Reprogramming the Evolution of High-Risk Prostate Cancer: Multidisciplinary Strategies to Delay Castration Resistance

Background/Objectives: High-risk prostate cancer is a biologically heterogeneous group of tumors carrying a substantial risk of progression to lethal, castration-resistant disease. Although androgen deprivation therapy (ADT) remains the therapeutic backbone, nearly all advanced disease eventually progresses to castration-resistant prostate cancer (CRPC) through Darwinian clonal evolution under sustained therapeutic pressure. This narrative review reframes high-risk prostate cancer management as an effort to reprogram the evolutionary trajectory and delay castration resistance, addressing current risk stratification, androgen receptor (AR)-dependent and AR-independent mechanisms of resistance, and multidisciplinary strategies that modify selective pressure. Methods: A narrative review of the literature was conducted, including peer-reviewed studies, pivotal phase III trial reports, and current clinical practice guidelines indexed in PubMed, Scopus, and Web of Science up to 2026. Sources on high-risk and castration-resistant prostate cancer, the biology of treatment resistance, and multidisciplinary treatment intensification were selected and synthesized. Results: Treatment intensification has been extended to high-risk biochemical recurrence (EMBARK), directed by biomarkers in PTEN-deficient disease (CAPItello-281), and moved earlier through prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PSMAfore, PSMAddition). In localized disease, effective AR-pathway intensification with abiraterone (STAMPEDE) contrasts with the failure of chemotherapy (PEACE-2) and enzalutamide (ENZARAD). Emerging therapies targeting lineage plasticity exploit its dynamic and potentially reversible biology, raising the prospect of reversing established resistance rather than merely delaying it. CAPItello-281 and PSMAddition have immature overall survival data and are not yet standard of care. Conclusions: Coordinated multidisciplinary care, matched to the disease stage and molecular context, offers a realistic path to delay castration resistance and improve survival.