The targeted alpha therapy radium-223 (223Ra) can prolong survival in men with castration-resistant prostate cancer (CRPC) who have symptomatic bone metastases and no known visceral metastases. Preclinical studies demonstrate that 223Ra preferentially incorporates into newly formed bone matrix within osteoblastic metastatic lesions. The emitted high-energy alpha particles induce DNA double-strand breaks that might be irreparable and lead to cell death in nearby exposed tumour cells, osteoblasts and osteoclasts. Consequently, tumour growth and abnormal bone formation are inhibited by these direct effects and by the disruption of positive-feedback loops between tumour cells and the bone microenvironment. 223Ra might also modulate immune responses within the bone. The clinical utility of 223Ra has encouraged the development of other anticancer targeted alpha therapies. A thorough understanding of the mechanism of action could inform the design of new combinatorial treatment strategies that might be more efficacious than monotherapy. On the basis of the current mechanistic knowledge and potential clinical benefits, combination therapies of 223Ra with microtubule-stabilizing cytotoxic drugs and agents targeting the androgen receptor axis, immune checkpoint receptors or DNA damage response proteins are being explored in patients with CRPC and metastatic bone disease.
Radium-223 (223Ra) deposited in the intralesional bone matrix emits high-energy alpha-particles that induce potentially cytotoxic DNA double-strand breaks in cells within a 100-µm distance while sparing surrounding normal tissue.
223Ra acts via a multi-modal mechanism, killing both tumour cells and the effector cells of pathological bone metabolism, osteoblasts and osteoclasts; 223Ra might also promote local antitumour immune responses.
Understanding the mode of action of 223Ra and its interactions with those of other anticancer agents offers potential for new treatment combinations for bone-metastatic cancers.
Clinical trials are investigating 223Ra in combination with agents targeting the androgen receptor signalling axis, cell microtubules, the immune response and the DNA damage response.
Current combination studies are preliminary and further clinical testing will be required to demonstrate safety, efficacy and clinical benefit.
223Ra treatment in patients with metastatic castration-resistant prostate cancer has led to the development of other targeted alpha therapies for the treatment of patients with different cancers that also have bone-predominant metastases.
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The authors thank P. Hoban (Cancer Communications and Consultancy Ltd, Knutsford, UK) for providing writing assistance funded by Bayer.
M.J.M. declares participation as a compensated member of advisory boards for Advanced Accelerated Applications, an uncompensated member of advisory boards for Bayer, Endocyte and Progenics and research funding (for institute) from Bayer, Endocyte, Progenics and Corcept. E.C. and T.A.G. declare participation as compensated members of a round-table meeting from Bayer and research funding (for institute) from Bayer. W.K.K. declares clinical trial support from Bayer. D.I.Q. declares participation as a compensated member of advisory boards from Astellas, Bayer, Janssen, Genzyme, Dendreon and AstraZeneca. A.S. is a full-time employee of Bayer. G.S. is a consultant for Bayer and holds ownership in a start-up company that Bayer has used for imaging and dosimetry analyses. J.L.G declares no competing interests.
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Morris, M.J., Corey, E., Guise, T.A. et al. Radium-223 mechanism of action: implications for use in treatment combinations. Nat Rev Urol 16, 745–756 (2019) doi:10.1038/s41585-019-0251-x