Characterisation and treatment of patients with castration-resistant metastatic prostate cancer (mCRPC) developing neuroendocrine clonal divergence (NCD): A case series.

Abstract

e16520 Background: The introduction of Abiraterone (Abi) and Enzalutamide (Enza) into treatment of mCRPC has led to a survival benefit. However, in a subset of patients treated with Enza/Abi, rapidly progressive disease with atpical metastatic spread develops. According to Eric Small et al. (ASCO 2015 Abstract 5003), 39% of metastases in mCRPC-patients treated with Enza/Abi have small cell neuroendocrine or mixed type histologies. Based on these findings we aimed at characterising NCD in a case series of 8 patients using 1) clinical, laboratory, radiological parameters, 2) molecular features generated by liquid biopsy and 3) to present outcome variables after treatment of these patients with combination chemotherapy carboplatin/etoposide (CE). Methods: Clinical, radiological, laboratory parameters, whole-genome sequencing of cfDNA (PlasmaSeq) and ctDNA taken at different time points during treatment were ascertained from 8 mCRPC-patients with NCD. Results: All patients presented with rapid tumour progression and atpical metastatic spread (3x liver, 3x lungs, 1x skin, 1x adrenal glands) during treatment with Enza/Abi. Laboratory findings revealed marked increase in CRP, AP and LDH levels and elevation of NSE ( > 5x times upper normal limit), whilst PSA levels were low or declining. All patients received Carboplatin AUC5 day 1 and Etoposid 100 mg/m3 day 1-3 q3w. In 7 out of 8 patients, initially high levels of CRP, LDH, AP and NSE decreased under CE therapy. Very good partial response on radiological examination was observed after 3-6 cycles of CE in these patients. One patient had progressive disease. Copy number profiles of ctDNA taken peri-interventionally revealed loss of androgen receptor and a clonal shift in comparison to profiles taken during endocrine treatment phase. Conclusions: Rapid clinical and radiologic progression, atypical metastases and sharp rise in LDH, CRP, AP and NSE levels combined with low PSA are indicative of NCD. For these patients, CE-based chemotherapy is a promising treatment option. In order to identify clonal shift from adenocarcinoma to neuroendocrine cancer, genetic profiling using ctDNA may be of use.