Next-generation therapeutic strategies in prostate cancer: Integrating targeted therapy, radioligand therapy, and precision oncology

Prostate cancer continues to present major clinical challenges, particularly in advanced and metastatic settings where therapeutic resistance and tumor heterogeneity limit the long-term efficacy of conventional treatments. This review provides a comprehensive and integrated analysis of next-generation therapeutic strategies, focusing on androgen receptor (AR)–targeted innovations, DNA damage repair–based therapies, PSMA-directed radioligand approaches, and emerging immuno-metabolic interventions. A key gap in the current literature is the fragmented evaluation of these modalities, which are often discussed in isolation and fail to address their mechanistic interplay or integration within precision oncology frameworks. Here, we bridge this gap by critically linking molecular drivers such as AR reactivation, DDR deficiencies, and PI3K/AKT pathway alterations to evolving therapeutic strategies, including PROTAC-based AR degraders, PARP inhibitor combinations, and PSMA theranostics. Notably, this review highlights the paradigm shift from single-agent therapies toward rational combination strategies guided by genomic and functional biomarkers. The incorporation of next-generation sequencing, liquid biopsy technologies, and PSMA-based imaging is redefining patient stratification and treatment selection. Furthermore, emerging approaches targeting tumor metabolism, epigenetic regulation, and immune modulation are discussed as key contributors to overcoming resistance and disease progression. Looking forward, the future of prostate cancer management lies in fully integrated precision oncology, where biomarker-driven decision-making, early incorporation of radioligand therapy, and adaptive combination regimens converge to improve outcomes. This review underscores the importance of translational research to optimize therapeutic sequencing, enhance patient selection, and develop novel synergistic strategies, ultimately paving the way toward more personalized and durable treatment paradigms in prostate cancer