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.
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.
There is no role for ketoconazole and doxorubicin alternating with vinblastine and
estramustine before emergence of a castrate-resistant phenotype.