The role of molecular profiling for castration-resistant prostate cancer treatment and therapy development

Early-stage prostate cancer (PCa) is overwhelmingly driven by aberrant androgen receptor (AR) signalling. Accordingly, standard-of-care treatments include androgen deprivation therapy (ADT) and AR pathway inhibitors (ARPIs), with disease detection and therapy-response monitoring relying on blood-borne PSA, a product of AR transcriptional programs. Crucially, resistance to these therapies is inevitable but heterogeneous in nature; potentially driven by a diverse array of alternate signalling pathways and differentiation mechanisms such as neuroendocrine conversion. Here, we review the current standard of care for CRPC and highlight this heterogeneity - between and even within patients - which demands a new paradigm to longitudinally monitor the evolving molecular profiles of each patient to guide rational selection of targeted therapies, as well as rational patient stratification to optimise clinical trials for emerging therapies. Since solid biopsies are incompatible with extensive longitudinal profiling, we here consider recent advances in liquid biopsy-based profiling methods and assess their potential as cornerstones in a new paradigm of personalised, adaptable disease monitoring and therapeutic decision-support.