In 2013 Radium-223 was FDA approved for treatment of prostate cancer patients with bone metastases on the basis of a large randomized trial, ASYMPCA, comparing the radioisotope to a placebo. In 708 heavily pretreated men, the overall median survival was extended by 3.2 months (14.9 v. 11.3 months). Compared to the placebo group, the treatment produced a 6 month extension in “time to first skeletal event’ (FSE), defined as a pathologic fracture, spinal cord compression or need for radiation therapy for bone pain from metastases. The safety profile was encouraging, the drug was easily administered in a one minute out-patient infusion, and it was quickly adopted into clinical practice.

 The biology of prostate cancer bone metastases:

 The biology underlying metastases to bone explains the formidable difficultly of its eradication. Homing to bone begins early in the disease – often before diagnosis. In an estimated 10% of men, circulating tumor cells (CTC) have already migrated from the prostate before diagnosis and become established in bone in a state of dormancy, which may last for years. The predilection for CTCs to spread to bone may be explained by small vesicles, exosomes, extruded from the prostate containing tumor causing RNA. Exosomes are attracted to the bone by signals from the bone marrow. Once there, the exosomes prepare a hospitable environment, termed the ‘metastatic niche’, where the CTCs cluster in close association with the bone forming cells, the osteoblasts. Fortunately, the process of metastases is inefficient. Only 0.001% – 0.02% of CTCs successfully colonize bone. If prostate cancer is not controlled by primary therapy, 70% – 80% of men will experience bone metastases during the course of their disease. 

 The radiobiology of Radium-223:

 The radiobiology of Radium-223 in relation to the anatomy of bone metastases supports its early use in mCRPC. Radium-223, like its cousin calcium, is directly guided to the bone forming cells, the osteoblasts, where the tumor cells cluster nearby. Radium-223 decays with half-life of 11.4 days over which it emits alpha particles, essential helium nuclei. 

 The particles are highly energetic, but have limited penetration, less than 100 microns. A prostate cancer cell on average has a diameter of about 8 micron. In its limited travel the particle could impact the DNA of 10 or so tumor cells causing lethal double stranded breaks.

 In their article, ‘Radium 223-Mediated Zonal Cytotoxicity of Prostate Cancer in Bone,” Dondossola et al, JNCI (2019) studied (in mice) the importance of the size of the tumor target in relation to cytotoxicity of the radioisotope. “Cancer cell lethality in response to Rad-223 was profound … ,” lethally impacting cells within the 100 micron range but leaving undisturbed cells lying at a distance of >300 microns.” Their conclusion: “Micro-tumors showed severe growth delay or eradication in response of Rad-223, whereas macro-tumors persisted and expanded.” 

 They cited Alva et al., Prostate. 2017, who reported that men with a lower tumor burden, as evidenced in pretreatment bone scans, showed significant improved survival. Dondossola concluded, taken “in aggregate, the data suggests that men at risk for metastatic progression and patients with early-stage tumors in bone may particularly benefit from Rad-223 treatment.”

 How has Radium-223 treatment fared in clinical practices?

 The multinational clinical trial of 921 men, ASYMPCA, remains the definitive documentation of the response to Radium-223. The men under study had advanced disease symptomatic from bone pain. Lymph node enlargement up to 6 cm was allowed. Fifty seven percent had already received docetaxel and 43% had between 6 to 20 sites of bone metastases. Further analysis found that the treatment group as compared to placebo had better to time to the first skeletal event: 15.6 vs 9.8 months. Interpretation of trial data and expert opinion suggest that Radium-223 if used at an earlier stage of mCRPC would improve survival.

 In a URO TODAY interview Dr. Neal Shore, a prominent prostate cancer researcher and Medical Director for the Carolina Urologic Research Center, offered his opinion: “Real-World Clinical Outcome with Radium-223 in Metastatic Castration -resistant Prostate Cancer. He pointed out that to get the full survival benefit of the drug, completing the suggested 6 monthly cycles is optimal. In his practice he finds that in his bone-predominant patients tolerance is best if Rad-223 were given before chemotherapy – “typically before or sometimes during an androgen receptor-targeted therapy,” (such as Zytiga or Xtandi). Of prime important is the concurrent use of bone-health agents such as Xgeva (denosumab) or Zometa without which an increase in bone fractures occur. Because Rad-223 produces minor bone marrow suppression, the subsequent use of chemotherapy is not compromised. 

 The sequencing of Rad-223 and chemotherapy was addressed also by McKay et al. Prostate Cancer and Prostatic Disease, Aug 19, 2020. They studied 64 patients with mCRPC with predominantly bone metastases who received Rad-223 prior to chemotherapy and 83 post chemotherapy. Median overall survival from start of treatment was similar (~ 38 months) but

Rad-223 given first allowed more treatment cycles (median, 5.3 v 4.3).

 New Directions:  The trend to combinations of agents with Radium-223

 Since the biology of bone metastases limits the effectiveness of Rad-223 treatment, multiple combinations of Rad-223 and other agents are under investigation. As of this date there are 68 studies involving Rad-223 on the website ClinicalTrials.Gov. Examples, to note only a few:

Rad-223 w/wo chemotherapy; stereotactic radiation (CyberKnife) in hormone sensitive disease with < 3 metastases; combinations and sequencing of abiraterone or enzalutamide; Rad-223 with Provenge or with a checkpoint inhibitor; and in combination with a PARP inhibitor (i.e. Olaparib).

 BOTTOM LINE:

 Therapy with Radium-223 (Xofigo) prolongs survival. If employed earlier in mCRPC it is likely to perform even better. The current trend of investigation is to combine Radium-223 with other agents to more effectively treat prostate cancer metastatic to bone.

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