Novel therapeutic strategies for metastatic castration‑resistant prostate cancer: Beyond androgen receptor pathway inhibition (Review).

Metastatic castration‑resistant prostate cancer (mCRPC) remains a lethal disease due to universal resistance to androgen‑receptor pathway inhibitors (ARPI). Tumor progression is orchestrated by a spectrum of androgen‑receptor‑independent drivers, including genomic alterations in DNA damage repair pathways, epigenetic shifts promoting lineage plasticity, metabolic adaptations and an immunosuppressive tumor microenvironment. This evolving understanding has catalyzed the development of novel therapeutic strategies. These include PARP inhibitors for tumors with homologous recombination repair deficiencies, protein kinase B inhibitors for the phosphatase and tensin homolog‑loss subset, prostate‑specific membrane antigen (PSMA)‑targeted radioligand therapy, bispecific T‑cell engagers, antibody‑drug conjugates and immune checkpoint inhibitors. Furthermore, liquid biopsy profiling, PSMA‑positron emission tomography‑based radiomics and artificial intelligence platforms are enhancing real‑time patient selection and response assessment. The present review synthesized these recent preclinical and clinical advances to delineate biomarker‑driven, mechanism‑based therapeutic sequencing and combination strategies for mCRPC in the post‑ARPI era.19.