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

Abstract

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.

Fig 1.

Enrollment and reporting.

Fig 2.

Time to progression (TTP) as defined by appearance of castrate-resistant phenotype. See text for definition of progression and details of stratification. (A) TTP by assigned treatment. (B) TTP by treatment, stratified by disease volume at entry.

Fig 3.

Overall survival. See text for details of stratification. (A) Survival by assigned treatment. (B) Survival by treatment, stratified by disease volume at entry.

Fig 4.

Overall survival among all patients by prostate-specific antigen (PSA) nadir after androgen ablation.