Radiotherapy is a major curative treatment modality for prostate cancer, the most common malignancy and the second-leading cause of cancer-related death in men. Despite the curative potential of radiotherapy in treating organ-confined/localized advanced prostate cancer, 50% of the patients experience recurrence of the disease. The current approach, treating patients with "one-size-fits-all" therapy, has failed to deliver favorable results. The goal of this proposal is to develop a non-invasive (human serum) biomarker(s) based test, “RADI-Sense” to personalize radiotherapy, which can guide clinicians to develop new therapeutic regimes for patients. The patients’ response to radiotherapy will be analyzed by monitoring the changes in the expression of genes from cellular pathways leading to failure of radiotherapy. The proposed approach will (i) radically transform the current clinical standard of measuring changes in tumor size to assess response to radiotherapy; (ii) aid in designing effective treatment regimens without the need of biopsy/serial biopsies; (iii) enable monitoring and sampling prior to, during and after radiation treatment; (iv) will enable suitable alternative treatments to high-risk patients and dose escalation to tumors in less sensitive patients during early phases of treatment; (v) introduce the possibility of using other modalities (e.g. immunotherapy, molecular targeted therapy) in combination with radiotherapy.