PSMA-targeted radioligand therapy in advanced prostate cancer: a narrative review of ^177Lu-PSMA, emerging ^225Ac-PSMA strategies, and therapeutic sequencing

Prostate cancer remains a leading cause of cancer-related morbidity and mortality among men, and metastatic castration-resistant prostate cancer continues to present substantial therapeutic challenges despite advances in androgen receptor pathway inhibitors, taxane chemotherapy, PARP inhibitors, and immunotherapy for selected molecular subgroups. Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy has emerged as a clinically important theranostic strategy that combines molecular imaging-based patient selection with targeted delivery of cytotoxic radiation to PSMA-expressing tumor sites. This narrative review summarizes the biological rationale, clinical evidence, safety profile, and evolving treatment-sequencing considerations for PSMA-targeted radioligand therapy in advanced prostate cancer. Particular emphasis is placed on ^177Lu-PSMA-617, which has demonstrated improved radiographic progression-free survival and overall survival in pivotal randomized trials, including VISION, TheraP, and PSMAfore. The review also examines investigational alpha-emitting PSMA-targeted therapies, particularly ^225Ac-PSMA compounds, which offer high-linear-energy-transfer cytotoxicity and may have activity in selected patients after progression on beta-emitting radioligand therapy, although definitive phase III evidence remains lacking. The established bone-targeted alpha-emitter ^223Ra is discussed separately as contextual therapy for selected patients with symptomatic bone-predominant mCRPC without visceral metastases. As clinical use of radioligand therapy expands, optimization of PSMA PET-based patient selection, management of salivary, hematologic, and renal toxicities, sequencing with other systemic therapies, and integration into multidisciplinary care pathways will be essential. Future research should prioritize randomized clinical trials, individualized dosimetry, predictive biomarkers, toxicity mitigation, and patient-centered implementation strategies.