PROJECT SUMMARY Development of treatment resistance is the main reason for disease progression in patients with mCRPC. What is under-appreciated is that many patients who are experiencing progression have the majority of individual lesions that continue to respond to therapy. Identification of resistant lesions would allow for administration of localized ablative therapies, especially if the systemic therapy is still effective for the majority of metastases. We hypothesize that selective treatment of resistant lesions (e.g. with stereotactic body radiation therapy) will extend duration of clinical benefit in men with mCRPC. We will identify resistant lesions by employing our unique advanced quantitative molecular image analytics - Quantitative Total Extensible Imaging (QTxI) which allows lesion-level assessment of treatment dynamics. We will test our hypothesis through the following aims: (1) To characterize resistance at early progression in men with mCRPC treated with second-generation androgen- signaling inhibitors by employing QTxI of PET/CT starting at nadir PSA response, PSA progression, and again in 12 weeks, (2) To conduct virtual selective radio-ablation study using different PET metrics for target lesion selection of resistant lesions and to model impact of radio-ablation on total tumor burden and anticipated improvement in clinical benefit and (3) To test clinical feasibility of radio-ablation using SBRT to selective resistant lesions in a prospective therapeutic clinical trial. This project is highly innovative as it explores lesion-level treatment resistance in mCRPC, uniquely characterized by our technology, as a treatment target. Assessment of resistance at the time of clinical progression is critical, as it triggers high anxiety in the patient and provider, and thus it is an urgent area of unmet clinical need. We will conduct the first trial of its kind to identify and treat resistant lesions in the setting of wide- spread metastatic disease with the goal of improving clinical benefit.