A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer

Michael A Carducci, Fred Saad, Per Anders Abrahamsson, David P. Dearnaley, Claude C. Schulman, Scott A. North, Darryl J. Sleep, Jeffrey D. Isaacson, Joel B. Nelson

Research output: Contribution to journalArticle

Abstract

BACKGROUND. The objective of this study was to evaluate the efficacy and safety of atrasentan (Xinlay), a selective endothelin-A receptor antagonist, in patients with metastatic hormone-refractory prostate cancer (HRPC). METHODS. This multinational, double-blind, placebo-controlled trial enrolled 809 men with metastatic HRPC. Patients were randomized 1:1 to receive either atrasentan 10 mg per day or placebo. The primary endpoint was time to disease progression (TTP), which was determined according to radiographic and clinical measures. Analyses of overall survival and changes in biomarkers also were performed. RESULTS. Atrasentan did not reduce the risk of disease progression relative to placebo (hazards ratio, 0.89; 95% confidence interval, 0.76-1.04; P = .136). Most patients progressed radiographically at the first 12-week bone scan without concomitant clinical progression. In exploratory analyses, increases from baseline to final bone alkaline phosphatase (BAP) and prostate-specific antigen (PSA) levels were significantly lower with atrasentan treatment (P < .05 for each). The median time to BAP progression (≥50% increase from nadir) was twice as long with atrasentan treatment (505 days vs 254 days; P < .01). The delay in time to PSA progression did not reach statistical significance. Atrasentan generally was tolerated well, and the most common adverse events associated with treatment were headache, rhinitis, and peripheral edema, reflecting the vasodilatory and fluid-retention properties of endothelin-A receptor antagonism. CONCLUSIONS. Atrasentan did not delay disease progression in men with metastatic HRPC despite evidence of biologic effects on PSA and BAP as markers of disease burden.

Original languageEnglish (US)
Pages (from-to)1959-1966
Number of pages8
JournalCancer
Volume110
Issue number9
DOIs
StatePublished - Nov 1 2007

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Prostatic Neoplasms
Randomized Controlled Trials
Hormones
Safety
Prostate-Specific Antigen
Alkaline Phosphatase
Disease Progression
Bone and Bones
Placebos
Endothelin A Receptors
atrasentan
Rhinitis
Survival Analysis
Headache
Edema
Therapeutics
Biomarkers
Confidence Intervals

Keywords

  • Atrasentan
  • Bone metastasis
  • Endothelin-A receptor antagonist
  • Hormone-refractory prostate cancer
  • Time to disease progression

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Carducci, M. A., Saad, F., Abrahamsson, P. A., Dearnaley, D. P., Schulman, C. C., North, S. A., ... Nelson, J. B. (2007). A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer, 110(9), 1959-1966. https://doi.org/10.1002/cncr.22996

A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. / Carducci, Michael A; Saad, Fred; Abrahamsson, Per Anders; Dearnaley, David P.; Schulman, Claude C.; North, Scott A.; Sleep, Darryl J.; Isaacson, Jeffrey D.; Nelson, Joel B.

In: Cancer, Vol. 110, No. 9, 01.11.2007, p. 1959-1966.

Research output: Contribution to journalArticle

Carducci, MA, Saad, F, Abrahamsson, PA, Dearnaley, DP, Schulman, CC, North, SA, Sleep, DJ, Isaacson, JD & Nelson, JB 2007, 'A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer', Cancer, vol. 110, no. 9, pp. 1959-1966. https://doi.org/10.1002/cncr.22996
Carducci, Michael A ; Saad, Fred ; Abrahamsson, Per Anders ; Dearnaley, David P. ; Schulman, Claude C. ; North, Scott A. ; Sleep, Darryl J. ; Isaacson, Jeffrey D. ; Nelson, Joel B. / A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. In: Cancer. 2007 ; Vol. 110, No. 9. pp. 1959-1966.
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abstract = "BACKGROUND. The objective of this study was to evaluate the efficacy and safety of atrasentan (Xinlay), a selective endothelin-A receptor antagonist, in patients with metastatic hormone-refractory prostate cancer (HRPC). METHODS. This multinational, double-blind, placebo-controlled trial enrolled 809 men with metastatic HRPC. Patients were randomized 1:1 to receive either atrasentan 10 mg per day or placebo. The primary endpoint was time to disease progression (TTP), which was determined according to radiographic and clinical measures. Analyses of overall survival and changes in biomarkers also were performed. RESULTS. Atrasentan did not reduce the risk of disease progression relative to placebo (hazards ratio, 0.89; 95{\%} confidence interval, 0.76-1.04; P = .136). Most patients progressed radiographically at the first 12-week bone scan without concomitant clinical progression. In exploratory analyses, increases from baseline to final bone alkaline phosphatase (BAP) and prostate-specific antigen (PSA) levels were significantly lower with atrasentan treatment (P < .05 for each). The median time to BAP progression (≥50{\%} increase from nadir) was twice as long with atrasentan treatment (505 days vs 254 days; P < .01). The delay in time to PSA progression did not reach statistical significance. Atrasentan generally was tolerated well, and the most common adverse events associated with treatment were headache, rhinitis, and peripheral edema, reflecting the vasodilatory and fluid-retention properties of endothelin-A receptor antagonism. CONCLUSIONS. Atrasentan did not delay disease progression in men with metastatic HRPC despite evidence of biologic effects on PSA and BAP as markers of disease burden.",
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N2 - BACKGROUND. The objective of this study was to evaluate the efficacy and safety of atrasentan (Xinlay), a selective endothelin-A receptor antagonist, in patients with metastatic hormone-refractory prostate cancer (HRPC). METHODS. This multinational, double-blind, placebo-controlled trial enrolled 809 men with metastatic HRPC. Patients were randomized 1:1 to receive either atrasentan 10 mg per day or placebo. The primary endpoint was time to disease progression (TTP), which was determined according to radiographic and clinical measures. Analyses of overall survival and changes in biomarkers also were performed. RESULTS. Atrasentan did not reduce the risk of disease progression relative to placebo (hazards ratio, 0.89; 95% confidence interval, 0.76-1.04; P = .136). Most patients progressed radiographically at the first 12-week bone scan without concomitant clinical progression. In exploratory analyses, increases from baseline to final bone alkaline phosphatase (BAP) and prostate-specific antigen (PSA) levels were significantly lower with atrasentan treatment (P < .05 for each). The median time to BAP progression (≥50% increase from nadir) was twice as long with atrasentan treatment (505 days vs 254 days; P < .01). The delay in time to PSA progression did not reach statistical significance. Atrasentan generally was tolerated well, and the most common adverse events associated with treatment were headache, rhinitis, and peripheral edema, reflecting the vasodilatory and fluid-retention properties of endothelin-A receptor antagonism. CONCLUSIONS. Atrasentan did not delay disease progression in men with metastatic HRPC despite evidence of biologic effects on PSA and BAP as markers of disease burden.

AB - BACKGROUND. The objective of this study was to evaluate the efficacy and safety of atrasentan (Xinlay), a selective endothelin-A receptor antagonist, in patients with metastatic hormone-refractory prostate cancer (HRPC). METHODS. This multinational, double-blind, placebo-controlled trial enrolled 809 men with metastatic HRPC. Patients were randomized 1:1 to receive either atrasentan 10 mg per day or placebo. The primary endpoint was time to disease progression (TTP), which was determined according to radiographic and clinical measures. Analyses of overall survival and changes in biomarkers also were performed. RESULTS. Atrasentan did not reduce the risk of disease progression relative to placebo (hazards ratio, 0.89; 95% confidence interval, 0.76-1.04; P = .136). Most patients progressed radiographically at the first 12-week bone scan without concomitant clinical progression. In exploratory analyses, increases from baseline to final bone alkaline phosphatase (BAP) and prostate-specific antigen (PSA) levels were significantly lower with atrasentan treatment (P < .05 for each). The median time to BAP progression (≥50% increase from nadir) was twice as long with atrasentan treatment (505 days vs 254 days; P < .01). The delay in time to PSA progression did not reach statistical significance. Atrasentan generally was tolerated well, and the most common adverse events associated with treatment were headache, rhinitis, and peripheral edema, reflecting the vasodilatory and fluid-retention properties of endothelin-A receptor antagonism. CONCLUSIONS. Atrasentan did not delay disease progression in men with metastatic HRPC despite evidence of biologic effects on PSA and BAP as markers of disease burden.

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