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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/m 2 i.v. days 1 and 8; V, 25 mg/m 2 i.v. days 1 and 8) or docetaxel and estramustine phosphate (D, 60-70 mg/m 2 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 421C>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 421C>A (Q141K) polymorphism may be an important predictor of response and survival in HRPC patients treated with docetaxel-based chemotherapy.Prostate cancer afflicts 234,000 men yearly and results in >27,000 deaths (1). Recent trials have shown a survival benefit for men with hormone-refractory prostate cancer (HRPC) treated with a docetaxel-based regimen (2, 3).Vinorelbine is a Vinca alkaloid that inhibits the microtubular apparatus in malignant cells and has documented activity in HRPC (4-6). Vinorelbine and docetaxel inhibit different portions of the microtubule apparatus in a synergistic manner in preclinical in vitro prostate cancer models (7-9). With this in mind, the Hoosier Oncology Group conducted a randomized phase II trial of weekly docetaxel and vinorelbine (DV) with docetaxel and estramustine phosphate (DE) as a parallel reference arm.This study also included a pharmacogenetic analysis of host genes with critical roles in docetaxel drug transport and metabolism. Clinical studies suggest that variant alleles in the thiopurine methyltransferase gene can identify patients at risk of severe hematologic toxicity after azathioprine, 6-mercaptopurine, or related agents (10). Similar toxicity associations are seen with dihydropyrimidine dehydrogenase gene mutations and 5-fluorouracil therapy (11) and with UGT1A1 mutations and irinotecan (12). Single-nucleotide polymorphisms (and other genetic variants) have also been observed, which affect docetaxel metabolism and transport. These include alt...

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