Eligibility and outcomes reporting guidelines for clinical trials for patients in the state of a rising prostate-specific antigen: Recommendations from the Prostate-Specific Antigen Working Group

Purpose: To define methodology to show clinical benefit for patients in the state of a rising prostate-specific antigen (PSA). Results: Hypothesis. A clinical states framework was used to address the hypothesis that definitive phase III trials could not be conducted in this patient population. Patient Population. The Group focused on men with systemic (nonlocalized) recurrence and a defined risk of developing clinically detectable metastases. Models to define systemic versus local recurrence, and risk of metastatic progression were discussed. Intervention. Therapies that have shown favorable effects in more advanced clinical states; meaningful biologic surrogates of activity linked with efficacy in other tumor types; and/or effects on a target or pathway known to contribute to prostate cancer progression in this state can be considered for evaluation. Outcomes. An intervention-specific posttherapy PSA-based outcome definition that would justify further testing should be described at the outset. Reporting. Trial reports should include a table showing the number of patients who achieve a specific PSA-based outcome, the number who remain enrolled onto the trial, and the number who came off study at different time points. The term PSA response should be abandoned. Trial Design. The phases of drug development for this state are optimizing dose and schedule, demonstration of a treatment effect, and clinical benefit. To move a drug forward should require a high bar that includes no rise in PSA in a defined proportion of patients for a specified period of time at a minimum. Agents that do not produce this effect can only be tested in combination. The preferred end point of clinical benefit is prostate cancer-specific survival; the time to development of metastatic disease is an alternative. Conclusion: Methodology to show that an intervention alters the natural history of prostate cancer is described. At each stage of development, only agents with sufficient activity should be moved forward.