroidal antiandrogenic drug devoid of hormonal agonist activity, is used in the treatment of advanced prostate cancer. In previously untreated patients, flutamide 750mg daily given alone is of comparable efficacy to diethylstibestrol (stilboestrol) 1 or 3mg daily and estramustine 560 or 840mg daily, but has the potential advantages of fewer cardiovascular effects and maintenance of some sexual potency. Its greatest therapeutic potential is as a component of combination androgen blockade, where administration with an agonist analogue of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LH-RH)] in both initial uncontrolled and randomised studies increased survival time relative to GnRH agonist monotherapy or orchidectomy. Subsequent multicentre trials, however, have been unable to confirm an improvement in survival time. Thus, while there seems to be little doubt that flutamide prevents the initial disease flare caused by GnRH agonists, an improvement in remission rate and survival remains contentious. Flutamide is generally well tolerated and is suitable monotherapy in patients with previously untreated advanced prostatic cancer who wish to preserve sexual potency. However, full assessment of the role of combination androgen blockade awaits publication of the final results of ongoing multicentre trials. Flutamide, a nonsteroidal antiandrogenic drug devoid of hormone agonist activity, is often termed a ‘pure’ antiandrogen. Such activity in intact animals is enhanced by the addition of a GnRH agonist and is associated with more pronounced prostate atrophy than the GnRH analogue alone. These and other findings form the basis of combination androgen blockade used to treat advanced prostatic cancer in men. Administration of flutamide 750mg daily to healthy male volunteers increases plasma concentrations of testosterone, estradiol, luteinising hormone (LH) and follicle-stimulating hormone (FSH). These effects are prevented by concomitant administration of a GnRH analogue. It is generally considered that flutamide and its principal active metabolite, 2-hydroxy-flutamide, act mainly by inhibiting the binding of dihydrotestosterone to nuclear androgen receptors, thus decreasing cell proliferation in androgen-dependent tissues. However, a recent study of the proliferative capacity of androgen-sensitive human prostate tumour cells in the presence of steroidal and nonsteroidal antiandrogens found poor correlation between relative binding affinity to androgen receptors and proliferative efficiency. 2-Hydroxy-flutamide appears to be largely responsible for the antiandrogenic activity of flutamide. In healthy elderly men (aged 65 to 68 years) and patients with prostate cancer (aged 59 to 82 years), mean maximum concentrations of unchanged flutamide are attained 0.5 to 1.5 hours after a single 250mg oral dose and 1 to 4 hours after a 500mg dose. Plasma flutamide and 2-hydroxy-flutamide concentrations achieve steady-state by the sixth and third day, respectively, of 3 times daily oral administration. At steady-state, mean maximum plasma concentrations are 3- to 5- fold higher than after the first dose. The area under the plasma flutamide concentration-time curve is similar in elderly and younger volunteers, although mean maximum plasma concentrations tend to be lower in the elderly. Following a single 250mg oral dose, the elimination half-life of 2-hydroxy-flutamide was 8.1 and 4 to 6.6 hours in elderly volunteers and in patients with prostate cancer, respectively. Comparisons of flutamide and estrogen therapy in generally small numbers of previously untreated patients with advanced prostate cancer have shown flutamide 750mg daily to be of similar efficacy to diethylstilbestrol 1 or 3mg daily. The efficacies of flutamide and estramustine also appeared similar. Uncontrolled trials of flutamide plus a GnRH analogue suggested improved survival with such regimens relative to GnRH analogues alone. Less impressive, though significantly prolonged, survival times relative to medical castration alone were achieved with combination androgen blockade in a subsequent large multicentre randomised trial. However, analyses of several later randomised trials did not find evidence for improved survival time with combined treatment compared with a GnRH agonist alone or orchidectomy. Subjective responses (based on symptom control and performance status) were similar in flutamide plus goserelin recipients and surgically castrated patients, although there was evidence of an approximately 8-month longer symptom-free survival in those receiving combination therapy in 1 study. Final judgement on the possible advantages of combination androgen blockade awaits completion of these trials. Not surprisingly, flutamide, like other systemic treatments affecting the sex hormones, is less effective in patients unresponsive to hormonal manipulation, with response usually limited and short. Nevertheless, substitution of flutamide for cyproterone acetate elicited a positive response in 31% of patients who relapsed during combined androgen blockade, including 58% of those with stage D₁ disease. Larger trials are needed to confirm these favourable results and to determine if equally satisfactory results can be achieved with a flutamide-containing regimen started at diagnosis. Apart from a high incidence of gynaecomastia (34 to 100%) and some gastrointestinal discomfort, flutamide has generally been well tolerated. Gynaecomastia is less frequent when flutamide is combined with a GnRH analogue, but hot flushes occur in at least 50% of patients treated with such a regimen. Flushing is not associated with flutamide monotherapy, and the incidence of cardiovascular complications may be less than with estrogen treatment. Another favourable feature of treatment with flutamide alone is the maintenance of sexual potency in about 80% of patients, although this advantage over estrogen or estramustine therapy is negated when a GnRH agonist is added. Elevation of liver enzymes has been reported in up to about one-third of patients in some studies. These values often return to normal during continued treatment, although a few instances of reversible liver failure or cholestatic hepatitis have been reported. When administered alone or combined with a subcutaneous or intranasal GnRH agonist analogue, the oral dosage of flutamide is 250mg 3 times daily in both newly diagnosed patients and those whose disease is refractory to hormonal manipulation.