Deep learning-based histologic classifiers enable molecular subtyping of metastatic prostate cancer.

Metastatic prostate cancer is a clinically and molecularly heterogeneous disease. Under the selective pressure of androgen receptor (AR)-directed therapies, resistant phenotypes frequently emerge, posing significant diagnostic and therapeutic challenges. Neuroendocrine prostate cancer (NEPC) is a clinically important phenotype characterized by lineage plasticity, neuroendocrine features, visceral metastases and poor prognosis. Accurately diagnosing NEPC remains difficult due to its histologic and molecular complexity but has high clinical relevance. In this study, we developed a deep learning model that leverages interpretable cellular features to improve feature extraction from H&E-stained tissue sections (NEURAL-PC). By incorporating a multiple instance learning (MIL) framework, NEURAL-PC enables robust NEPC classification solely from H&E tumor images, achieving an area under the receiver operating characteristic curve (AUROC) of 0.921 in independent external validation. In addition to its diagnostic utility, NEURAL-PC provides prognostic information that enables further subclassification of advanced prostate cancer across diverse datasets supporting its strong prognostic value and generalizability. Broadly, our work highlights a hybrid approach that integrates features across different domains, offering a promising strategy for developing reliable deep learning tools in pathology. Built on this framework, NEURAL-PC represents an extensively validated diagnostic and prognostic model for advanced prostate cancer.