PSMA Theranostics: Expanding Horizons in Oncology

PSMA theranostics have reshaped prostate cancer care by pairing sensitive localization with lesion-directed radioligand therapy, improving detection and enabling targeted systemic treatment. PSMA-PET identifies small-volume nodal and distant disease at low PSA thresholds, while radioligand therapy (RLT) delivers tumor-focused systemic doses for patients with metastatic castration-resistant disease. Together, these tools shorten the interval from diagnosis to actionable therapy and sharpen selection for focal versus systemic interventions, with immediate effects on diagnostic precision and treatment decisions.

PSMA now anchors contemporary prostate cancer workflows: PSMA-PET informs initial staging and localizes biochemical recurrence, and RLT treats PSMA-avid mCRPC. Imaging performance is assessed with SUV-based metrics and lesion-level detection rates; RLT efficacy is judged by PSA response and progression-free survival. Cohort-level data consistently show improved lesion detection and meaningful response rates in selected patients, though effect sizes depend on baseline tumor burden and PSMA expression. A key constraint remains inconsistent target expression—heterogeneous PSMA levels and neuroendocrine differentiation can produce PSMA-negative phenotypes that reduce both imaging sensitivity and therapeutic yield.

PSMA-negative or heterogeneous disease creates demand for adjunctive diagnostics and combined approaches. These phenotypes—including neuroendocrine differentiation and intratumoral heterogeneity—can evade PSMA-PET and blunt RLT benefit, prompting complementary strategies: multiplex molecular diagnostics, serial circulating biomarkers (ctDNA, CTCs, exosomes), multi-target PET panels, and targeted tissue/genomic profiling. Dual-tracer PET (PSMA plus FDG) and focused genomic assays frequently reveal discordant biology and guide alternative or combined therapies. Emerging biomarkers and multimodal profiling can recover cases where PSMA alone underperforms and better define candidates for RLT.

PSMA expression in tumor neovasculature broadens mechanistic opportunity beyond prostate cancer, supporting imaging and vascular-targeted approaches in malignancies such as renal cell carcinoma and glioblastoma. Endothelial PSMA permits ligand binding in proliferative neovasculature, enabling PET visualization and, in early reports, targeted radioligand delivery to vascular compartments. Initial clinical series report signal in RCC and GBM that reflects vascular rather than epithelial expression, with variable lesion-level contrast. Different expression profiles and off-target uptake mean cautious endpoint expectations; non-prostate indications will require disease-specific validation and dosimetry optimization before broader adoption.