Metastatic prostate cancer with neuroendocrine differentiation and liver metastases: prognosis and response to platinum-based chemotherapy

Purpose Neuroendocrine differentiation represents an aggressive prostate cancer subtype with poor prognosis. Platinum-based chemotherapy (PT) is standard of care, yet responses are often short-lived. This study aimed to define histopathological subgroups and identify predictors of survival in patients with liver-metastatic prostate cancer with neuroendocrine differentiation treated with PT. Methods We retrospectively analyzed 950 patients with metastatic prostate cancer treated between 2006 and 2025, identifying 31 patients with neuroendocrine differentiation, liver metastases and PT. Tumors were classified into four subgroups based on the proportion of neuroendocrine features. Clinical characteristics, treatment response, tumor markers, and molecular alterations ( TP53 , RB1 , PTEN , BRCA1/2 ) were evaluated. Overall survival (OS) was analyzed using Kaplan–Meier estimates and Cox regression. Results Median OS following PT initiation was 8.5 months. Disease control was achieved in 81% of patients, but responses were transient. Patients with a high proportion of remaining adenocarcinoma features showed the longest median OS (15 months), while pure neuroendocrine subtypes had the poorest outcomes (6–10 months). Osteolytic bone metastases (HR 2.48; 95% CI 1.08–5.72), TP53 loss-of-function variants (HR 2.43; 95% CI 1.14–5.16), and ≥ 2 concurrent alterations in TP53/RB1/PTEN (HR 2.13; 95% CI 1.03–4.41) were associated with inferior OS. Early reduction in liver metastasis size (HR 0.41; 95% CI 0.19–0.89) and decline in LDH (HR 0.50; 95% CI 0.23–1.09) after two treatment cycles predicted improved survival. Conclusions Metastatic prostate cancer with neuroendocrine differentiation and liver metastases is characterized by extreme aggressiveness. There seems to be only limited durable benefit from PT especially in the presence of pure neuroendocrine morphology and tumor suppressor gene alterations. Therefore, these characteristics seem to be promising criteria to be investigated in larger prospective trials to further validate their clinical implications.