Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone analog remains the cornerstone for treating metastatic prostate cancer (mPC). Recent clinical practice has added docetaxel chemotherapy and/or the androgen receptor signaling inhibitor (ARSI, e.g., abiraterone, enzalutamide, darolutamide or apalutamide) to ADT to manage newly diagnosed mPC. This has prolonged survival but mPC remains incurable. We hypothesize the current, continuous maximum tolerated dose, treatment-until-progression, approach is not evolutionarily optimal, and outcomes can be improved by integrating evolutionary dynamics into treatment of mPC. Mathematical models like the game therapy model were applied to two adaptive therapy trials (NCT03511196, NCT02415621) with ADT and ARSI and confirmed both feasibility and improved outcomes in mPC while also building an experienced team of oncologists, mathematicians, evolutionary biologists, and cancer biologists. NCT03511196 is our adaptive therapy trial for castration sensitive mPC, which showed the feasibility of using serum total PSA and testosterone levels to decide when to stop and restart ADT and or ARSI (PMID: 36358643). This study has now a median follow-up of 6 years and we have not reached the median progression free survival on the 16 enrolled patients. Exploratory biomarker analyses demonstrate patients with high post induction PSA value, high average PSA/testosterone ratio during the induction phase and the first adaptive therapy cycle tend to develop early progression if the universal 50% PSA decline criteria is used to trigger the start of treatment break. Based on what we learned from NCT03511196, we are conducting a new adaptive therapy trial with personalized PSA thresholds to trigger treatment breaks based on mathematical modeling of individual patient’s PSA and testosterone kinetics during the initial adaptive therapy cycle (NCT06734130). This study has enrolled 11/25 castration sensitive mPC pts since its opening in January 2025.