Heller, G., McCormack, R., Kheoh, T., Molina, A., Smith, M. R., Dreicer, R., Saad, F., de Wit, R., Aftab, D. T., Hirmand, M., Limon, A., Fizazi, K., Fleisher, M., de Bono, J. S., Scher, H. I. (2018) Circulating Tumor Cell Number as a Response Measure of Prolonged Survival for Metastatic Castration-Resistant Prostate Cancer: A Comparison With Prostate-Specific Antigen Across Five Randomized Phase III Clinical Trials. JOURNAL OF CLINICAL ONCOLOGY, 36 (6). pp. 572-580. ISSN 0732-183X

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Abstract

PurposeMeasures of response that are clinically meaningful and occur early are an unmet need in metastatic castration-resistant prostate cancer clinical research and practice. We explored, using individual patient data, week 13 circulating tumor cell (CTC) and prostate-specific antigen (PSA) response end points in five prospective randomized phase III trials that enrolled a total of 6,081 patientsCOU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4, and COMET-1ClinicalTrials.Gov identifiers: NCT00638690, NCT00974311, NCT01193257, NCT01193244, and NCT01605227, respectively.MethodsEight response end points were explored. CTC nonzero at baseline and 0 at 13 weeks (CTC0); CTC conversion ( 5 CTCs at baseline, 4 at 13 weeksthe US Food and Drug Administration cleared response measure); a 30%, 50%, and 70% decrease in CTC count; and a 30%, 50%, and 70% decrease in PSA level. Patients missing week-13 values were considered nonresponders. The discriminatory strength of each end point with respect to overall survival in each trial was assessed using the weighted c-index.ResultsOf the eight response end points, CTC0 and CTC conversion had the highest weighted c-indices, with smaller standard deviations. For CTC0, the mean (standard deviation) was 0.81 (0.04); for CTC conversion, 0.79 (0.03); for 30% decrease in CTC count, 0.72 (0.06); for 50% decrease in CTC count, 0.72 (0.06); for 70% decrease in CTC count, 0.73 (0.05); for 30% decrease in PSA level, 0.71 (0.03); for 50% decrease in PSA level, 0.72 (0.06); and for 70% decrease in PSA level, 0.74 (0.05). Seventy-five percent of eligible patients could be evaluated with the CTC0 end point, compared with 51% with the CTC conversion end point.ConclusionThe CTC0 and CTC conversion end points had the highest discriminatory power for overall survival. Both are robust and meaningful response end points for early-phase metastatic castration-resistant prostate cancer clinical trials. CTC0 is applicable to a significantly higher percentage of patients than CTC conversion.

Item Type:	Article
Authors (ICR Faculty only):	De Bono, Johann
All Authors:	Heller, G., McCormack, R., Kheoh, T., Molina, A., Smith, M. R., Dreicer, R., Saad, F., de Wit, R., Aftab, D. T., Hirmand, M., Limon, A., Fizazi, K., Fleisher, M., de Bono, J. S., Scher, H. I.
Additional Information:	ISI Document Delivery No.: FW6OF Times Cited: 1 Cited Reference Count: 18 Heller, Glenn McCormack, Robert Kheoh, Thian Molina, Arturo Smith, Matthew R. Dreicer, Robert Saad, Fred de Wit, Ronald Aftab, Dana T. Hirmand, Mohammad Limon, Ana Fizazi, Karim Fleisher, Martin de Bono, Johann S. Scher, Howard I. National Institutes of Health (NIH) [P30-CA008748]; NIH [P50-CA92629, R01-CA207220]; Sidney Kimmel Center for Prostate and Urologic Cancers; Prostate Cancer Foundation; Department of Defense Prostate Cancer Research Program [PC121111]; Janssen Diagnostics a division of Janssen Pharmaceutica NV; Ortho Biotech Oncology Research and Development (a unit of Cougar Biotechnology); Medical Research Council of the United Kingdom; Movember Centre of Excellence funding; Experimental Cancer Medical Centre; National Institute for Health Research Biomedical Research Centre; Medivation; Astellas Pharma Global Development; Takeda Pharmaceuticals International; Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical; Exelixis Supported by National Institutes of Health (NIH) Grant No. P30-CA008748 (G.H., M.F., and H.I.S. are recipients of the Cancer Center Support Grant); NIH Grant No. P50-CA92629 (G.H. and H.I.S. are recipients of a Specialized Programs of Research Excellence grant); NIH Grant No. R01-CA207220 (G.H. and H.I.S.); Sidney Kimmel Center for Prostate and Urologic Cancers (H.I.S.); Prostate Cancer Foundation (G.H. and H.I.S.); Department of Defense Prostate Cancer Research Program Grant No. PC121111 (G.H. and H.I.S.); and Janssen Diagnostics a division of Janssen Pharmaceutica NV (G.H.). The COU-AA-301 study/publication was supported by Ortho Biotech Oncology Research and Development (a unit of Cougar Biotechnology) and grants from the Medical Research Council of the United Kingdom, Movember Centre of Excellence funding, Experimental Cancer Medical Centre, National Institute for Health Research Biomedical Research Centre, and Prostate Cancer Foundation (H.I.S.). The AFFIRM study/publication was supported by Medivation and Astellas Pharma Global Development. The ELM-PC-5 study/publication was supported by Takeda Pharmaceuticals International. The ELM-PC-4 study/publication was supported by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical. The COMET-1 study/publication was supported by Exelixis. 1 0 Amer soc clinical oncology Alexandria 1527-7755
Uncontrolled Keywords:	plus prednisone abiraterone acetate antitumor-activity double-blind multicenter docetaxel therapy chemotherapy prognosis Oncology
Research teams:	ICR divisions > Cancer Therapeutics > Cancer Biomarkers ICR divisions > Clinical Studies > Cancer Biomarkers ICR divisions > Clinical Studies > Prostate Cancer Targeted Therapy Group
Depositing User:	Barry Jenkins
Date Deposited:	12 Mar 2018 14:41
Last Modified:	12 Mar 2018 14:41
URI:	http://publications.icr.ac.uk/id/eprint/16663

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