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

## TL;DR

Neuroendocrine prostate cancer is a rare, aggressive form of prostate cancer that resists common treatments and is becoming more common due to new therapies.

## Contribution

This review integrates recent findings on NEPC biology, diagnostics, and therapeutics to provide a forward-looking analysis.

## Key findings

- NEPC is resistant to androgen receptor-directed therapies and has a poor prognosis.
- The incidence of NEPC is increasing, likely due to the use of new AR pathway inhibitors.
- NEPC often evolves from castration-resistant prostate cancer due to tumor lineage plasticity.

## Abstract

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.