Is Prostate-Specific Antigen a Valid Surrogate End Point for Survival in Hormonally Treated Patients With Metastatic Prostate Cancer? Joint Research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals

Abstract

It is a common misconception that high correlation between biomarkers and true end point justify the use of the former as surrogates. To statistically validate surrogate end points, a high correlation between the treatment effects on the surrogate and true end point needs to be established across groups of patients treated with two alternative interventions. The levels of association observed in this study indicate that the effect of hormonal treatment on OS cannot be predicted with a high degree of precision from observed treatment effects on PSA end points, and thus statistical validity is unproven. In practice, non-null treatment effects on OS can be predicted only from precisely estimated large effects on time to PSA progression (TTPP; hazard ratio, < 0.50).

Leukemia-free survival as a surrogate end point for overall survival in the evaluation of maintenance therapy for patients with acute myeloid leukemia in complete remission

“…Other criteria have been proposed in the literature for the validation of surrogate end points, but those adopted here have been used extensively in solid tumors both in the adjuvant treatment and advanced disease settings. [3][4][5]7,13,15,16,23,[31][32][33][34] The trial on which this analysis was based did not achieve significance in its secondary overall survival end point; however, it is noteworthy that the presence or lack of a significant overall survival benefit appears to have little bearing on the success or failure of surrogate validations in solid tumor trials. 3,7 With the available follow-up data in the HDC/IL-2 trial at the time of the database lock, 236 patients had experienced an event contributing to the leukemia-free survival end point (110 in the treatment group and 126 in the control group).…”

Biomarkers for the Development of Cancer Vaccines

“…Asymptomatic individuals often still possess an intact immune system, and hence immunotherapy is a viable option. Whilst the principle that the immune system is capable of controlling cancer is well established [38,[42][43][44], it is only in recent years that advances in immunotherapy have begun to show real clinical benefit [30,45]. Although this is attractive, pitfalls still exist, since it is important to identify patients with fully active immune systems to give them both the optimal chance of mounting a meaningful response and also to avoid subjecting them to treatments with a low probability of success.…”

“…Despite this, PSA is not acceptable as a clinical trial end point for regulatory approvals [47]. One reason for this is that despite being able to confirm the association between PSA and overall survival (OS) at an individual patient level, neither prospective nor retrospective analyses have been able to establish a high correlation between the treatment effects on PSA and the true clinical end point (OS) across two or more interventions [45]. Furthermore, recent data suggest that screening PSA levels are a poor indicator of tumor burden in either black individuals or individuals older than 62 years [48].…”

“…Not all biomarkers are surrogate markers, since the latter have to be statistically proven to correlate with a clinical end point, such as overall survival (OS) [1]. Biomarkers vary from being highly disease and stage specific, for example, prostate specific antigen (PSA) [2], to the nonspecific parameters of measuring inflammation that may correlate with an increased risk of a number of diseases, including ischemic heart disease and cancer.…”

Perioperative therapy in HER2+ patients

“…Although it is tempting to view biomarker changes as surrogate endpoints, it is important to remember that to identify a surrogate endpoint it is not enough to simply show that the biomarker level correlates with outcome. It must also be shown that changes in the biomarker correlate with changes in outcome [24].…”