Clinical characteristics and molecular evolution of treatment-emergent small-cell/neuroendocrine prostate cancer in the era of doublet and triplet systemic therapy.

240 Background: Transformation to treatment-emergent small-cell/neuroendocrine prostate cancer (teSC/NEPC) represents one mechanism of progression in prostate adenocarcinoma. Other rare treatment-associated histologies, including adenocarcinoma with neuroendocrine features and squamous carcinoma, have been described. We present 52 cases with clinical, pathologic, and molecular features of transformed prostate cancer, including comparative genomic analyses with available paired specimens. Methods: Records of 52 patients from four Cancer Centers were reviewed under IRB approval to identify prostate adenocarcinoma that transformed to teSC/NEPC or other variant histologies (pathologically confirmed). Demographic, clinical, and molecular data were abstracted using a standardized template. When available, paired next-generation sequencing (NGS) results were analyzed from baseline and transformation biopsies. The primary outcome was 1-year overall survival (OS) after transformation. Results: 42 patients with teSC/NEPC (Cohort 1) and 10 with other transformed variants (Cohort 2) met inclusion criteria. Median age at diagnosis was 64 (IQR 13.8) years. Median time from metastatic adenocarcinoma diagnosis to transformation was 27.0 (IQR 40.0) and 32.5 months (IQR 24.5) in Cohort 1 and 2 respectively. All patients received androgen-deprivation therapy; 34 (65.4%) received AR-signaling inhibitors, and 26 (50%) chemotherapy. PSA at transformation was frequently discordant with disease progression (median 0.08 and 2.15 ng/mL in Cohort 1 vs 2). 1-year OS from transformation was 45.8% for teSC/NEPC and 50.0% for other variants. Paired NGS was available for 16 cases. 15 (93.8%) exhibited shared genomic alterations (alt) between biopsies, indicating clonal continuity. Baseline TP53 alt was common (69%) and stable through transformation (75%). Marked enrichment of alt in other tumor suppressor genes (TSG) was apparent. Notably, the prevalence of RB1 alt increased from 12.5% (baseline) to 81.3% (transformation), while PTEN inactivation increased from 37.5% to 62.5%. The prevalence of HRR gene alt increased from 35.7% to 57.1%, mainly involving BRCA2 (31.3%), ATM (12.5%), BRCA1 and CHEK2 (6.3% each). Triple TSG alt was found in 31.3% of baseline vs 100% of transformed biopsies. MYC amplification emerged in 25% of cases. Conclusions: Transformation from adenocarcinoma to other variant histologies is an area of active investigation. Comparative genomic profiling permitted analysis of clonal evolution. RB1 loss emerged as the most frequent acquired event, underscoring its central role in lineage reprogramming. Treatment-associated transformation after doublet or triplet therapy confers poor survival, emphasizing the need to investigate mechanisms of transformation and develop precision-directed interventions.