Phase II trial of docetaxel with rapid androgen cycling for progressive noncastrate prostate cancer

Purpose: We evaluated rapid androgen cycling in combination with docetaxel for men with progressive noncastrate prostate cancers. Patients and Methods: Noncastrate patients with ≤ 6 months of hormone therapy were eligible. Cohort 1 (62 patients) received six 28-day cycles of docetaxel (75 mg/m²), leuprolide, and 7 days of topical testosterone. Cohort 2 (38 patients) received nine 21-day cycles of docetaxel (70 mg/m²), leuprolide, and 3 days of testosterone. The primary end point was the proportion of patients at 18 months who achieved noncastrate testosterone levels (> 150 ng/dL) and an undetectable prostate-specific antigen (PSA; ≤ 0.05, ≤ 0.5, or ≤ 2.0 ng/mL with prior prostatectomy, radiation therapy, or no definitive therapy, respectively). Cytochrome P450 3A4 (CYP3A4) activity and docetaxel pharmacokinetics were evaluated. Results: A higher proportion of patients achieved the undetectable PSA outcome at 18 months in cohort 2 relative to cohort 1 (13% v 0%). The 16% incidence of febrile neutropenia was higher than that observed in patients was castration-resistant disease, which may have been related to a 50% reduction in overall docetaxel clearance in the noncastrate group. There was no alteration in CYP3A4 activity (P = .87) or docetaxel clearance (P = .88) between cycles. Conclusion: The undetectable PSA end point allows for a rapid screening of interventions for further study. Increasing the number of docetaxel cycles after a shorter period of testosterone repletion, and a longer duration of testosterone depletion, increased the proportion of men who achieved an undetectable PSA. The higher-than-expected incidence of febrile neutropenia may have been related to the reduced overall docetaxel clearance in patients with noncastrate versus castrate testosterone levels.