Background: We report on the emergence of a rare and atypical variant of castrate-resistant prostate cancer (CRPC) that is characterised by transformation into poorly differentiated neuroendocrine small-cell carcinoma (NSCC). The existence of this variant was previously described in isolated case reports and small case-studies, but as yet there has been no UK series reported in the literature. , eight cases were presented in our local multi-disciplinary team meeting having a diagnosis of NSCC arising on a background of prostate cancer treated with androgen deprivation therapy. We performed a retrospective review of the clinical records of these patients, to identify the mode of presentation, diagnostic investigations, pathological characteristics, and subsequent treatment and survival outcomes. Results: The median patient age was 77 years (range, 68 -84), with a median time interval of 25 months (range, 7 -83) between the original diagnosis and subsequent transformation to NSCC. The median prostate-specific antigen (PSA) was 4 ng/ml, at presentation. Most patients presented with local progression, combined with high-volume and atypical sites of metastasis (e.g. brain, pancreas and penis). Patients developed a good initial response to platinum-based chemotherapy, but responses were short-lived and prognosis poor, with a median overall survival (OS) of 8 months. Conclusion: Prostate NSCC represents an atypical variant of CRPC with significant therapeutic and prognostic implications. Based on our observations, we have proposed a clinical algorithm for early diagnosis and appropriate management of these patients.