PSMA-targeted radioligand therapy in prostate cancer: evidence hierarchy, platform maturity of ¹⁷⁷Lu-PSMA-617, and the clinical differentiation challenge for emerging radionuclides.

Abstract

Among prostate-specific membrane antigen (PSMA)-directed radioligand therapies (RLT), ¹⁷⁷Lu-PSMA-617 is supported by two peer-reviewed phase III randomised controlled trials in metastatic castration-resistant prostate cancer (VISION and PSMAfore) and one in metastatic hormone-sensitive prostate cancer (PSMAddition). This structured narrative review uses eight predefined PubMed evidence sets, yielding 931 unique records after deduplication, to describe the study-design distribution and evidence-maturity profile of established and emerging PSMA-RLT strategies, including ¹⁷⁷Lu-PSMA-617, other Lu-177 PSMA agents, ²²⁵Ac, ¹⁶¹Tb, ²¹²Pb, ²¹¹At, and ⁹⁰Y. The review addresses five evidence questions: the differential patient-selection criteria between TheraP and VISION; rPFS-to-OS interpretation in PSMAfore; the sequencing implications of earlier hormone-sensitive RLT use; xerostomia and daughter-nuclide redistribution as unresolved development barriers for ²²⁵Ac-PSMA; and whether the microdosimetric rationale for ¹⁶¹Tb-PSMA is supported by clinical comparative data. The current evidence base identifies ¹⁷⁷Lu-PSMA-617 as the most mature PSMA-RLT platform, while emerging radionuclides remain dependent on prospective clinical differentiation.