Journal
JOURNAL OF CLINICAL ONCOLOGY
Volume 36, Issue 6, Pages 572-+Publisher
AMER SOC CLINICAL ONCOLOGY
DOI: 10.1200/JCO.2017.75.2998
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Funding
- 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
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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.
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