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J Clin Oncol. 2015 Apr 20;33(12):1348-55. doi: 10.1200/JCO.2014.55.3487. Epub 2015 Mar 23.

Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer.

Author information

1
Howard I. Scher, Glenn Heller, Daniel C. Danila, and Martin Fleisher, Memorial Sloan Kettering Cancer Center; Howard I. Scher and Daniel C. Danila, Weill Cornell Medical College; Xiaoyu Jia, Columbia University, New York, NY; Arturo Molina, Janssen Research & Development, Menlo Park; Weimin Peng, Janssen Research & Development, Los Angeles; Thian Kheoh, Janssen Research & Development, San Diego, CA; Gerhardt Attard, Shahneen K. Sandhu, David Olmos, Ruth Riisnaes, and Johann S. de Bono, Institute of Cancer Research; Gerhardt Attard, Shahneen K. Sandhu, David Olmos, and Johann S. de Bono, Royal Marsden Hospital, Sutton, United Kingdom; Robert McCormack, Janssen Research & Development, Raritan, NJ; and Tomasz Burzykowski and Marc Buyse, International Drug Development Institute, Louvain-la-Neuve, Belgium. scherh@mskcc.org.
2
Howard I. Scher, Glenn Heller, Daniel C. Danila, and Martin Fleisher, Memorial Sloan Kettering Cancer Center; Howard I. Scher and Daniel C. Danila, Weill Cornell Medical College; Xiaoyu Jia, Columbia University, New York, NY; Arturo Molina, Janssen Research & Development, Menlo Park; Weimin Peng, Janssen Research & Development, Los Angeles; Thian Kheoh, Janssen Research & Development, San Diego, CA; Gerhardt Attard, Shahneen K. Sandhu, David Olmos, Ruth Riisnaes, and Johann S. de Bono, Institute of Cancer Research; Gerhardt Attard, Shahneen K. Sandhu, David Olmos, and Johann S. de Bono, Royal Marsden Hospital, Sutton, United Kingdom; Robert McCormack, Janssen Research & Development, Raritan, NJ; and Tomasz Burzykowski and Marc Buyse, International Drug Development Institute, Louvain-la-Neuve, Belgium.

Abstract

PURPOSE:

Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome measure.

PATIENTS AND METHODS:

Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level.

RESULTS:

A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs ≥ 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively.

CONCLUSION:

A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00638690.

PMID:
25800753
PMCID:
PMC4397279
DOI:
10.1200/JCO.2014.55.3487
[Indexed for MEDLINE]
Free PMC Article

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