Phase III trial of androgen ablation with or without three cycles of systemic chemotherapy for advanced prostate cancer

Purpose: We conducted a phase III trial in patients with previously untreated metastatic prostate cancer to test the hypothesis that three 8-week cycles of ketoconazole and doxorubicin alternating with vinblastine and estramustine, given in addition to standard androgen deprivation, would delay the appearance of castrate-resistant disease. Patients and Methods: Eligible patients had metastatic prostate cancer threatening enough to justify sustained androgen ablation and were fit enough for chemotherapy. The primary end point was time to castrate-resistant progression as shown by increasing prostate-specific antigen, new radiographic lesions, worsening cancer-related symptoms, or receipt of any other systemic therapy. Results: Three hundred six patients were registered; 286 are reported. Median time to progression was 24 months (95% CI, 18 to 39 months) in the standard therapy arm, and 35 months (95% CI, 26 to 44 months) in the chemohormonal group (P = .39). At median follow-up of 6.4 years, overall survival was 5.4 years (95% CI, 4.7 to 7.8 years) in the standard therapy arm versus 6.1 years (95% CI, 5.1 to 10.1 years; P = .41). Prostate-specific antigen kinetics at the time of androgen ablation and the nadir after hormone treatment were strongly correlated with survival. Chemotherapy significantly increased the burden of therapy, with 51% of patients experiencing an adverse event of grade 3 or worse, especially thromboembolic events. Conclusion: There is no role for ketoconazole and doxorubicin alternating with vinblastine and estramustine before emergence of a castrate-resistant phenotype.