Precision Targeting in Metastatic Prostate Cancer: Molecular Insights to Therapeutic Frontiers

Metastatic prostate cancer (mPCa) remains a significant global health concern and cause of cancer-related mortality in men. Advances in molecular profiling have illuminated the critical drivers of disease progression and therapeutic resistance, notably within the androgen receptor (AR) axis, DNA damage repair (DDR) pathways, and PI3K/AKT/mTOR network. Despite the established benefits of hormone therapy, chemotherapy, and bone-targeting agents, mPCa commonly evolves into a treatment-resistant state, typified by intrapatient heterogeneity and clonal evolution. Recent breakthroughs have highlighted the importance of identifying actionable genetic alterations such as BRCA2 or ATM defects that render tumors sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Parallel efforts have refined imaging—particularly prostate-specific membrane antigen (PSMA) PET-CT—to detect and localize metastatic lesions with high sensitivity, thereby guiding patient selection for PSMA-targeted radioligand therapies (177Lu-PSMA, 225Ac-PSMA). Multi-omics innovations, including liquid biopsy technologies, enable real-time tracking of emergent AR splice variants (e.g., AR-V7) or reversion mutations, supporting adaptive therapy paradigms. Nonetheless, the complexity of mPCa necessitates combination strategies—for example, pairing AR inhibition with PI3K/AKT blockade or PARP inhibitors—to intercept tumor plasticity. Immuno-oncology approaches remain challenging in unselected patients; however, subsets with mismatch repair deficiency (MSI-high) or neuroendocrine phenotypes may benefit from immune checkpoint blockade or targeted epigenetic interventions. We present these pivotal advances and discuss how biomarker-guided integrative treatments can improve the management of mPCa.