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Effect of Endothelin-A Receptor Blockade With Atrasentan on Tumor Progression in Men With Hormone-Refractory Prostate Cancer: A Randomized, Phase II, Placebo-Controlled Trial

Michael A. Carducci, Robert J. Padley, Jurgen Breul, Nicholas J. Vogelzang, Bernard A. Zonnenberg, Danai D. Daliani, Claude C. Schulman, Azmi A. Nabulsi, Rod A. Humerickhouse, Mark A. Weinberg, Jennifer L. Schmitt, Joel B. Nelson

From the Sidney Kimmel Comprehensive Cancer Center, the Johns Hopkins University School of Medicine, Baltimore, MD; Abbott Laboratories, Abbott Park, IL; Urologische Klinik und Poliklinik, Klinikum rechts der Isar, Munich, Germany; Department of Medicine, Section of Hematology/Oncology and the Cancer Research Center, University of Chicago, Chicago, IL; Department of Medical Oncology, University Medical Center, Utrecht, the Netherlands; Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Department of Urology, University Hospital Erasme, Brussels, Belgium.

Address reprint requests to Joel B. Nelson, MD, University of Pittsburgh School of Medicine, 5200 Centre Ave, Pittsburgh, PA 15232; email: nelsonjb{at}msx.upmc.edu.

Purpose: To evaluate the efficacy and safety of atrasentan (ABT-627), an endothelin-A receptor antagonist, in the treatment of asymptomatic, hormone-refractory prostatic adenocarcinoma.

Patients and Methods: A double-blind, randomized, placebo-controlled clinical trial of hormone-refractory prostate cancer (HRPCa) patients was conducted in the United States and Europe. Two hundred eighty-eight asymptomatic patients with HRPCa and evidence of metastatic disease were randomly assigned to one of three study groups receiving a once-daily oral dose of placebo, 2.5 mg atrasentan, or 10 mg atrasentan, respectively. Primary end point was time to progression; secondary end points included time to prostate-specific antigen (PSA) progression, bone scan changes, and changes in bone and tumor markers.

Results: The three treatment groups were similar in all baseline characteristics. Median time to progression in intent-to-treat (ITT) patients (n = 288) was longer in the 10-mg atrasentan group compared with the placebo group: 183 v 137 days, respectively; (P = .13). Median time to progression in evaluable patients (n = 244) was significantly prolonged, from 129 days (placebo group) to 196 days (10-mg atrasentan group; P = .021). For both ITT and evaluable populations in the 10-mg atrasentan group, median time to PSA progression was twice that of the placebo group (155 v 71 days; P = .002). Patients who received placebo continued to have significant increases from baseline in serum (lactate dehydrogenase [LDH]), a marker of disease burden; elevations in LDH were uniformly attenuated by atrasentan in the ITT population. Headache, peripheral edema, and rhinitis were primary side effects, typically of mild to moderate severity. Quality of life was not adversely affected by atrasentan.

Conclusion: Atrasentan is an oral, targeted therapy with favorable tolerability and the potential to delay progression of HRPCa.

Supported by a grant from Abbott Laboratories, Abbott Park, IL. N.J. Vogelzang was supported in part by grant no. P30-CA-14599 from the National Institutes of Health, Department of Health and Human Services, Bethesda, MD. M.A. Carducci and J.B. Nelson were supported in part by NIH/NCI grant no. K08-CA-69164 from the National Cancer Institute, National Institutes of Health, and by the Association for the Cure of Cancer of the Prostate, Santa Monia, CA.

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