The role of multimodality imaging in selection, response assessment, and follow-up of patients receiving Lutetium-PSMA-therapy.

Prostate cancer is the most commonly diagnosed cancer among men in 112 countries, accounting for approximately 15% of all cancer cases. Whilst the 5-year survival rate for localised disease exceeds 90%, there is a significant drop to 50% if metastases are present. Following the VISION and TheraP trials, Lu-PSMA-therapy was approved for treatment of metastatic castrate resistant prostate cancer by the FDA and EMA 2022. Patient selection for Lu-PSMA-therapy is now relatively well defined, guided by PSMA-PET/CT criteria established in pivotal trials. Nevertheless, clinical consensus on appropriate criteria is still evolving, and additional imaging modalities such as F-FDG PET, post-therapy SPECT/CT, or emerging techniques such as whole-body diffusion-weighted MRI may serve as valuable adjuncts to identify PSMA-negative or treatment-resistant disease that may not be apparent on PSMA-PET/CT alone. This review examines the current evidence on imaging biomarkers and complementary diagnostic techniques used for patient selection, treatment monitoring, and response assessment in [¹⁷⁷Lu]Lu-PSMA-617 therapy for metastatic castrate resistant prostate cancer. Baseline imaging biomarkers on PSMA-PET/CT, such as mean standardised uptake value (SUV), PSMA-avid total tumour volume, and inter-lesional PSMA heterogeneity, have shown promise in predicting treatment response and assessing outcomes. Additionally, statistical prognostic models have been developed to predict treatment efficacy, though further validation is required. Imaging plays a crucial role and should be considered alongside blood biomarkers, clinic-demographic history, and circulating tumour markers to improve patient selection for Lu-PSMA-therapy. CRITICAL RELEVANCE STATEMENT: PSMA-PET/CT is the established imaging modality for patient selection for ¹⁷⁷Lu-PSMA-therapy, while ¹⁸F-FDG PET, post-therapy SPECT/CT, and emerging techniques such as whole-body diffusion-weighted MRI can be adjunctive for patient selection, response assessment and long-term monitoring. KEY POINTS: PSMA-PET/CT is the mainstay for patient selection for ¹⁷⁷Lu-PSMA-therapy. F-FDG PET, SPECT/CT or whole-body diffusion-weighted MRI could be used as adjuncts. Interim and longitudinal PSMA-PET/CT offer sensitive detection of progression, quantitative biomarkers for response assessment, and standardised frameworks. Advances in AI, radiomics, and standardisation frameworks may refine prognostication, enable personalised dosimetry, and integrate imaging biomarkers into clinical practice, though further validation is required.