Integrative molecular profiling identifies predictors of response to sacituzumab govitecan in advanced prostate cancer

Prostate cancer is the second leading cause of cancer related death in men. Potent therapies that inhibit the androgen receptor (AR) transcription factor have improved survival of patients with prostate cancer, however many cases progress to lethal castration resistant prostate cancer (CRPC). Resistance to AR-targeted therapies is frequently mediated by reactivation of AR signaling or transition to AR-independent, non-luminal subtypes. Identifying new treatment strategies for patients with CRPC who are resistant to available therapies is critical for improving survival outcomes. One promising therapeutic target for CRPC is the trophoblastic cell surface antigen (Trop-2). Found to be highly expressed in many solid tumors, Trop-2 has oncogenic activities implicated in CRPC progression and could provide a target for treatment of prostate cancer resistant to AR targeted therapies. Sacituzumab Govitecan (SG) is an anti-Trop-2 antibody drug conjugate that provides targeted delivery of the topoisomerase I inhibitor SN-38. As part of a completed phase II clinical trial assessing the efficacy of SG in CRPC, we performed integrative whole exome DNA-seq and RNA-seq on metastatic biopsies obtained from 29 patients at baseline (pre-treatment with SG) and during treatment with SG. We characterized the gene expression profiles and mutational landscapes to evaluate the prognostic value of gene signatures and acquired genetic alterations. Baseline biopsies from patients that responded to SG displayed enrichment for gene signatures that define basal subtypes of CRPC and inflammatory response. Conversely, baseline biopsies from patients that did not respond to SG displayed enrichment for pathways related to high proliferation and AR activity. These findings provide a framework for interpreting response to SG that may inform future clinical development as well as selection of laboratory models to enhance mechanistic knowledge of SG response and resistance.