Maximal androgen blockade for patients with metastatic prostate cancer: outcome of a controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy

Abstract

Objectives. To review the outcome of therapy with maximal androgen blockade and compare the efficacy and safety of bicalutamide and flutamide, each used in combination with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy, in patients with untreated metastatic (Stage D2) prostate cancer. Methods. Randomized, double-blind (for antiandrogen therapy), multicenter study with a 2 × 2 factorial design. A total of 813 patients were allocated 1:1 to bicalutamide (50 mg once daily) or flutamide (250 mg three times daily), plus 2:1 to goserelin acetate (3.6 mg every 28 days) or leuprolide acetate (7.5 mg every 28 days). Results. At the time of analysis (median follow-up, 49 weeks), bicalutamide plus LHRH-A was associated with a statistically significant improvement in time-to-treatment failure, the primary endpoint, when compared with flutamide plus LHRH-A. The results with longer follow-up (median, 95 weeks) support previous findings of an improved time-to-treatment failure with bicalutamide plus LHRH-A; however, the difference between groups was not statistically significant. A treatment failure endpoint was reached by 68% of patients in the bicalutamide plus LHRH-A group, compared with 72% of patients in the flutamide plus LHRH-A group. The hazard ratio of bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.87 (95% confidence interval [CI], 0.74–1.03; P = 0.10). The upper one-sided 95% confidence limit for survival was 1.00, meeting the definition for equivalence (<1.25). With longer follow-up, overall mortality was 34%, with equivalent survival between groups: 32% of patients in the bicalutamide plus LHRH-A group died, compared with 35% in the flutamide plus LHRH-A group. The hazard ratio of bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.88 (95% Cl, 0.69–1.11; P = 0.29). The upper one-sided 95% confidence limit for survival was 1.07, meeting the definition for equivalence (<1.25). Diarrhea occurred in 24% of patients in the flutamide plus LHRH-A group compared with 10% of patients in the bicalutamide plus LHRH-A group ( P <0.001). Conclusion. In patients with metastatic prostate cancer, bicalutamide plus LHRH-A is effective and well tolerated. Because of its efficacy and tolerability profile, together with its convenient once-daily dosing formulation, bicalutamide represents a prime candidate for antiandrogen of first choice in combination with LHRH-A therapy in the treatment of men with metastatic prostate cancer.