87 Background: Treatment-emergent neuroendocrine prostate cancer (tNEPC) arises as a phenotype of metastatic castration-resistant prostate cancer (mCRPC) under therapeutic pressure. Despite its poor prognosis, no consensus diagnostic criteria exist for tNEPC. Its clinical and molecular features remain unclear due to the rarity of disease. This study assessed clinical characteristics, biomarkers and outcomes of tNEPC as compared to adenocarcinoma (ACPC) in the mCRPC setting. Methods: This was a retrospective study of adult patients with tNEPC and a matched ACPC cohort (up to 1:2 ratio based on the biopsy date) diagnosed with mCRPC from 01/01/2013 to 12 months before data collection (04/15/2024-11/30/2024) at two US academic institutions. Biopsies obtained after mCRPC diagnosis (index biopsy) were reviewed by two central pathologists to confirm histological diagnosis, using pre-specified standardized definition and pathology criteria. Patients’ characteristics, immunohistochemistry (IHC) markers, treatments and outcomes were compared between tNEPC and ACPC. Results: This study included 79 patients (28 site-defined tNEPC and 51 matched ACPC). The majority were >65 years (mean age: 73 vs 72 years) and white (84% vs 83%), with comparable baseline clinical characteristics between groups. Median follow-up was 13.3 months (tNEPC 6.3; ACPC 15.6). The central pathologists confirmed site diagnoses in 76 patients (κ agreement= 0.91), leaving 71 matched patients (25 tNEPC 24 small cell carcinoma; 46 ACPC) in the final analysis. All biopsies were metastatic and most came from the liver (tNEPC 44.0% vs ACPC 35.2%). For IHC markers, tNEPC patients had higher positivity of synaptophysin (92% vs 35%) and chromogranin (79% vs 33%), while NKX3.1 positivity was higher in ACPC (24% vs 97%). The most common first lines of therapy (1L) after index were platinum-based chemotherapy (50%) for tNEPC, and androgen receptor pathway inhibitors (53%) for ACPC, but 20% of tNEPC and 22% of ACPC had no record of mCRPC-specific treatments constituting a 1L. While PSA response (≥50% decline) in the post-index period was similar between tNEPC and ACPC (41% vs 42%), tNEPC patients had significantly worse overall survival (OS) after index than ACPC (median OS: 6.3 vs 14.7 months; HR=1.99, 95% CI 1.14–3.42). In tNEPC patients, NKX3.1 positivity appeared associated with better OS (HR=0.29; 95% CI: 0.1-0.9). Conclusions: tNEPC shows distinct histological and IHC profiles, treatment patterns, and worse OS compared with ACPC. These findings highlight important unmet medical need in tNEPC. While the high concordance between central review and site pathologists’ review could be due to expertise in genitourinary/prostate pathology at the academic institutions, our results suggest standardized histopathologic criteria for tNEPC, along with IHC markers, help improve disease classification and diagnostic accuracy in clinical practice.
Haffner et al. (Sun,) studied this question.