839P - Clinico-genomic profiling and outcome prediction of neuroendocrine prostate cancer (NEPC)

Abstract

Background: NEPC is a variant of prostate cancer that may present “de novo” or after androgen receptor (AR)-targeted therapies (“treatment related”) with a spectrum spanning both small cell prostate cancer (SCPC) and adenocarcinoma with neuroendocrine differentiation (adeno-NE). The comprehensive clinical and molecular landscape of different NEPC subtypes and its potential impact on outcome is poorly understood. Methods: 274 prostate cancer patients (pts) with metastatic biopsy tumor morphology confirming NEPC (n = 97; 36 with SCPC and 51 with adeno-NE) or castration resistant adenocarcinoma (CRPC) (n = 187) between 2004 and 2017 in a single academic center were evaluated. Baseline, treatment and outcomes data along with tumor whole-exome and RNA-seq data were retrospectively reviewed. Statistical comparisons utilized Cox regression analysis and Kaplan-Meier method for association with NEPC, CRPC and overall/progression-free survival (OS/PFS). Results: In NEPC, PSA at time of biopsy was lower compared with CRPC (median 1.18 vs 38.0, p = 0.001) and liver metastases were more common (32.2% vs 52.1%, p = 0.027). OS from time of prostate cancer diagnosis differed by subtype, with SCPC having shortest survival (median 2.98 years), followed by adeno-NE (median 5.98 years) then CRPC (median 12.14 years) (log rank p < 0.0001), with similar results seen with time from metastases (log rank p < 0.0001). AR alterations were more frequent in CRPC (p < 0.001), while RB1 (p = 0.001) and TP53 (p = 0.048) alterations and high NEPC mRNA score (p = 0.007) were more common in NEPC. For CRPC pts treated with abiraterone or enzalutamide, shorter PFS was observed when somatic alterations in RB1 (p = 0.067) or TP53 (p < 0.0001) were present. Elevated NEPC score (p = 0.006), serum CGA above upper limit of normal (p = 0.033), and presence of liver metastases (p < 0.001) were prognostic for time to death from diagnosis among pts with CRPC. Conclusions: NEPC is associated with lower PSA, higher frequency of liver metastases, and worse prognosis compared with CRPC, with SCPC having the shortest OS. The presence of NEPC clinical or molecular features in CRPC is also prognostic. Further studies of this aggressive form of prostate cancer are warranted. Legal entity responsible for the study: Weill Cornell Medicine. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.