Background: Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial, we found that adding the antiandrogen flutamide to leuprolide acetate (a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate. In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy. Methods: We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status. Results: Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall the incidence of toxic effects was minimal; the only notable differences between the groups were the greater rates of diarrhea and anemia with flutamide. There was no significant difference between the two groups in overall survival (P=0.14). The estimated risk of death (hazard ratio) for flutamide as compared with placebo was 0.91 (90 percent confidence interval, 0.81 to 1.01). Flutamide was not associated with enhanced benefit in patients with minimal disease. Conclusions: The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.
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