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A Phase I-II Study of Docetaxel and Atrasentan in Men with Castration-Resistant Metastatic Prostate Cancer

Authors' Affiliations: ¹ Duke Prostate Center; ² Division of Medical Oncology, Department of Medicine, Duke Comprehensive Cancer Center; ³ Division of Urologic Surgery, Department of Surgery; ⁴ Department of Radiology, Duke University, Durham, North Carolina; ⁵ Department of Basic Pharmaceutical Sciences and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia; and ⁶ Abbott Laboratories, Abbott Park, Illinois

Requests for reprints: Andrew J. Armstrong, 2424 Erwin Road, Hock Plaza, Suite 606, Durham, NC 27705. Phone: 919-668-8108; Fax: 919-668-7117; E-mail: andrew.armstrong{at}duke.edu.

Purpose: The primary aims of this phase I-II study were to determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary efficacy of the combination of docetaxel and the endothelin A receptor antagonist atrasentan as first-line treatment for men with metastatic castration-resistant prostate cancer.

Experimental Design: Patients were treated with docetaxel at doses ranging from 60 to 75 mg/m² every 21 days, with daily oral atrasentan 10 mg starting on day 3. Patients were treated until evidence of disease progression or unacceptable toxicity.

Results: Thirty-one patients were enrolled over three docetaxel dose levels (8 at 60 mg/m², 19 at 70 mg/m², and 4 at 75 mg/m²) including dose expansion at 70 mg/m². The maximum tolerated dose of docetaxel was 70 to 75 mg/m². Drug-related grade 3-4 toxicities included neutropenia (50-63%) and febrile neutropenia (16-25%); other grade 1-2 toxicities included fatigue, peripheral edema, diarrhea, headache, rhinitis, anorexia, and nausea. Confirmed prostate-specific antigen (PSA) responses were observed in 23% [95% confidence interval (95% CI), 10-41%]; the rate of >30% declines in PSA was 35% (95% CI, 19-55%). Median overall survival was 17.6 months (95% CI, 13.0-23.2) and median progression-free survival was 4.2 months (95% CI, 2.3-5.8). Significant declines in bone alkaline phosphatase and serum N-telopeptides were observed with therapy.

Conclusions: The maximum tolerated dose of every-3-week docetaxel with 10 mg atrasentan is 70 to 75 mg/m². Overall survival and progression-free survival are comparable to that seen with docetaxel and prednisone, whereas the rates of PSA decline are slightly lower than expected. A phase III study of this combination with prednisone has been initiated and is ongoing.