Men with biochemical recurrence after prostatectomy receiving salvage radiation (RT) may benefit from added anti-androgen therapy (AAT) by decreasing their likelihood of progressing to distant metastasis and death. However, in RTOG 9601, not all men benefitted. No predictive biomarker currently exists to identify who is more likely or less likely to benefit from aggressive salvage therapy (RT+AAT). To address this unmet need for precision treatment decision-making, we will evaluate the telomere biomarker as a predictive biomarker for treatment response in this setting. Our conceptually innovative hypothesis is that the telomere biomarker – the combination of cancer cell-to-cell variability in telomere length coupled with stromal cell telomere length – captures information about tumor behavior beyond currently used indicators and thus, identifies men who are more likely or less likely to benefit from aggressive salvage therapy. We discovered that the telomere biomarker is an independent prognostic marker for lethal disease in surgically-treated men, identifying 3 prognostic categories: good, intermediate, and poor. The telomere biomarker has not been tested as predictive of treatment response in any setting. We will address the aims in 2 complementary settings, trial and clinical practice, totaling 839 men and 165 metastatic events. In the trial setting, we will use RTOG 9601, in which men were randomized to RT+/-AAT. In the clinical practice setting, we use cohorts who received RT+/-AAT at Johns Hopkins or Boston Medical Center and have tissue microarrays; in the analysis, we will weight by a propensity score to minimize bias due to patient and tumor factors. We will evaluate these aims stratified by the telomere biomarker: 1. In the standardized setting, test if rate of progression to metastasis and death from prostate cancer differs between RT+AAT and RT only. 2. In the clinical practice setting, test if rate of progression to metastasis and death from prostate cancer differs between RT+AAT and RT only. We will stain for telomeres and cell-type specific immunofluorescence markers and perform image capture and quantitative image analysis, and derive each man’s telomere biomarker. We will stratify by biomarker category and use Cox models to estimate associations between RT+AAT and progression, and determine if the biomarker adds to predictive capability for response to RT+AAT beyond currently used post-biochemical recurrence prognostic indicators. In men with the biomarker category associated with intermediate prognosis, we hypothesize that the progression rate is lower in men who received RT+AAT compared to men who received RT only. In men with biomarker categories associated with good or poor prognosis, we hypothesize that the progression rate in men who received RT+AAT is similar to the rate in men who received RT only. In RTOG 9601, RT+AAT was more efficacious than RT only in some subgroups. For optimized decision-making, we will determine if...