A new era for radium-223? Optimizing treatment by balancing efficacy and toxicity through combination therapies

The pronounced bone tropism of prostate cancer (PCa) has prompted the development of therapies that specifically act in areas of increased bone deposition and selectively exert anti-tumor effects in osteoblastic metastases. Radium-223 dichloride is a calcium-mimetic agent that targets bone lesions, disrupting the vicious circle between tumor cells and the bone microenvironment, and it has been shown to improve survival in metastatic castration-resistant prostate cancer (mCRPC) patients. Moreover, the combination of radium-223 with androgen receptor pathway inhibitors (ARPIs), despite showing promising antitumor activity, have also produced conflicting safety results, highlighting the importance of bone health in optimizing radium-223 use. The therapeutic landscape of PCa is rapidly evolving, with several other agents approved over the past fifteen years that have repeatedly reshaped the treatment algorithm since the introduction of radium-223. Furthermore, the capacity of radium-223 to induce DNA damage in tumor cells provides a strong rationale for potential synergy with PARP inhibitors and immunotherapeutic agents. This review refocuses attention on this radionuclide, providing an updated perspective to re-evaluate the role of radium-223 in the era of radioligands and precision medicine, along with a critical overview of promising future combinations for the treatment of PCa.