Neuroendocrine prostate cancer (NEPC) in focus: state of the art and future prospectives

Neuroendocrine Prostate Cancer (NEPC) is a rare and clinically aggressive subtype of Prostate Cancer (PCa) with its own biological behavior, unfavorable prognosis, and resistance to androgen receptor (AR) directed therapies. 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 15–20% 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. By integrating emerging data on NEPC biology, diagnostics, and therapeutics, this review aims to provide a critical and forward-looking description of the current landscape.