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No Benefit of Adding Atrasentan to Docetaxel in Advanced Castration-resistant Prostate Cancer

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Key Points

  • The addition of atrasentan to docetaxel did not improve progression-free survival or overall survival in men with metastatic castration-resistant prostate cancer and bone metastases.
  • According to the investigators, single-agent docetaxel should remain as one of the standard treatments for metastatic castration-resistant prostate cancer.

The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer, and the investigational endothelin receptor antagonist atrasentan has shown activity in prostate cancer. In the SWOG S0421 trial reported in Lancet Oncology by David I. Quinn, FRACP, of University of Southern California Norris Comprehensive Cancer Center, and colleagues, men with advanced castration-resistant prostate cancer received docetaxel plus either atrasentan or placebo. The study showed no progression-free survival or overall survival benefit with the addition of atrasentan.

Study Details

In this phase III double-blind trial, 994 patients with metastatic castration-resistant prostate cancer with bone metastases were randomly assigned to receive docetaxel at 75 mg/m2 every 21 days plus oral atrasentan at 10 mg/d (n = 498) or placebo (n = 496) until disease progression or unacceptable toxicity for up to 52 weeks. Patients were stratified for progression type (prostate-specific antigen [PSA] or radiologic), baseline pain, extraskeletal metastases, and bisphosphonate use. The co-primary endpoints were progression-free survival and overall survival.

The placebo and atrasentan groups were balanced for age (median, 69 years in both), ethnicity (81% white in both), progression of measurable or evaluable disease (79% and 82%), bisphosphonate use (61% in both), worst pain on Brief Pain Inventory scale (43% and 42%), metastases (skeletal only in 42% and 41%), ECOG performance status of 0 or 1 (92% and 93%), and Gleason scores of 5 to 6 (10% in both), 7 (28% in both), and 8 to 10 (55% in both).

No Difference in Survival

The trial was stopped early for futility in April 2011 after a planned interim analysis. Median progression-free survival was 9.2 months in the atrasentan group vs 9.1 months in the placebo group (hazard ratio [HR] = 1.02, P = .81). Median overall survival was 17.8 months in the atrasentan group vs 17.6 months in the placebo group (HR = 1.04, P = .64). Approximately 50% of patients in both groups had a reduction in PSA to 50% below baseline. There was no difference in objective response rate between the two groups; a nonsignificantly greater rate of unconfirmed partial response was observed in the atrasentan group (27% vs 22%). On multivariate analysis adjusting for stratification factors and other patient and disease characteristics, the overall survival hazard ratio for atrasentan vs placebo remained virtually unchanged (HR = 1.03, P = .67).

Overall, 57% of patients in the atrasentan group and 60% of the placebo group had grade 3 or higher toxicity. Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to study treatment.

The investigators concluded: “Atrasentan, when added to docetaxel, does not improve overall survival or [progression-free survival] in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments.

The study was funded by the National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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