Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): A randomised phase 3 trial

David I. Quinn, Catherine M. Tangen, Maha Hussain, Primo N Lara, Amir Goldkorn, Carol M. Moinpour, Mark G. Garzotto, Philip Mack, Michael A. Carducci, J. Paul Monk, Przemyslaw W. Twardowski, Peter J. Van Veldhuizen, Neeraj Agarwal, Celestia S. Higano, Nicholas J. Vogelzang, Ian M. Thompson

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

Background: The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases. Methods: In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m2 every 21 days, intravenously) with atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00134056. Findings: 498 patients were randomly assigned to the atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95% CI 8·5-9·9) in the atrasentan group and 9·1 months (8·4-10·2) in the placebo group (hazard ratio 1·02, 0·89-1·16; p=0·81). Median overall survival was 17·8 months (16·4-19·8) in the atrasentan group versus 17·6 months (16·4-20·1) in the placebo group (1·04, 0·90-1·19; p=0·64). 278 (57%) of 492 patients in the atrasentan group had grade 3 and greater toxicity compared with 294 (60%) of 486 in the placebo group (p=0·22). Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment. Interpretation: Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments. Funded: National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.

Original languageEnglish (US)
Pages (from-to)893-900
Number of pages8
JournalThe Lancet Oncology
Volume14
Issue number9
DOIs
StatePublished - Aug 2013

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docetaxel
bis(2,3,3,3-tetrachloropropyl) ether
Castration
Prostatic Neoplasms
Placebos
Neoplasm Metastasis
Disease-Free Survival
Bone Neoplasms
Survival
Medical Futility
atrasentan
Intention to Treat Analysis
National Cancer Institute (U.S.)
Endothelins
Diphosphonates
Prostate-Specific Antigen
Clinical Protocols

ASJC Scopus subject areas

  • Oncology

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Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421) : A randomised phase 3 trial. / Quinn, David I.; Tangen, Catherine M.; Hussain, Maha; Lara, Primo N; Goldkorn, Amir; Moinpour, Carol M.; Garzotto, Mark G.; Mack, Philip; Carducci, Michael A.; Monk, J. Paul; Twardowski, Przemyslaw W.; Van Veldhuizen, Peter J.; Agarwal, Neeraj; Higano, Celestia S.; Vogelzang, Nicholas J.; Thompson, Ian M.

In: The Lancet Oncology, Vol. 14, No. 9, 08.2013, p. 893-900.

Research output: Contribution to journalArticle

Quinn, DI, Tangen, CM, Hussain, M, Lara, PN, Goldkorn, A, Moinpour, CM, Garzotto, MG, Mack, P, Carducci, MA, Monk, JP, Twardowski, PW, Van Veldhuizen, PJ, Agarwal, N, Higano, CS, Vogelzang, NJ & Thompson, IM 2013, 'Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): A randomised phase 3 trial', The Lancet Oncology, vol. 14, no. 9, pp. 893-900. https://doi.org/10.1016/S1470-2045(13)70294-8
Quinn, David I. ; Tangen, Catherine M. ; Hussain, Maha ; Lara, Primo N ; Goldkorn, Amir ; Moinpour, Carol M. ; Garzotto, Mark G. ; Mack, Philip ; Carducci, Michael A. ; Monk, J. Paul ; Twardowski, Przemyslaw W. ; Van Veldhuizen, Peter J. ; Agarwal, Neeraj ; Higano, Celestia S. ; Vogelzang, Nicholas J. ; Thompson, Ian M. / Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421) : A randomised phase 3 trial. In: The Lancet Oncology. 2013 ; Vol. 14, No. 9. pp. 893-900.
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abstract = "Background: The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases. Methods: In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m2 every 21 days, intravenously) with atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00134056. Findings: 498 patients were randomly assigned to the atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95{\%} CI 8·5-9·9) in the atrasentan group and 9·1 months (8·4-10·2) in the placebo group (hazard ratio 1·02, 0·89-1·16; p=0·81). Median overall survival was 17·8 months (16·4-19·8) in the atrasentan group versus 17·6 months (16·4-20·1) in the placebo group (1·04, 0·90-1·19; p=0·64). 278 (57{\%}) of 492 patients in the atrasentan group had grade 3 and greater toxicity compared with 294 (60{\%}) of 486 in the placebo group (p=0·22). Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment. Interpretation: Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments. Funded: National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.",
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T1 - Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421)

T2 - A randomised phase 3 trial

AU - Quinn, David I.

AU - Tangen, Catherine M.

AU - Hussain, Maha

AU - Lara, Primo N

AU - Goldkorn, Amir

AU - Moinpour, Carol M.

AU - Garzotto, Mark G.

AU - Mack, Philip

AU - Carducci, Michael A.

AU - Monk, J. Paul

AU - Twardowski, Przemyslaw W.

AU - Van Veldhuizen, Peter J.

AU - Agarwal, Neeraj

AU - Higano, Celestia S.

AU - Vogelzang, Nicholas J.

AU - Thompson, Ian M.

PY - 2013/8

Y1 - 2013/8

N2 - Background: The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases. Methods: In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m2 every 21 days, intravenously) with atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00134056. Findings: 498 patients were randomly assigned to the atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95% CI 8·5-9·9) in the atrasentan group and 9·1 months (8·4-10·2) in the placebo group (hazard ratio 1·02, 0·89-1·16; p=0·81). Median overall survival was 17·8 months (16·4-19·8) in the atrasentan group versus 17·6 months (16·4-20·1) in the placebo group (1·04, 0·90-1·19; p=0·64). 278 (57%) of 492 patients in the atrasentan group had grade 3 and greater toxicity compared with 294 (60%) of 486 in the placebo group (p=0·22). Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment. Interpretation: Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments. Funded: National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.

AB - Background: The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases. Methods: In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m2 every 21 days, intravenously) with atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00134056. Findings: 498 patients were randomly assigned to the atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95% CI 8·5-9·9) in the atrasentan group and 9·1 months (8·4-10·2) in the placebo group (hazard ratio 1·02, 0·89-1·16; p=0·81). Median overall survival was 17·8 months (16·4-19·8) in the atrasentan group versus 17·6 months (16·4-20·1) in the placebo group (1·04, 0·90-1·19; p=0·64). 278 (57%) of 492 patients in the atrasentan group had grade 3 and greater toxicity compared with 294 (60%) of 486 in the placebo group (p=0·22). Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment. Interpretation: Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments. Funded: National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.

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