Assessing therapeutic response to Radium-223

Radium-223 (²²³Ra), an alpha-emitting radiopharmaceutical targets bone and prolongs overall survival (OS) while reducing skeletal-related events (SREs) in metastatic castration-resistant prostate cancer patients (mCRPC). However, assessing ²²³Ra therapeutic response is difficult due to its distinct mechanism of action on bone remodeling and tumor microenvironment. Therefore, a multimodal approach to evaluate response is required, beyond conventional serum tumor biomarkers such as PSA and ALP. This review integrates current and emerging strategies for evaluating ²²³Ra response. We discuss classic serum biomarkers, highlighting their prognostic and monitoring roles. We also examine emerging liquid biopsy tools, such as circulating tumor cells, circulating tumor DNA, bone metabolism markers and exosomes that may reflect the metabolic changes induced by ²²³Ra. We also explore the clinical response patterns and limitations of imaging biomarkers that play a central role in response assessment such as ¹⁸F-fluoride PET/CT, whole-body diffusion-weighted MRI and PSMA PET/CT. We cover RECIST-based assessments and innovative technologies, including radiomics and artificial intelligence, that integrate clinical, molecular, and imaging data to enhance outcome prediction, automate lesion analysis, and reveal patterns related to treatment response, supporting personalized care. In conclusion, a multimodal approach that combines biological and imaging markers with modern analytical methods enhances ²²³Ra therapy response evaluation, leading to improved clinical outcomes in mCRPC.