Bicalutamide 150mg

Summary

Abstract

Bicalutamide (Casodex®) is a competitive androgen receptor antagonist that inactivates androgen-regulated prostate cell growth and function, leading to cell apoptosis and inhibition of prostate cancer growth. It is administered orally as a once-daily dose. In the EU and a number of other countries, bicalutamide 150 mg/day is approved in men with locally advanced nonmetastatic prostate cancer as immediate therapy either as an adjuvant to active treatment or as monotherapy as an alternative to surgical or medical castration.

Combined analysis of the three trials that comprise the bicalutamide Early Prostate Cancer (EPC) programme showed that bicalutamide administered in conjunction with standard care in men with locally advanced prostate cancer offers disease-free survival benefits over standard care alone and is generally well tolerated. Overall survival was improved to a greater extent in the subgroup of patients who received bicalutamide plus radiation therapy compared with radiation therapy alone. Men with localised prostate cancer do not benefit from the addition of bicalutamide to standard care. Combined analysis of two other studies in men with locally advanced prostate cancer show that bicalutamide monotherapy offers better tolerability and higher health-related quality-of-life (HR-QOL) scores for sexual interest and physical capacity compared with surgical or medical castration, while achieving disease-free and overall survival durations that were not significantly different. Thus, when treatment options are being evaluated, bicalutamide as adjuvant therapy or monotherapy should be considered as an alternative to other available hormonal therapies in men with locally advanced prostate cancer, especially in those who wish to maintain an active lifestyle.

Pharmacological Properties

Bicalutamide, a competitive androgen receptor antagonist, binds to cytosolic androgen receptors in prostate cells and inactivates androgen-regulated prostate cell growth and function. This leads to cell apoptosis and inhibition of prostate cancer growth. Unlike steroidal antiandrogens, bicalutamide has no progestogenic activity and does not suppress gonadotropin secretion or sex hormone production. Rather, it increases serum levels of luteinising hormone, testosterone, dihydrotestosterone, estradiol and follicle-stimulating hormone. Although increased estradiol levels may cause some unwanted hormonal effects, they protect against hot flushes and preserve bone mineral density.

After oral administration, the pharmacologically active (R)-enantiomer of bicalutamide is slowly and extensively absorbed. Mean steady-state plasma concentrations of (R)-bicalutamide are seen after about 4 weeks’ administration of bicalutamide 150 mg/day in men with prostate cancer. (R)-bicalutamide is >99% bound to plasma albumin. Consistent with a long plasma half-life (t½β) of almost 6 days, (R)-bicalutamide accumulates 10-fold after repeated administration. Bicalutamide undergoes extensive hepatic metabolism, and is excreted in approximately equal proportions in urine and faeces. In patients with severe hepatic impairment, the t½β of (R)-bicalutamide is increased 1.75-fold. Although metabolism of (R)-bicalutamide is predominantly mediated via the cytochrome P450 (CYP) 3A4 isoenzyme, there is no evidence of clinically significant drug interactions when bicalutamide ≤150 mg/day is coadministered with drugs that induce or inhibit CYP enzyme activity.

Therapeutic Efficacy

The efficacy of bicalutamide has been evaluated in conjunction with standard care in men with early (localised or locally advanced) prostate cancer in the EPC programme (n = 8113) and as monotherapy in men with locally advanced prostate cancer in two comparative studies. Combined data from the three EPC trials showed that bicalutamide plus standard care (watchful waiting, radical prostatectomy or radiation therapy) was more effective than standard care alone in improving objective progression-free survival in men with locally advanced prostate cancer at a median follow-up of 7.4 years. In addition, overall survival was improved to a greater extent in men with locally advanced prostate cancer who received bicalutamide plus radiation therapy compared with radiation therapy alone. Bicalutamide did not confer a progression-free or overall survival benefit to men with localised prostate cancer in the EPC programme.

Although equivalence could not be established, progression-free and overall survival durations with bicalutamide were not significantly different from those with surgical or medical castration at a median 6.3 years’ follow-up in the combined results of the two monotherapy studies (n = 480). However, at 12 months’ follow-up, HR-QOL scores for sexual interest and physical capacity were higher in bicalutamide recipients than in men who had been castrated.

Tolerability

The most frequently occurring adverse events associated with bicalutamide as adjuvant therapy or monotherapy were gynaecomastia and breast pain, although these adverse events were generally mild to moderate in severity. Adverse events, such as hot flushes (9.2% vs 5.4%), decreased libido (3.6% vs 1.2%), impotence (9.3% vs 6.5%) and abnormal liver function tests (3.1% vs 1.7%), and death from heart failure (1.2% vs 0.6%) were infrequent in both the bicalutamide and placebo arms in the EPC programme. In the monotherapy trials, the incidence of hot flushes in men who had been castrated was 50% compared with 13% in bicalutamide recipients. After 96 weeks’ treatment in another trial, mean bone mineral density was maintained with bicalutamide, but had decreased in castrated patients.