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25-02-2019 | Castration-resistant prostate cancer | News

Combined radium-223, abiraterone acetate not endorsed for CRPC

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

medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group

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