Clinical Characteristics and Survival Outcomes of a Clinically Defined Treatment-Emergent Neuroendocrine/Aggressive-Variant Prostate Cancer Phenotype: A Retrospective Study.

Background and Objectives: Treatment-emergent neuroendocrine prostate cancer (t-NEPC) is an aggressive resistance phenotype arising during metastatic castration-resistant prostate cancer (mCRPC). Because metastatic biopsy is not routinely feasible in advanced disease, real-world data on clinically defined t-NEPC/aggressive-variant prostate cancer (AVPC)-like disease remain limited. We aimed to characterize the clinical features, treatment patterns, survival outcomes, and prognostic factors of this clinically defined phenotype. Materials and Methods: We retrospectively reviewed 354 patients with prostate cancer treated at our institution between 2010 and 2020. Seventy-four patients with mCRPC who were clinically identified as having a t-NEPC/AVPC-like phenotype and had a treatment plan for platinum- and/or etoposide-based neuroendocrine-directed systemic therapy were included. Overall survival (OS) and radiographic progression-free survival (rPFS) were estimated using the Kaplan-Meier method, and prognostic factors were evaluated using Cox regression analyses. Results: At clinical identification of the phenotype, the median age was 66.4 years, and visceral metastases were present in 67.6% of patients, most commonly in the liver (55.4%). Median intervals from prostate cancer diagnosis and CRPC onset to clinical identification of the phenotype were 47.5 and 22.7 months, respectively. Neuroendocrine-directed therapy was initiated in 72 patients; platinum-etoposide was the most common first-line regimen (n = 41, 55.4%). Median OS was 4.4 months (95% confidence interval [CI], 2.9-5.8), and median rPFS was 3.5 months (95% CI, 2.7-4.2). In an exploratory, unadjusted analysis, median OS did not differ significantly between doublet chemotherapy and monotherapy (7.0 vs. 3.5 months; p = 0.167). Gleason score ≥9, hemoglobin <12 g/dL, and albumin <3.5 g/dL were independently associated with inferior OS. Conclusions: The clinically defined t-NEPC/AVPC-like phenotype was associated with an aggressive clinical course and poor survival. Earlier recognition, improved biomarker-based diagnostic strategies, and more effective therapeutic approaches are needed.