TY - JOUR
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, R.
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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=84890583838&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-13-1581
DO - 10.1158/1078-0432.CCR-13-1581
M3 - Article
C2 - 24255071
AN - SCOPUS:84890583838
SN - 1078-0432
VL - 19
SP - 6891
EP - 6901
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -