Surrogate endpoints in early prostate cancer research

Clinical research into clinically-localized prostate cancer (PC) is a highly challenging environment. The protracted durations and large numbers required to achieve survival endpoints have placed much pressure on validating early surrogate endpoints. Further confounding is the predominance of deaths from causes other than PC. The analysis of multiple randomized clinical trials in early PC has shown MFS to be a robust surrogate for OS, using a contemporary analytic framework that identify patient-level and trial-level associations. This could potentially save around one year of trial follow-up in some therapies. Identification of a similarly robust surrogate at a substantially earlier timepoint remains a major challenge. Multiple biochemical indices based on PSA have been proposed in the literature, but all remain to be validated at the trial-level. Operationally, many of these indices have inherent biases such as immortal-time bias (ITB) and interval censoring that potentially weakens associations and the individual- or trial-level. The complexity of a failure definition can also impact the reliability of the derived outcomes. Confounding issues such as the impact of comorbidities leading to non-cancer deaths have been largely dealt with by their exclusion using cancer-specific endpoints and advanced statistical methods, while issues such as PSA "bounce" and recovery from androgen deprivation therapy remain important to account for in cohorts treated with radiotherapy. Several potential surrogate endpoints based on serum prostate-specific antigen (PSA) levels show promising associations with PC-specific and overall survival (OS) in individual studies. Further large collaborative projects will continue to refine potential indices with these issues in mind, and explore the objective of an early surrogate of OS.