Chicago, Illinois—Risk for fracture significantly increases when Ra223 is added to enzalutamide in the treatment of asymptomatic patients with metastatic castration resistant prostate cancer (mCRPC), requiring the use of bone-protecting agents (BPAs), according to data presented at the 2019 ASCO Annual Meeting.

“Skeletal fractures, pathological or not, are a frequent and underestimated side-effect of systemic treatment of [mCRPC],” explained lead investigator Bertrand F. Tombal, MD, PhD, Université Catholique de Louvain, Brussels, Belgium, and colleagues.

“The ERA223 trial…was recently unblinded following the report of a significant increase in the fracture rates when abiraterone is combined with Ra223. Hence, FDA and EMA advised against this combination,” they continued.

Thus, the question arose about whether the authorized use of BPAs (zoledronic acid or denosumab) could alleviate fracture risk. In addition, it is currently unknown whether this risk exists with the use of enzalutamide plus Ra223.

EORTC-1333-GUCG/PEACEIII, the phase 3 study by Dr Tombal et al, compared the use of enzalutamide monotherapy with that of a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic patients with mCRPC.

Following the unblinding of ERA223, the EORTC-1333-GUCG/PEACEIII trial was amended to include that all patients must be initiated with a BPA. In the data presented at ASCO 2019, Dr Tombal and his co-investigators reported the fracture rate in the safety population of 146 treated patients.

In total, 54.2% and 51.4% of patients in the enzalutamide plus Ra223 arm and enzalutamide-alone arm did not receive a BPA. However, 18.0% in the enzalutamide plus Ra223 arm and 27.0% in the enzalutamide-alone arm did not use BPAs at randomization, but began using them according to the trial amendment; in each arm, 27.8% and 21.6% of patients received BPA as of randomization, respectively.

Overall, 45.8% of patients receiving enzalutamide plus Ra223 and 48.6% of patients receiving enzalutamide-alone received bone protection at treatment.

Findings demonstrated a 13% risk for fracture with enzalutamide alone in asymptomatic patients with mCRPC, which matched previous study findings. This risk, however, was significantly increased to 33% when Ra223 was added to enzalutamide therapy.

“Strikingly, the risk is almost abolished by mandatory continuous administration of BPA starting at least 6 weeks before the first injection of Ra223, thus emphasizing the importance of treating mCRPC patients with BPA,” Dr Tombal et al concluded.—Hina Khaliq

Tombal BF, Loriot Y, Saad F, et al. 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. Presented at: the 2019 ASCO Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 5007.