Phase II, Randomized, Placebo-Controlled Trial of Neoadjuvant Celecoxib in Men with Clinically Localized Prostate Cancer: Evaluation of Drug-Specific Biomarkers

Emmanuel Antonarakis, Elisabeth I. Heath, Janet R. Walczak, William G Nelson, Helen Fedor, Angelo Michael Demarzo, Marianna L. Zahurak, Steven Piantadosi, Andrew J. Dannenberg, Robin T. Gurganus, Sharyn D. Baker, Howard L. Parnes, Theodore DeWeese, Alan Wayne Partin, Michael A Carducci

Research output: Contribution to journalArticle

Abstract

Purpose: Cyclooxygenase-2 (COX-2) is a potential pharmacologic target for the prevention of various malignancies, including prostate cancer. We conducted a randomized, double-blind trial to examine the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy. Patients and Methods: Patients with localized prostate cancer and Gleason sum ≥ 7, prostate-specific antigen (PSA) ≥ 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy. The primary end point was the difference in prostatic prostaglandin levels between the two groups. Secondary end points were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. Tertiary end points were drug safety and compliance. Results Seventy-three patients consented, and 64 were randomly assigned and included in the intentionto-treat analysis. There were no treatment differences in any of the primary or secondary outcomes. Multivariable regression revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67 (P <.0001). Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities. Conclusion Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies.

Original languageEnglish (US)
Pages (from-to)4986-4993
Number of pages8
JournalJournal of Clinical Oncology
Volume27
Issue number30
DOIs
StatePublished - Oct 20 2009
Externally publishedYes

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Celecoxib
Drug Evaluation
Prostatic Neoplasms
Randomized Controlled Trials
Biomarkers
Placebos
Prostate
Cyclooxygenase 2
Prostatectomy
Prostate-Specific Antigen
Pharmaceutical Preparations
Compliance
Prostaglandins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase II, Randomized, Placebo-Controlled Trial of Neoadjuvant Celecoxib in Men with Clinically Localized Prostate Cancer : Evaluation of Drug-Specific Biomarkers. / Antonarakis, Emmanuel; Heath, Elisabeth I.; Walczak, Janet R.; Nelson, William G; Fedor, Helen; Demarzo, Angelo Michael; Zahurak, Marianna L.; Piantadosi, Steven; Dannenberg, Andrew J.; Gurganus, Robin T.; Baker, Sharyn D.; Parnes, Howard L.; DeWeese, Theodore; Partin, Alan Wayne; Carducci, Michael A.

In: Journal of Clinical Oncology, Vol. 27, No. 30, 20.10.2009, p. 4986-4993.

Research output: Contribution to journalArticle

Antonarakis, Emmanuel ; Heath, Elisabeth I. ; Walczak, Janet R. ; Nelson, William G ; Fedor, Helen ; Demarzo, Angelo Michael ; Zahurak, Marianna L. ; Piantadosi, Steven ; Dannenberg, Andrew J. ; Gurganus, Robin T. ; Baker, Sharyn D. ; Parnes, Howard L. ; DeWeese, Theodore ; Partin, Alan Wayne ; Carducci, Michael A. / Phase II, Randomized, Placebo-Controlled Trial of Neoadjuvant Celecoxib in Men with Clinically Localized Prostate Cancer : Evaluation of Drug-Specific Biomarkers. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 30. pp. 4986-4993.
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abstract = "Purpose: Cyclooxygenase-2 (COX-2) is a potential pharmacologic target for the prevention of various malignancies, including prostate cancer. We conducted a randomized, double-blind trial to examine the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy. Patients and Methods: Patients with localized prostate cancer and Gleason sum ≥ 7, prostate-specific antigen (PSA) ≥ 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45{\%} risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy. The primary end point was the difference in prostatic prostaglandin levels between the two groups. Secondary end points were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. Tertiary end points were drug safety and compliance. Results Seventy-three patients consented, and 64 were randomly assigned and included in the intentionto-treat analysis. There were no treatment differences in any of the primary or secondary outcomes. Multivariable regression revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67 (P <.0001). Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities. Conclusion Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies.",
author = "Emmanuel Antonarakis and Heath, {Elisabeth I.} and Walczak, {Janet R.} and Nelson, {William G} and Helen Fedor and Demarzo, {Angelo Michael} and Zahurak, {Marianna L.} and Steven Piantadosi and Dannenberg, {Andrew J.} and Gurganus, {Robin T.} and Baker, {Sharyn D.} and Parnes, {Howard L.} and Theodore DeWeese and Partin, {Alan Wayne} and Carducci, {Michael A}",
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T1 - Phase II, Randomized, Placebo-Controlled Trial of Neoadjuvant Celecoxib in Men with Clinically Localized Prostate Cancer

T2 - Evaluation of Drug-Specific Biomarkers

AU - Antonarakis, Emmanuel

AU - Heath, Elisabeth I.

AU - Walczak, Janet R.

AU - Nelson, William G

AU - Fedor, Helen

AU - Demarzo, Angelo Michael

AU - Zahurak, Marianna L.

AU - Piantadosi, Steven

AU - Dannenberg, Andrew J.

AU - Gurganus, Robin T.

AU - Baker, Sharyn D.

AU - Parnes, Howard L.

AU - DeWeese, Theodore

AU - Partin, Alan Wayne

AU - Carducci, Michael A

PY - 2009/10/20

Y1 - 2009/10/20

N2 - Purpose: Cyclooxygenase-2 (COX-2) is a potential pharmacologic target for the prevention of various malignancies, including prostate cancer. We conducted a randomized, double-blind trial to examine the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy. Patients and Methods: Patients with localized prostate cancer and Gleason sum ≥ 7, prostate-specific antigen (PSA) ≥ 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy. The primary end point was the difference in prostatic prostaglandin levels between the two groups. Secondary end points were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. Tertiary end points were drug safety and compliance. Results Seventy-three patients consented, and 64 were randomly assigned and included in the intentionto-treat analysis. There were no treatment differences in any of the primary or secondary outcomes. Multivariable regression revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67 (P <.0001). Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities. Conclusion Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies.

AB - Purpose: Cyclooxygenase-2 (COX-2) is a potential pharmacologic target for the prevention of various malignancies, including prostate cancer. We conducted a randomized, double-blind trial to examine the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy. Patients and Methods: Patients with localized prostate cancer and Gleason sum ≥ 7, prostate-specific antigen (PSA) ≥ 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy. The primary end point was the difference in prostatic prostaglandin levels between the two groups. Secondary end points were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. Tertiary end points were drug safety and compliance. Results Seventy-three patients consented, and 64 were randomly assigned and included in the intentionto-treat analysis. There were no treatment differences in any of the primary or secondary outcomes. Multivariable regression revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67 (P <.0001). Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities. Conclusion Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies.

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