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Hoosier Oncology Group Randomized Phase II Study of Docetaxel, Vinorelbine, and Estramustine in Combination in Hormone-Refractory Prostate Cancer with Pharmacogenetic Survival Analysis

Authors' Affiliations: ¹ Department of Medicine and ² Division of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana; ³ Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; ⁴ Medical Consultants, P.C., Muncie, Indiana; ⁵ Nebraska Methodist Hospital and Cancer Center, Omaha, Nebraska; ⁶ Northern Indiana Cancer Research Consortium, South Bend, Indiana; and ⁷ Oncology Hematology Associates of Southwest Indiana, Evansville, Indiana

Requests for reprints: Christopher J. Sweeney, Division of Hematology and Oncology, Indiana University Cancer Center, 535 Barnhill Drive, Indiana University Cancer Pavilion, Room 473, Indianapolis, IN 46202. Phone: 317-274-3515; Fax: 317-274-3636; E-mail: chsweene{at}iupui.edu.

Purpose: To determine the safety and efficacy of two docetaxel doublets in hormone-refractory prostate cancer (HRPC) patients and to examine the prognostic role of polymorphisms in host genes important to docetaxel metabolism and transport.

Experimental Design: Sixty-four chemotherapy-naive patients with HRPC were randomized to docetaxel and vinorelbine (D, 20 mg/m² i.v. days 1 and 8; V, 25 mg/m² i.v. days 1 and 8) or docetaxel and estramustine phosphate (D, 60-70 mg/m² i.v. day 1; E, 280 mg oral thrice daily days 1-5) administered q21d. Primary end point was clinically significant toxicity. A pharmacogenetic analysis of host genes was done in patients who received at least one cycle of docetaxel therapy.

Results: Grade 3/4 toxicity occurred in 15.6% of DV patients and in 28.6% DE patients. Neither arm exceeded the threshold of clinically significant toxicity. In the DV arm, objective response rate was 33%, prostate-specific antigen response rate was 20%, and median survival was 16.2 months. In the DE arm, objective response rate was 67%, prostate-specific antigen response rate was 43%, and median survival was 19.7 months. Pharmacogenetic analyses showed a significant association between survival beyond 15 months and the ABCG2 421 C>A (Q141K) polymorphism compared with the wild-type (C/C) genotype (66% versus 27%; P = 0.05).

Conclusions: DV and DE doublets are active with a tolerable toxicity profile in patients with HRPC; however, efficacy does not seem superior to standard single-agent docetaxel. The ABCG2 421 C>A (Q141K) polymorphism may be an important predictor of response and survival in HRPC patients treated with docetaxel-based chemotherapy.

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