Of the 33,330 men who died from prostate cancer in United States last year, over 80% of these patients presented with localized disease. Thus, a majority of PCa patients are diagnosed at a potentially curable stage and are often treated with radical prostatectomy (RP). Following RP, patients with aggressive disease face the risk of prostate cancer recurrence, which manifests as persistently elevated or increasing serum PSA. While salvage radiation therapy (RT) represents a standard treatment option for post-surgical recurrences, it results in long-term disease control in only 30-40% of patients. Thus, the post-surgical recurrence state presents multiple opportunities to improve patient care by addressing three critical challenges: (1) determining which patients will benefit from the addition of androgen deprivation therapy (ADT), (2) identifying which patients treated with RT and ADT will require further treatment intensification, and (3) identifying the appropriate treatment intensification strategy for RT and ADT treated patients. Since androgen-directed therapies represent the backbone of treatment for PCa (that have progressed through local therapies) the RTOG 96-01 and RTOG 05-34 phase III clinical trials represent a unique resource of banked prostatectomy cohorts from patients that were randomized to the presence or absence of treatment with ADT. For patients whose clinical and pathologic features place them at highest risk of dying from PCa, these landmark trials have defined the standard of care by showing that the addition of ADT to RT resulted in significant improvements to patient survival compared to RT alone. This presents an unparalleled opportunity to develop and validate predictive and prognostic biomarkers addressing multiple unmet clinical needs throughout patient care following surgery. Aim 1 will focus on using high-throughput DNA and RNA sequencing to develop a predictive classifier for identifying which patients would benefit from ADT using patients from RTOG 96-01 and 05-34. In Aim 2 we will develop and validate a prognostic classifier that integrates genomic and clinicopathologic data for PCa patients treated with RT+ADT that may benefit from treatment intensification. Aim 3 will focus on identifying RT+ADT patients requiring treatment intensification that could benefit from receiving pelvic lymph node radiation therapy using patients from RTOG 05-34. The proposed study would have significant impact by developing and optimizing prognostic and predictive biomarkers that could have enormous potential for rapid clinical translation to personalize therapy and transform the management of PCa patients following surgery.