PURPOSE: To define methodology to show clinical benefit for patients in the state of a rising prostate-specific antigen (PSA). 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.
PURPOSE: To define methodology to show clinical benefit for patients in the state of a rising prostate-specific antigen (PSA). 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.
Authors: Charles J Ryan; Shreya Shah; Eleni Efstathiou; Matthew R Smith; Mary-Ellen Taplin; Glenn J Bubley; Christopher J Logothetis; Thian Kheoh; Christine Kilian; Christopher M Haqq; Arturo Molina; Eric J Small Journal: Clin Cancer Res Date: 2011-06-01 Impact factor: 12.531
Authors: Emmanuel S Antonarakis; Yongmei Chen; Sally I Elsamanoudi; Stephen A Brassell; Mario V Da Rocha; Mario A Eisenberger; David G McLeod Journal: BJU Int Date: 2010-11-23 Impact factor: 5.588
Authors: Jianqing Lin; Marianna Zahurak; Tomasz M Beer; Charles J Ryan; George Wilding; Paul Mathew; Michael Morris; Jennifer A Callahan; Gilad Gordon; Steven D Reich; Michael A Carducci; Emmanuel S Antonarakis Journal: Urol Oncol Date: 2011-08-04 Impact factor: 3.498