Emergence of Neuroendocrine Tumors in Patients Treated with Androgen Receptor Pathway Inhibitors for Metastatic Prostate Cancer: A Systematic Review and Meta-analysis

Background and objective: It has been shown that androgen receptor pathway inhibitor (ARPIs) treatment for metastatic castration-resistant prostate cancer (mCRPC) improves overall survival rates, but ARPIs appear to be associated with a higher frequency of treatment-related neuroendocrine prostate cancer (t-NEPC). Our aim was to quantify the proportion of prostate adenocarcinoma cases that transition to t-NEPC following ARPI therapy.

Methods: We conducted a comprehensive search of the literature on t-NEPC using databases including MEDLINE and Scopus. Eligible studies reported outcome data for NEPC in patients with prior mCRPC treated with an ARPI. To determine the pooled frequency of neuroendocrine transformation, the Freeman-Tukey variance-stabilizing arcsine transformation was applied to individual frequencies.

Key findings and limitations: Among the 938 patients in eight eligible studies, t-NEPC diagnosis was confirmed in 171 patients, predominantly via pathology. Baseline biopsy verification to ensure the absence of NEPC was performed in most cases. The definition of t-NEPC varied among the studies. Five studies used a morphological definition based on histopathology, and three studies used NEPC biomarker detection on circulating tumor cells. A meta-analysis of aggregate data revealed an overall NEPC frequency following ARPI therapy of 16% (95% confidence interval 9-24%).

Conclusion and clinical implications: ARPI-related NEPC represents a frequently underdiagnosed late complication of mCRPC. Given the absence of biomarkers for diagnosis, routine repeat biopsy at the mCRPC stage should be considered to diagnose t-NEPC transitions.