Systems-level liquid biopsy in advanced prostate cancer

Treatment for castration-resistant prostate cancer (CRPC) primarily involves the suppression of androgen receptor (AR) activity using androgen receptor signaling inhibitors (ARSIs). While ARSIs have extended patient survival, resistance inevitably develops. Mechanisms of resistance include genomic aberrations at the AR locus that reactivate AR signaling, or lineage plasticity that drives emergence of AR-independent phenotypes. Given the diverse mechanisms of ARSI resistance in CRPC, there is a need for more effective monitoring strategies that detect signs of resistance to inform prognosis and guide use of alternative therapies. Liquid biopsy is a blood test that has emerged as a powerful, minimally invasive tool for investigating advanced cancer. In CRPC, liquid biopsy has been shown to reflect genomic and transcriptomic features in tumor tissue and has been utilized to detect an array of resistance signatures. Liquid biopsy is uninhibited by spatial restrictions and allows for longitudinal monitoring of disease progression. However, current clinical liquid biopsy tests provide limited actionable information. This review highlights recent advancements to the understanding of mechanisms driving treatment resistance in CRPC through use of research-grade liquid biopsy assays. We explore novel methods of disease characterization developed using liquid biopsy and emphasize the clinical potential of a multi-omic molecular profiling approach to comprehensively detect emerging therapeutic resistance. Routine assessment of therapy resistance via a liquid biopsy assay has the potential to enhance prognostication and improve outcomes of men with CRPC.