medwireNews: Combining radium-223 with abiraterone acetate plus prednisone or prednisolone is not recommended for patients with castration-resistant prostate cancer (CRPC) and bone metastases, ERA 223 researchers report.
They found that use of this combination did not improve symptomatic skeletal event-free survival (EFS) or overall survival (OS) and was associated with an increased fracture risk compared with placebo plus abiraterone acetate and prednisone or prednisolone.
“As a result of our findings, the US Food and Drug Administration and the European Medicines Agency have revised prescribing recommendations for radium-223,” Matthew Smith (Massachusetts General Hospital Cancer Center, Boston, USA) and ERA 223 (Evaluation of Radium-223 dichloride in combination with Abiraterone) co-investigators write in The Lancet Oncology.
The phase III trial included 806 participants from 19 countries who had progressive, chemotherapy-naïve, asymptomatic or mildly symptomatic CRPC and bone metastases, and a life expectancy of at least 6 months.
At a median follow-up of 21.2 months, 49% of 401 patients randomly assigned to receive up to six intravenous injections of radium-223 (55 kBq/kg) with concurrent oral abiraterone acetate 1000 mg once daily plus oral prednisone or prednisolone 5 mg twice daily had experienced at least one symptomatic skeletal event or died.
This compared with 47% of 405 patients given placebo alongside abiraterone acetate and prednisone or prednisolone group and corresponded to median symptomatic skeletal EFS times of 22.3 and 26.0 months in the radium-223 and placebo groups, respectively, a difference that was not statistically significant.
There was also no significant difference in median OS between the groups, at 30.7 months with radium-223 and 33.3 months with placebo.
There was, however, a higher rate of clinical fracture of any grade among the patients in the radium-223 groupthan among those in the placebo group, at 29% versus 11%, with most fractures outside of bone metastasis sites in both treatment groups.
This difference, along with a higher rate of early deaths in the radium-223 group reported in a previous analysis, led the study to be unblinded prematurely, the researchers note.
Serious treatment-emergent adverse events occurred in 41% of patients in the radium-223 group and 39% of those in the placebo group. There were also two treatment-related deaths, from acute myocardial infarction and interstitial lung disease, in the radium-223 group and one, from arrhythmia, in the placebo group.
“Although our results show that radium-223 should not be administered in combination with abiraterone acetate plus prednisone or prednisolone, radium-223 remains a treatment option for patients with bone-dominant, metastatic [CRPC] and disease progression after other appropriate therapies,” Smith et al conclude.
In a comment that accompanies the study, Daniel Spratt, from the University of Michigan in Ann Arbor, USA, discusses the potential reasons for an increased fracture risk with radium-223.
He says: “In the context of multifactorial insult to bone health from chronic chemical castration, abiraterone, glucocorticoids, low use of bone health agents (approximately 40% in both groups in ERA 223), and unknown use of preventative bone health measures (eg, weight-bearing exercise), radium-223 was possibly the final factor that increased the frequency of fractures in ERA 223.”
He adds: “The ERA 223 trial is an important example of why randomised trials are necessary, and early-access or post-marketing data should not be the sole source of safety information about the combination of approved therapies already on the market.”
Spratt concludes: “The results of trials assessing the benefit of radium-223 in combination with other agents are eagerly awaited to clarify whether such combination therapy can be both effective and safe.”
By Laura Cowen
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