Why BCR is a poor measure of RT success for intermediate & high risk

Event-Free Survival, a Prostate-Specific Antigen-Based Composite End Point, Is Not a Surrogate for Overall Survival in Men With Localized Prostate Cancer Treated With Radiation (2020, Full Text)

[Use the link near the top of the page to download the Full Text in pdf]

ABSTRACT:
Purpose

Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)-based composite end point, may further expedite trial completion.

Methods
EFS was defined as the time from random assignment to the date of first evidence of disease recurrence, including biochemical failure, local or regional recurrence, distant metastasis, or death from any cause, or was censored at the date of last PSA assessment. Individual patient data from trials within the Intermediate Clinical Endpoints in Cancer of the Prostate-ICECaP-database with evaluable PSA and disease follow-up data were analyzed. We evaluated the surrogacy of EFS for OS using a 2-stage meta-analytic validation model by determining the correlation of EFS with OS (patient level) and the correlation of treatment effects (hazard ratios [HRs]) on both EFS and OS (trial level). A clinically relevant surrogacy was defined a priori as an R2 ≥ 0.7.

Results
Data for 10,350 patients were analyzed from 15 radiation therapy-based trials enrolled from 1987 to 2011 with a median follow-up of 10 years. At the patient level, the correlation of EFS with OS was 0.43 (95% CI, 0.42 to 0.44) as measured by Kendall's tau from a copula model. At the trial level, the R2 was 0.35 (95% CI, 0.01 to 0.60) from the weighted linear regression of log(HR)-OS on log(HR)-EFS.

Conclusion
EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy-based trials."

From the Full Text:

"DISCUSSION
This work clearly shows that EFS is a weak surrogate for both OS and DSS for men with intermediate- and high-risk localized prostate cancer treated with curative-intent radiation with a 10% chance of dying as a result of prostate cancer and approximately a 60% OS at 10 years. Notably, this analysis included only patients treated with primary radiation, and therefore, the findings should not be extrapolated to trials of patients treated with prostatectomy or salvage radiation after prostatectomy26. As the estimated hazard curves over time (Fig 1) depict, there are many early EFS events (mostly PSA relapses) with few MFS and OS events. This indicates that despite 80% of men being younger than 75 years old and fit for a clinical trial, they are still more likely to die a non–prostate cancer death even if they have a PSA relapse. This provides additional evidence that many PSA relapses are indolent and/or are controlled by testosterone suppression.34,35"

[Emphasis mine]

Djin