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

Purpose Measures 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 patients-COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4, and COMET-1- ClinicalTrials. Gov identifiers: NCT00638690, NCT00974311, NCT01193257, NCT01193244, and NCT01605227, respectively. Methods Eight response end points were explored. CTC nonzero at baseline and 0 at 13 weeks (CTC0); CTC conversion (≥ 5 CTCs at baseline, ≤ 4 at 13 weeks-the 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. Results Of 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. Conclusion The 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.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017 Dec 22 [Epub ahead of print]

Glenn Heller, Robert McCormack, Thian Kheoh, Arturo Molina, Matthew R Smith, Robert Dreicer, Fred Saad, Ronald de Wit, Dana T Aftab, Mohammad Hirmand, Ana Limon, Karim Fizazi, Martin Fleisher, Johann S de Bono, Howard I Scher

Glenn Heller, Martin Fleisher, and Howard I. Scher, Memorial Sloan Kettering Cancer Center; Howard I. Scher, Weill Cornell Medical College, New York, NY; Robert McCormack, Janssen Research & Development, Raritan, NJ; Thian Kheoh and Arturo Molina, Janssen Research & Development, Los Angeles; Dana T. Aftab, Exelixis, South San Francisco; Mohammad Hirmand, Medivation, San Francisco, CA; Matthew R. Smith, Massachusetts General Hospital, Boston; Ana Limon, Takeda Oncology, Cambridge, MA; Robert Dreicer, University of Virginia Medical School, Charlottesville, VA; Fred Saad, University of Montreal, Montreal, Quebec, Canada; Ronald de Wit, Erasmus Medical Center, Rotterdam, the Netherlands; Karim Fizazi, Institut Gustave Roussy, Villejuif, and University of Paris Sud, Orsay, France; and Johann S. de Bono, The Institute of Cancer Research, and The Royal Marsden Hospital, Sutton, Surrey, United Kingdom.

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