Design and End Points of Clinical Trials for Patients with Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group

PURPOSE: To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone.

METHODS: A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data.
RESULTS: The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as "new lesions" or "no new lesions," changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group.

CONCLUSION: PCWG2 recommends increasing emphasis on time-to-event endpoints (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate endpoints to predict clinical benefit.

Howard I. Scher, MD,1 Susan Halabi, MD,2 Ian Tannock, MD, PhD, DSc,3 Michael Morris,MD,4 Cora N. Sternberg, MD, FACP,5 Michael A. Carducci,MD, FACP,6 Mario A. Eisenberger, MD,6 Celestia Higano, MD,7 Glenn J. Bubley, MD,8 Robert Dreicer,MD, MS, FACP, FASCO,9 Daniel Petrylak,10 Philip Kantoff, MD,4 Ethan Basch, MD, MSc,4 William Kevin Kelly,11 DO, William D. Figg, Pharm D,12 Eric J. Small, MD,13 Tomasz M. Beer, MD, FACP,14 George Wilding, MD,15 Alison Martin, PA-C,16 Maha Hussain, MD, FACP, FASCO17

1. Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, New York
2. Duke University Medical Center, Durham, North Carolina
3. Princess Margaret Cancer Centre and University of Toronto, Canada
4. Memorial Sloan-Kettering Cancer Center, New York, New York
5. Clinical Director of the Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, Former Chief of the Department of Medical Oncology at the San Camillo-Forlanini Hospital in Rome, Italy
6. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
7. Seattle Cancer Care, Seattle, Washington
8. Beth Israel Deaconess Medical Center, Boston, Massachusetts
9. Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, Virginia
10. Yale University Cancer Center, New Haven, Connecticut
11. Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania
12. Center for Cancer Research, National Institutes of Health, Bethesda, Maryland
13. UCSF Comprehensive Cancer Center, San Francisco, California
14. Deputy Director of the Oregon Health & Science University (OSHU) Knight Cancer Institute and a Professor of Medicine in the OSHU Division of Hematology & Medical Oncology, Portland, Oregon
15. Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas
16. Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
17. University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan

DOI: 10.1200/JCO.2007.12.4487 Journal of Clinical Oncology 26, no. 7 (March 2008) 1148-1159.
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