Long-term survival and biomarker correlates of tasquinimod efficacy in a multicenter randomized study of men with minimally symptomatic metastatic castration-resistant prostate cancer

A. J. Armstrong, M. Häggman, W. M. Stadler, J. R. Gingrich, V. Assikis, J. Polikoff, J. E. Damber, L. Belkoff, Ö Nordle, G. Forsberg, M. A. Carducci, Roberto Pili

Research output: Contribution to journalArticle

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Abstract

Purpose: Tasquinimod (Active Biotech) is an oral immunomodulatory, anti-angiogenic, and antimetastatic agent that delayed metastatic disease progression in a randomized placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). Here, we report long-term survival with biomarker correlates from this trial. Experimental Design: Two hundred and one (134 tasquinimod and 67 placebo) men withmCRPCwere evaluated. Forty-one men randomized to placebo crossed over to tasquinimod. Survival data were collected with a median follow-up time of 37 months. Exploratory biomarker studies at baseline and over time were collected to evaluate potential mechanism-based correlates with tasquinimod efficacy including progression-free survival (PFS) and overall survival (OS). Results: With 111 mortality events, median OS was 33.4 months for tasquinimod versus 30.4 months for placebo overall, and 34.2 versus 27.1 months in men with bone metastases (n = 136), respectively. Multivariable analysis demonstrated an adjusted HR of 0.52 [95% confidence interval (CI), 0.35-0.78; P = 0.001] for PFS and 0.64 (95% CI, 0.42-0.97; P = 0.034) for OS, favoring tasquinimod. Time-tosymptomatic progression was improved with tasquinimod (P = 0.039, HR = 0.42). Toxicities tended to be mild in nature and improved over time. Biomarker analyses suggested a favorable impact on bone alkaline phosphatase and lactate dehydrogenase (LDH) over time and a transient induction of inflammatory biomarkers, VEGF-A, and thrombospondin-1 levels with tasquinimod. Baseline levels of thrombospondin-1 less than the median were predictive of treatment benefit. Conclusions: The survival observed in this trial ofmen withminimally symptomaticm CRPC suggests that the prolongation in PFS with tasquinimodmay lead to a survival advantage in this setting, particularly among men with skeletalmetastases, and has a favorable risk:benefit ratio.

Original languageEnglish (US)
Pages (from-to)6891-6901
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number24
DOIs
StatePublished - Dec 15 2013
Externally publishedYes

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Castration
Multicenter Studies
Prostatic Neoplasms
Biomarkers
Survival
Placebos
Disease-Free Survival
Thrombospondin 1
Confidence Intervals
Bone and Bones
tasquinimod
L-Lactate Dehydrogenase
Vascular Endothelial Growth Factor A
Alkaline Phosphatase
Disease Progression
Research Design
Odds Ratio
Neoplasm Metastasis
Mortality

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Long-term survival and biomarker correlates of tasquinimod efficacy in a multicenter randomized study of men with minimally symptomatic metastatic castration-resistant prostate cancer. / Armstrong, A. J.; Häggman, M.; Stadler, W. M.; Gingrich, J. R.; Assikis, V.; Polikoff, J.; Damber, J. E.; Belkoff, L.; Nordle, Ö; Forsberg, G.; Carducci, M. A.; Pili, Roberto.

In: Clinical Cancer Research, Vol. 19, No. 24, 15.12.2013, p. 6891-6901.

Research output: Contribution to journalArticle

Armstrong, AJ, Häggman, M, Stadler, WM, Gingrich, JR, Assikis, V, Polikoff, J, Damber, JE, Belkoff, L, Nordle, Ö, Forsberg, G, Carducci, MA & Pili, R 2013, 'Long-term survival and biomarker correlates of tasquinimod efficacy in a multicenter randomized study of men with minimally symptomatic metastatic castration-resistant prostate cancer', Clinical Cancer Research, vol. 19, no. 24, pp. 6891-6901. https://doi.org/10.1158/1078-0432.CCR-13-1581
Armstrong, A. J. ; Häggman, M. ; Stadler, W. M. ; Gingrich, J. R. ; Assikis, V. ; Polikoff, J. ; Damber, J. E. ; Belkoff, L. ; Nordle, Ö ; Forsberg, G. ; Carducci, M. A. ; Pili, Roberto. / Long-term survival and biomarker correlates of tasquinimod efficacy in a multicenter randomized study of men with minimally symptomatic metastatic castration-resistant prostate cancer. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 24. pp. 6891-6901.
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T1 - Long-term survival and biomarker correlates of tasquinimod efficacy in a multicenter randomized study of men with minimally symptomatic metastatic castration-resistant prostate cancer

AU - Armstrong, A. J.

AU - Häggman, M.

AU - Stadler, W. M.

AU - Gingrich, J. R.

AU - Assikis, V.

AU - Polikoff, J.

AU - Damber, J. E.

AU - Belkoff, L.

AU - Nordle, Ö

AU - Forsberg, G.

AU - Carducci, M. A.

AU - Pili, Roberto

PY - 2013/12/15

Y1 - 2013/12/15

N2 - Purpose: Tasquinimod (Active Biotech) is an oral immunomodulatory, anti-angiogenic, and antimetastatic agent that delayed metastatic disease progression in a randomized placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). Here, we report long-term survival with biomarker correlates from this trial. Experimental Design: Two hundred and one (134 tasquinimod and 67 placebo) men withmCRPCwere evaluated. Forty-one men randomized to placebo crossed over to tasquinimod. Survival data were collected with a median follow-up time of 37 months. Exploratory biomarker studies at baseline and over time were collected to evaluate potential mechanism-based correlates with tasquinimod efficacy including progression-free survival (PFS) and overall survival (OS). Results: With 111 mortality events, median OS was 33.4 months for tasquinimod versus 30.4 months for placebo overall, and 34.2 versus 27.1 months in men with bone metastases (n = 136), respectively. Multivariable analysis demonstrated an adjusted HR of 0.52 [95% confidence interval (CI), 0.35-0.78; P = 0.001] for PFS and 0.64 (95% CI, 0.42-0.97; P = 0.034) for OS, favoring tasquinimod. Time-tosymptomatic progression was improved with tasquinimod (P = 0.039, HR = 0.42). Toxicities tended to be mild in nature and improved over time. Biomarker analyses suggested a favorable impact on bone alkaline phosphatase and lactate dehydrogenase (LDH) over time and a transient induction of inflammatory biomarkers, VEGF-A, and thrombospondin-1 levels with tasquinimod. Baseline levels of thrombospondin-1 less than the median were predictive of treatment benefit. Conclusions: The survival observed in this trial ofmen withminimally symptomaticm CRPC suggests that the prolongation in PFS with tasquinimodmay lead to a survival advantage in this setting, particularly among men with skeletalmetastases, and has a favorable risk:benefit ratio.

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