[Therapy-Associated Neuroendocrine Prostate Cancer (tNEPC): A Diagnostic and Therapeutic Challenge in Uro-Oncology...

Therapy-associated neuroendocrine prostate cancer (tNEPC) is a rare, prognostically unfavourable variant of castration-resistant prostate cancer that typically arises under conditions of androgen deprivation or androgen receptor signalling inhibition. The underlying process of transdifferentiation is promoted by genetic alterations - most notably the loss of TP53, RB1, and PTEN - as well as epigenetic reprogramming and influences from the tumour microenvironment. Clinically, tNEPC is characterised by aggressive behaviour, the development of visceral and osteolytic metastases, lack of correlation between PSA levels and tumour burden, and PSMA-negative imaging findings. The updated German S3 guideline recommends histological re-biopsy in appropriate clinical scenarios.Histologically, tNEPC is categorised into three subtypes: small-cell neuroendocrine carcinoma (SCNEC), large-cell neuroendocrine carcinoma (LCNEC), and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) with both neuroendocrine and adenocarcinomatous components. In its fifth edition, the WHO formally recognised tNEPC as a distinct pathological entity. Immunohistochemical diagnosis relies on the detection of markers such as synaptophysin, chromogranin A, CD56, and INSM1.In addition to histology, [¹⁸F]-FDG and DOTA-based PET/CT imaging modalities, as well as emerging liquid biopsy approaches (e.g., circulating tumour cells, cfDNA methylation), are increasingly relevant for diagnostic and disease-monitoring purposes. At present, platinum-based chemotherapy remains the standard treatment. Novel therapeutic approaches target molecular structures such as AURKA, EZH2, and DLL3. In selected cases, peptide receptor radionuclide therapy (PRRT) may be considered in patients with positive somatostatin receptor expression. Due to biological heterogeneity and limited evidence, tNEPC requires individualised, interdisciplinary management. This review summarises current insights into the pathogenesis, diagnosis, and therapeutic strategies of tNEPC and provides an outlook on future developments.