On May 31, 2019 Interim results from the EORTC 1333/PEACE phase III trial were reported at ASCO (Free ASCO Whitepaper) 2019 annual meeting in Chicago, USA (Press release, EORTC, MAY 31, 2019, View Source [SID1234536753]). This phase III study evaluates the benefit of combine Radium-233 (Ra-233) to enzalutamide in early asymptomatic or mildly symptomatic. The trial was amended, following the publications of the ERA223, to impose the co-administration bone protecting agents such as zoledronic acid or denosumab. The safety analysis of 146 patients with or without the addition of these agents was shown.

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Ra-223, enzalutamide, and abiraterone are the cornerstone modern treatment of mCRPC. They are usually used sequentially, enzalutamide and abiraterone being used usually in asymptomatic or mildly-symptomatic patients and Ra-223 being prescribed when the patients become more symptomatic from bone metastases. There is a strong rationale for combined RA-223 earlier with abiraterone or enzalutamide. Two trials were thus conducted: the ERA223 trial1 comparing the combination of RA-223 and abiraterone to abiraterone only and the EORTC-GUCG-1333(PEACE 3) trial comparing the combination of enzalutamide and RA-233 to enzalutamide alone. The ERA 223 was unfortunately unblinded in December 2017 following the demonstration of a significant increase of the risk of fracture and death in the RA-223/abiraterone combination arm.

It was recommended not to use this combination. Following these results, the ESMO (Free ESMO Whitepaper) clinical guidelines were adapted to include that mCRPC patients treated with Ra233 must also be given bone-protecting agents. In the EORTC 1333/PEACE phase III trial, it was seen that this guideline was not followed; therefore when the ERA trial was unblinded an amendment was made to enforce the use of bone protecting agents.

Overall, so far, 45% of the patients were treated without bone protecting agents and their median follow-up is 20 months, and 55% were treated with bone protection. The median follow-up of this group is only 13 months. At one year, the there was a 12.4% cumulative risk of fracture with enzalutamide that increased to 37.4% when Ra223 is added to enzalutamide. However, with mandatory continuous administration of bone protecting agents starting at least 6 weeks before the first injection of Ra223, the cumulative risk at one year was almost abolished with 0 fractures on enzalutamide alone and 2.2% with the combination.

"This safety analysis confirms the importance of complying to international recommendations when treating mCRPC patients, and especially about the importance of preventing skeletal complications in patients with bone metastases," says Professor Bertrand Tombal, leading investigator and urologist from Cliniques Universitaires Saint-Luc in Brussels, Belgium.

"These early results strongly suggest that the risk of fractures is very well controlled in both arms when patients receive bone-protecting agents. The study is closely monitored as recruitment and follow-up continues," says Laurence Collette, leading study statistician and Head of the Statistics Department, EORTC Headquarters, Brussels, Belgium

Abstract number: #5007: Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone; an interim safety analysis.

Bertrand F. Tombal, Yohann Loriot, Fred Saad, Raymond S. McDermott, Tony Elliott, Alejo Rodriguez Vida, Franco Nole, Beatrice Fournier, Laurence Collette, Silke Gillessen

1Smith, M. et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol; 20: 408–19 (2019).