Prostate cancer is the most frequent malignant tumor in the male genitourinary system, and it has become the fourth most common cancer in the world.1 Most cases of prostate cancer are curable if diagnosed at an early stage. However, 30%–40% of patients will still progress from organ-confined disease to metastatic prostate cancer.1,2 About 90% of patients with metastatic castration-resistant prostate cancer (mCRPC) will develop bone metastases, which reduces survival and represents a significant clinical challenge.3

Precision oncology approaches with alpha-emitting radionuclides complexed with chelators and conjugated to targeting molecules that direct the radiolabeled compound to tumor-specific sites (targeted alpha therapy - TAT) has gained increasing attention for its ability to deliver highly cytotoxic alpha radiation directly to tumor cells, while causing minimum damage to surrounding healthy tissues.4

Among alpha-emitting radiopharmaceuticals, radium-223 dichloride (223Ra) is the first TAT approved for clinical use and represents a major advance in the treatment of bone metastases associated with mCRPC, showing improvement in overall survival (OS) and delay in skeletal-related events (SREs).5

Unlike conventional chemotherapy or ARPIs, 223Ra does not target tumor cells systemically or modulate androgen receptor signaling.6 Instead, due to its chemical similarity to calcium, 223Ra accumulates in areas of increased bone turnover, characteristic of osteoblastic metastases.7,8223Ra emits high linear energy transfer (LET) alpha particles over a short range, inducing potent, localized and irreparable double-strand DNA damage in tumor cells, achieving high local efficacy while preserving bone marrow and soft tissues.9

However, assessing the therapeutic response to 223Ra presents some challenges. In contrast to conventional cytotoxic treatments, 223Ra does not induce rapid tumor size reduction, and standard imaging modalities may not reflect treatment effects on bone metastases.10 Traditional biomarkers, such as prostate-specific antigen (PSA), are often limited in use when it comes to predicting response to 223Ra therapy.11 This highlights the need for alternative approaches to assess treatment effectiveness, such as functional imaging, bone turnover markers, and new dosimetry strategies.12

In this review, we discuss current methods and emerging strategies for evaluating therapeutic response to 223Ra, focusing on radiobiological aspects, biochemical markers and imaging to provide a comprehensive overview of best practices and future directions in the management of mCRPC patients.