Over the last decade, new systemic treatments for advanced prostate cancer have extended patient survival, but raised new clinical challenges. Castration-resistant prostate cancer (CRPC) can be treated with second generation AR-directed inhibitors, such as abiraterone or enzalutamide; however, tumors inevitably develop diverse molecular and phenotypic mechanisms of resistance. To identify novel treatments, new models that accurately represent the changing clinico-pathologic features of CRPC are required. Unfortunately, there is a shortage of such models, due in part to the difficulty in propagating prostate tumours in vitro and in vivo compared to other cancers. To address these issues, we established the Melbourne Urological Research Alliance (MURAL) as part of the international effort to develop new patient-derived models of prostate cancer. We successfully established a new collection of PDXs from abiraterone and enzalutamide-resistant prostate cancer, which closely represent the features of the original patient tumours. These PDXs exemplify the heterogeneity of CRPC, exhibiting differing genomic features and distinct mechanisms of AR-driven resistance, including genomic structural rearrangements of the AR gene driving AR variant expression, known and novel AR mutations, and transformation to an AR-null phenotype. We used these PDXs, as well as explants and organoids derived from them, to test candidate treatments. This revealed the effectiveness of dual inhibition of ribosome biogenesis and function, downstream of c-MYC signaling. Together, this work provides both a new collection of contemporary patient-derived models and a promising therapeutic strategy to target a diverse range of CRPC.