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

ABSTRACT

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, ¹⁷⁷ Lu‐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 ¹⁷⁷ Lu‐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 ¹⁷⁷ Lu‐PSMA radioligand therapy, highlights interpretive and implementation pitfalls, and outlines practical priorities for the Japanese clinical and academic community.