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 androgen receptor (AR)-directed inhibitors, such as abiraterone or enzalutamide; however, tumours inevitably develop diverse genomic and phenotypic mechanisms of resistance. New patient-derived models that accurately represent these changing clinico-pathologic features of CRPC are required to identify novel treatments. Unfortunately, there is a shortage of contemporary models, since prostate tumours are difficult to grow compared to other cancers. To address these issues, we established the Melbourne Urological Research Alliance (MURAL) to develop new patient-derived models of prostate cancer. We collected 153 tumours from 69 men undergoing surgery or biopsy or who consented to the CASCADE rapid autopsy program. We successfully established a new collection of 18 serially transplantable PDXs, including of soft tissue metastases of abiraterone and enzalutamide-resistant prostate cancer. The PDXs closely reflected the genomic, transcriptomic and histopathological features of the original tumours. They also exemplify the heterogeneity of CRPC, with distinct mechanisms of AR-driven resistance, including genomic structural rearrangements of the AR gene that drive 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 a panel of candidate treatments. This revealed that dual inhibition of ribosome biogenesis and function downstream of c-MYC signaling was effective in diverse, therapy-resistant tumours, including aggressive AR-null subtypes. This treatment strategy, with a combination of RNA Pol I and PIM Kinase inhibitors, decreased proliferation, increased apoptosis, activated the DNA damage response, and reduced tumour growth in vivo. Therefore, this study demonstrates that ribosome-targeting drugs may be effective against diverse CRPC subtypes including AR-null disease, and highlights the potential of contemporary patient-derived models to prioritise treatment strategies for clinical translation.