Double-Negative Prostate Cancer: Evolutionary Mechanisms, Microenvironmental Remodeling, and Clinical Translation.

The management of metastatic castration-resistant prostate cancer (mCRPC) is continuously challenged by the emergence of therapeutic resistance. Under the selective pressure of profound androgen inhibition, a significant proportion of tumors undergo lineage plasticity, evolving into double-negative prostate cancer (DNPC). Defined by the concomitant loss of androgen receptor (AR) dependence and the absence of classic neuroendocrine markers, DNPC represents a highly aggressive, independent evolutionary steady state. The fundamental drivers of this phenotypic transition include the concurrent functional loss of TP53 and RB1, coupled with pervasive epigenetic reprogramming. These genetic and epigenetic events profoundly rewire core transcriptional networks, activate alternative kinase pathways, and establish an immunosuppressive microenvironment. Because the downregulation of conventional targets renders standard diagnostic and therapeutic interventions ineffective, a paradigm shift in clinical strategy is imperative. This review delineates the molecular ontogeny of DNPC. We further explore mechanistically grounded therapeutic modalities, including epigenetic modulation, synthetic lethality, and precision delivery systems. Ultimately, we advocate for the concept of "evolutionary interception," providing a strategic roadmap to dismantle the survival networks of advanced DNPC.