Targeting TROP2 in aggressive variant and neuroendocrine prostate cancer.

171 Background: Aggressive variant prostate cancer (AVPC) including neuroendocrine prostate cancer (NEPC) is characterized by rapid, androgen-independent tumor growth. Standard therapies often show limited efficacy. Alternative treatment strategies are therefore urgently required. Here, we present preclinical and first clinical results on the potential impact of TROP2 targeting in AVPC/NEPC. Methods: TROP2 expression was assessed in AVPC/NEPC cell lines, circulating tumor cells (CTCs) and metastatic biopsies. Efficacy of the TROP2 targeted antibody drug conjugate (ADC) Sacituzumab Govitecan (SG) was evaluated in prostate cancer (PC) cell lines with high and low/- TROP2 expression. TROP2+ AVPC/NEPC patients with exhausted standard therapy options are currently undergoing treatment with SG in an individual approach. Results: TROP2 expression was detected at varying levels in PC cell lines, with increased expression in docetaxel-resistant cells. CTCs of AVPC and NEPC patients were TROP2+ in 74.0% (37/50) and 48.6% (17/35), respectively, while the vast majority of biopsies from both cohorts expressed TROP2. SG was highly effective in TROP2+ cells in vitro , regardless of their degree of resistance to standard therapies while reduced activity was seen in TROP2 low/- cells after short-term exposure. Remarkably, SG exhibited a pronounced antiproliferative effect and/or apoptosis induction in TROP2-low LNCaP and PC3 cells, when co-cultured with TROP2+ DU145-DR or PC3-DR cells, indicating a bystander effect. The antiproliferative activity of SG was attributed to an increased G2/M cell cycle arrest. Proteomic analyses suggested suppression of cell cycle related processes and proliferation as well as signaling pathways involved in neuronal dedifferentiation and cell stemness. First clinical results of heavily pretreated TROP2+ AVPC/NEPC patients (n=9) revealed partial remission (PR) or stable disease in 44% and 33% at radiological follow-up, with a disease control rate of 78% and 44% at 3 and 6 months, respectively. Of note, in a NEPC patient with sudden, rapid progression following initial PR, loss of TROP2 expression on CTCs was detected. In addition, preclinical data suggested AKT activation and upregulation of p-glycoprotein as further possible resistance mechanisms. Conclusions: TROP2-directed therapy with SG demonstrates promising preclinical and clinical activity in AVPC and NEPC. A clinical trial evaluating a TROP2-directed ADC in AVPC is in preparation.