Bicalutamide in Advanced Prostate Cancer

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Abstract
Bicalutamide is a nonsteroidal antiandrogen with a long elimination half-life (t½) that permits once-daily administration. When combined with a gonadorelin (gonadotrophin releasing hormone; GnRH) agonist in maximum androgen blockade (MAB) regimens, bicalutamide 50mg once daily is at least as effective as flutamide 250mg 3 times daily, as shown in a large randomised trial. Rate of treatment failure, the primary end-point, was significantly lower at 49 weeks with bicalutamide in this study, mainly because of a lower rate of withdrawal due to adverse events. Final results at a median follow-up of 160 weeks revealed longer median times to progression and death with bicalutamide than flutamide, but between-group differences were not significant overall. Although early trials demonstrated clinical benefits with bicalutamide 50 mg/day as monotherapy, the drug in this dosage is less effective than castration. Increasing the dosage to 150 mg/day has improved its efficacy in patients with non-metastatic disease: combined data from 2 trials demonstrate similar survival with bicalutamide in this dosage compared with castration. Accumulating evidence from these and other studies indicates that sexual interest appears to be better preserved with bicalutamide than with castration. The tolerability profile of bicalutamide is characteristic of antiandrogens, with breast pain and gynaecomastia occurring most often. Bicalutamide has not been causally associated with problems such as interstitial pneumonitis and difficulty with light/dark adaptation seen with nilutamide, and in a 50 mg/day dosage causes a lower incidence of diarrhoea than flutamide 750 mg/day. Changes in hepatic function are generally transient and resolve or improve during therapy or after bicalutamide treatment is withdrawn. Conclusions. Bicalutamide, with its once-daily regimen and good tolerability, is an attractive option when combined with a GnRH agonist in patients with advanced prostate cancer who are suitable to receive MAB regimens. The role of bicalutamide as monotherapy in the management of this common malignancy is currently being assessed. Bicalutamide binds to androgen receptors in the prostate and prevents the physiological effects of dihydrotestosterone (DHT). The R-enantiomer is largely responsible for the activity of the drug. In most, although not all, in vitro studies bicalutamide had a 2- to 4-fold higher affinity than hydroxyflutamide for the androgen receptor. Bicalutamide displays antiandrogenic, but no androgenic, activity in several androgenic tumour cell lines and has antitumour activity in rats with prostate tumours. Animal studies demonstrate a regressive effect for bicalutamide on testicular and prostate tissue. Based on limited evidence, the drug does not appear to stimulate Leydig cell hyperplasia in men. In men with advanced prostate cancer, bicalutamide as monotherapy increases serum levels of gonadotrophins (luteinising hormone and follicle-stimulating hormone) and sex hormones (testosterone, DHT and estradiol). In the majority of patients, hormone levels remain within normal ranges: serum testosterone levels exceed the upper limit of normal in only a few patients. The absolute bioavailability of bicalutamide is not known, but the drug is apparently well absorbed after an oral dose. Food does not affect bicalutamide absorption, which is dose-dependent and prolonged. Peak plasma concentrations are reached within 1 to 2 days, and the active R-enantiomer accounts for 99% of steady-state plasma concentrations. Consistent with its long elimination half-life (t½) [about a week], bicalutamide accumulates 10-fold in plasma after repeated administration and can be given once daily. The drug is >95% bound to plasma proteins. Bicalutamide undergoes extensive hepatic biotransformation via glucuronidation and oxidation. About 80% of a single radioactive dose is retrieved in urine (35.8%) and faeces (42.6%) within 9 days of administration. The parent drug is present in faeces but not in urine. The R-enantiomer is eliminated much more slowly than the S-enantiomer, which may undergo extensive first-pass metabolism. Bicalutamide pharmacokinetics are not altered by increasing age, renal dysfunction or mild to moderate hepatic impairment; however, there is some evidence that t½ is prolonged by severe hepatic dysfunction. Maximum androgen blockade (MAB) combines surgical castration (bilateral orchidectomy) or medical castration [using a gonadorelin (gonadotrophin releasing hormone; GnRH) agonist] with an antiandrogen. MAB with bicalutamide 50mg orally once daily plus a GnRH agonist is at least as effective as oral flutamide 250mg 3 times daily plus a GnRH agonist, as shown in a large randomised double-blind trial. Fewer bicalutamide than flutamide recipients failed treatment (the primary end-point) at 49 weeks, mainly because of a lower withdrawal rate due to adverse events in the bicalutamide group (see Tolerability summary). Results at 160 weeks for median time to progression and death favoured bicalutamide but between-group differences were not statistically significant. Despite promising results obtained in noncomparative trials, bicalutamide 50mg once daily as monotherapy is not as effective as surgical or medical castration. Efforts to improve the efficacy of bicalutamide monotherapy by increasing the dosage to 150 mg/day have met with some success, particularly in patients with non-metastatic disease. Combined findings from 2 randomised trials indicate a similar effect on survival but a better quality of life (in the aspects of sexual interest and physical capacity) with bicalutamide compared with castration in these patients. Conversely, patients with metastatic disease appear to respond less well (evidenced by a 6-week deficit in survival time) to bicalutamide 150 mg/day monotherapy than to castration. Preliminary results suggest that bicalutamide 150 mg/day as monotherapy may have similar effects to MAB (flutamide 750 mg/day or nilutamide 150 mg/day plus castration) on survival and objective progression in patients with locally advanced or metastatic cancer, but this remains to be confirmed. There is limited evidence that bicalutamide 150 mg/day may have a palliative role as second-line therapy in patients failing orchidectomy, GnRH agonist or flutamide treatment. An emergent trend points to better maintenance of sexual interest with bicalutamide than with castration. Quality of life did not differ between groups receiving bicalutamide 50 mg/day or flutamide 750 mg/day, each given with a GnRH agonist. Bicalutamide 50 mg/day monotherapy has less effect than castration on serum prostate specific antigen (PSA) levels. Combining bicalutamide in this dosage with a GnRH agonist, or increasing the dosage to 150 mg/day as monotherapy, reduces serum PSA levels further than bicalutamide 50 mg/day and to a similar extent to flutamide plus a GnRH agonist. The syndrome of antiandrogen withdrawal describes a reduction in serum PSA levels, associated in some instances with clinical response, after antiandrogen therapy is stopped in patients with objective progression following an initial response. Case reports indicate that this syndrome occurs with bicalutamide. There is evidence, albeit sparse, that bicalutamide reduces serum PSA levels in patients who manifest the antiandrogen withdrawal syndrome after discontinuing flutamide therapy. Adverse events experienced most often during bicalutamide therapy (breast pain or tenderness and gynaecomastia) are those typically associated with an antiandrogen. These occur more frequently than with castration, which in turn is more commonly associated with hot flushes. Breast discomfort or gynaecomastia caused patient withdrawal in <1% of patients receiving bicalutamide monotherapy in randomised clinical trials. Other events reported during bicalutamide therapy include diarrhoea, vomiting, nausea, haematuria, asthenia and skin changes such as rash. No causal relationship has been shown between bicalutamide therapy and the problems of interstitial pneumonitis or light/dark adaptation seen with nilutamide. Abnormalities in liver function tests developed in similar low proportions of patients receiving bicalutamide or undergoing castration in clinical trials. Hepatic changes such as elevated liver enzyme levels were usually transient and disappeared or improved with continued therapy or treatment withdrawal. Antiandrogen-related adverse events are predictably more common with bicalutamide 100 or 150 mg/day monotherapy than with nilutamide plus surgical or medical (goserelin) castration. On the other hand, visual disorders and hot flushes were less frequent during bicalutamide treatment than with MAB containing nilutamide. Bicalutamide 50 mg/day plus a GnRH agonist as MAB has a similar general adverse event profile to flutamide 750 mg/day plus a GnRH agonist but causes significantly less diarrhoea, as shown in a comparative trial. The incidence of liver enzyme abnormalities appears to be higher with bicalutamide plus a GnRH agonist than with bicalutamide monotherapy. The recommended dosage of bicalutamide when combined with a GnRH agonist in MAB regimens is 50mg orally once daily in the morning or evening, with or without food. Measurement of serum PSA levels may assist in monitoring patient response. Dosage adjustment is not needed in patients with renal dysfunction, but caution is required when using bicalutamide in patients with moderate to severe hepatic impairment. Periodic liver function tests should be considered. Because bicalutamide may displace warfarin and other coumarin anticoagulants from binding sites, prothrombin times should be closely monitored after starting bicalutamide therapy in patients already receiving coumarin anticoagulants. The dosage and efficacy of bicalutamide as monotherapy are currently being assessed.

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