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.

Abstract

5007 Background: Skeletal fractures, pathological or not, are a frequent and underestimated side-effect of systemic treatment of metastatic castration resistant prostate cancer (mCRPC). The ERA223 trial (NCT02043678) 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. The question whether mandated use of bone protecting agents (BPA), zoledronic acid or denosumab, would have mitigated the fracture risk and whether this risk also exists in the enzalutamide/Ra223 combination is presently unknown. Methods: The phase III EORTC-1333-GUCG/PEACEIII (NCT02194842) trial compares enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic mCRPC patients (https://www.eortc.org/research_field/clinical-detail/1333/). After the unblinding of ERA223, the trial was amended (v4.0, April 19, 2018) to mandate that all patients must start a BPA. We report the fracture rate in the safety population of 146 treated patients as of 28/01/2019. Results: Overall, 54.2% of the patients in the enza/Ra223 arm and 51.4% of the enza arm did not receive BPA; 18.0% in the enza/Ra223 arm and 27.0% in the enza arm did not use BPA at randomization, but started during protocol treatment according to the v4.0 amendment. 27.8% and 21.6% respectively, received BPA as of randomization. In total, 45.8% of enza/Ra223 patients and 48.6% of enza only patients receive bone protection on treatment. The fracture rate is reported in the table. Conclusions: There is a 13% risk of fracture with enzalutamide in asymptomatic mCRPC, in line with previous reports. This risk is significantly increased to 33% when Ra223 is added to enzalutamide. 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. Clinical trial information: NCT02194842. [Table: see text]

Combination treatment in metastatic castration-resistant prostate cancer: can we safely boost efficacy by adding radium-223?

“…19 As a result, the cumulative risk of fracture at 12 months dropped to 0% in both treatment groups. 19 While the results of the PEACE III study have not been fully validated, it is striking that only one fracture has been observed since mandating OPA administration. 19 The decrease in fracture risk was not as dramatic in the ERA 223 trial, and many of the patients who sustained a fracture while receiving Ra-223 and AAP (21%) or AAP alone (24%) were also taking an OPA.…”

“…denosumab, zoledronic acid) in combination with Ra-223. 19 The use of OPAs in prostate cancer is not a new idea. In fact, a phase III study has examined the relative efficacies of denosumab, a RANKL inhibitor, and zoledronic acid, a bisphosphonate, in patients with prostate cancer, finding that denosumab was superior for the prevention of SREs.…”

“…15 Preliminary findings from the PEACE III trial, a multicenter, placebo-controlled, openlabel, randomized, phase III study examining co-treatment with Ra-223 and enzalutamide, demonstrated similar results to ERA 223, with patients in the co-treatment group experiencing a higher cumulative risk of fracture at 12 months than those receiving enzalutamide alone (37.4% vs. 12.4%). 19 Amendments to the PEACE III trial were implemented in response to the ERA 223 study, requiring patients in both treatment arms to receive continuous administration of denosumab or bisphosphonate beginning ≥ 6 weeks before the first dose of Ra-223. 19 As a result, the cumulative risk of fracture at 12 months dropped to 0% in both treatment groups.…”

“…19 Amendments to the PEACE III trial were implemented in response to the ERA 223 study, requiring patients in both treatment arms to receive continuous administration of denosumab or bisphosphonate beginning ≥ 6 weeks before the first dose of Ra-223. 19 As a result, the cumulative risk of fracture at 12 months dropped to 0% in both treatment groups. 19 While the results of the PEACE III study have not been fully validated, it is striking that only one fracture has been observed since mandating OPA administration.…”

“…19 While the results of the PEACE III study have not been fully validated, it is striking that only one fracture has been observed since mandating OPA administration. 19 The decrease in fracture risk was not as dramatic in the ERA 223 trial, and many of the patients who sustained a fracture while receiving Ra-223 and AAP (21%) or AAP alone (24%) were also taking an OPA. 15 The summation of these data further suggests the significance of glucocorticoid administration in the ERA 223 trial, and thus, Ra-223 with enzalutamide might prove to be the safer combination.…”