Prostate cancer (PCa) is the second most common malignancy in men worldwide and remains a leading cause of death (Rawla, 2019). Around 95% of newly diagnosed prostatic neoplasms are prostate adenocarcinoma (PRAD), a tumour derived from the epithelial cells of the prostate; the remainder comprises several rare histological subtypes (Shah & Zhou, 2019). Neuroendocrine prostate cancer (NEPC) is the most important of these subtypes, representing a constellation of tumours with a neuroendocrine phenotype that is histologically markedly distinct from PRAD (Epstein et al., 2014). Less than 2% of newly diagnosed prostate cancers are neuroendocrine, termed de novo NEPC. More commonly, NEPC is a late-stage PCa manifestation, occurring as a mechanism of treatment resistance to second-generation androgen receptor (AR)-targeted therapies and termed treatment-emergent neuroendocrine prostate cancer (t-NEPC) (Clermont et al., 2019, Davies et al., 2018).

Transdifferentiation from PRAD to NEPC is underpinned by genetic and epigenetic alterations. The first step is an adaptive loss of sensitivity to androgen-deprivation therapy (ADT), a state termed castration-resistant prostate cancer (CRPC) (Huang, Jiang, Liang, & Jiang, 2018). A subset of CRPC tumours will continue to progress to NEPC, with complete resistance to second-generation AR-targeted therapies, and median survival is very poor (7 months) once t-NEPC is diagnosed (Wang, Yao, et al., 2014). In addition, the clinical diagnosis of t-NEPC is hampered by difficulties in tissue accessibility, because it generally arises following prostatectomy and ADT, thus tumours are often distant metastases. The difficulty in obtaining timely t-NEPC diagnosis further impairs efforts to investigate emerging treatment options in clinical trials. Ongoing research in the NEPC field thus needs to investigate molecular biology, emerging drug treatments, and diagnostics, in order to improve what are currently very poor outcomes for NEPC patients.

In this paper, we briefly describe the current clinical approach to prostate adenocarcinoma and NEPC, including the lack of effective NEPC treatments currently available in the clinic. We next discuss the key genetic and epigenetic features underpinning the transition between PRAD and NEPC. We then explore several emerging treatment options, including both preclinical research and ongoing clinical trials. Finally, we consider the potential for liquid biopsy techniques to improve NEPC diagnosis and clinical management.