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De novo NEPC account for less than 1% of PCa cases, whereas a later evolution from castration-resistant PCa (CRPC) to NEPC is more frequent (approximately 15\u201320% of cases), because of tumor lineage plasticity. The loss of AR signaling, low prostate-specific antigen (PSA) levels, visceral metastases, and significantly reduced survival are the main characteristics of this tumor subtype. In the last decade, the incidence of NEPC has increased, in conjunction with the increasingly frequent use of new AR pathway inhibitors (ARPIs) such as abiraterone, enzalutamide, apalutamide and darolutamide. The increasing incidence of NEPC and especially its disproportionate contribution to mortality in advanced PCa justify the clinical relevance and the growing scientific interest regarding this tumor subtype. 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