AbstractBackgroundAlthough most patients with prostate cancer (PC) respond to initial androgen deprivation therapy (ADT), castration‐resistant disease invariably develops. Progression to treatment‐emergent neuroendocrine PC (t‐NEPC) represents a unique mechanism of resistance to androgen receptor (AR)‐targeted therapy in which lineage plasticity and neuroendocrine differentiation induce a phenotypic switch from an AR‐driven adenocarcinoma to an AR‐independent NEPC. t‐NEPC is characterized by an aggressive clinical course, increased resistance to AR‐targeted therapies, and a poor overall prognosis.MethodsThis review provides an overview of our current knowledge of NEPC, with a focus on the unmet needs, diagnosis, and clinical management of t‐NEPC.ResultsEvidence extrapolated from the literature on small cell lung cancer or data from metastatic castration‐resistant PC (mCRPC) cohorts enriched for t‐NEPC suggests an increased sensitivity to platinum‐based chemotherapy. However, optimal strategies for managing t‐NEPC have not been established, and prospective clinical trial data are limited. Intertumoral heterogeneity within a given patient, as well as the lack of robust molecular or clinical biomarkers for early detection, often lead to delays in diagnosis and prolonged treatment with suboptimal strategies (i.e., conventional chemohormonal therapies for mCRPC), which may further contribute to poor outcomes.ConclusionsRecent advances in genomic and molecular classification of NEPC and the development of novel biomarkers may facilitate an early diagnosis, help to identify promising therapeutic targets, and improve the selection of patients most likely to benefit from NEPC‐targeted therapies.