PSMA Theranostics for Prostate Cancer: Evidence, Pitfalls, and Implementation in Japan

Prostate-specific membrane antigen (PSMA) is a Type II transmembrane glycoprotein markedly overexpressed on prostate cancer cells, enabling a single molecular target to support both positron emission tomography (PET) imaging and targeted radionuclide therapy. Over the past decade, PSMA-PET/CT has been incorporated into international guidelines for primary staging of high-risk prostate cancer and for biochemical recurrence, with the landmark proPSMA trial establishing its diagnostic superiority over conventional imaging; whether PSMA-PET-guided management improves long-term oncologic outcomes, however, remains an open question addressable only by prospective PSMA-specific trials. On the therapeutic side, ¹⁷⁷Lu-PSMA-617 has become a standard treatment option for metastatic castration-resistant prostate cancer (mCRPC) after androgen-receptor pathway inhibitor (ARPI) and taxane chemotherapy, and is moving into earlier lines of disease. Alpha-emitting and next-generation ligands, together with quantitative whole-body imaging and artificial intelligence, are redefining both patient selection and response assessment, although randomized evidence for many of these approaches remains limited. In Japan, the concurrent 2025 approval of ¹⁷⁷Lu-vipivotide tetraxetan and its companion PSMA diagnostic has initiated a national roll-out that will depend on a hub-and-spoke framework of regional PSMA-PET centers and therapy spokes, a prepared nuclear medicine workforce, and domestic registries to refine Japanese-specific evidence. This review summarizes the current clinical evidence for PSMA-PET/CT and ¹⁷⁷Lu-PSMA radioligand therapy, highlights interpretive and implementation pitfalls, and outlines practical priorities for the Japanese clinical and academic community.