Combining abiraterone acetate with radium-223 not recommended as first-line therapy for metastatic castration-resistant prostate cancer patients with bone metastases
Results of the randomised, phase III ERA 223 trial indicate that combining abiraterone acetate and prednisone/prednisolone (AAP) with radium-223 does not delay the time to the occurrence of a symptomatic skeletal event (SSE) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Also with respect to overall survival (OS), the combination of AAP and radium-223 did not provide a benefit compared to AAP and placebo. Moreover, the combination therapy was shown to be associated with a higher rate of clinical fractures than what was seen with AAP and placebo. As such, these data do not support the concurrent use of AAP and radium-223 in the upfront management of mCRPC patients with bone metastases.
ERA 223 is a phase 3, double-blind, placebo-controlled trial in which 806 asymptomatic, or mildly symptomatic men with chemotherapy-naïve mCRPC and bone metastases were randomised (1:1) to AAP (AA 1,000 mg qd and P 5 mg bid) + radium-223 (55 kBq/kg IV every 4 weeks for 6 cycles) or AAP + matching placebo. The choice to combine AAP with radium-223 was backed by the fact that both agents have non-overlapping toxicity profiles and by data from a post-hoc analyses of an international, early-access, open-label phase 3b study suggesting a survival benefit with radium-223 plus AAP or enzalutamide vs. radium-223 alone. The primary endpoint of ERA 223 was SSE free survival (SSE-FS), with OS, radiographic progression-free survival (rPFS), time to chemotherapy, time to opiate use for cancer-related pain and safety as secondary objectives. For this analysis, SSE was defined as the use of external-beam radiation therapy (EBRT) to relieve skeletal symptoms, new symptomatic pathological bone fractures, spinal cord compression, or a tumour-related orthopaedic surgical intervention. Bone health agents (BHAs, either bisphosphonates or denosumab) were only allowed in patients receiving them at baseline.
The median age of patients in the study was 71 years, 70% were Caucasian and 60% of patients had a Gleason score of 8 or more at diagnosis. Two thirds of patients had more than 5 bone metastases and approximately 40% were receiving BHAs at baseline. The trial was unblinded early after more fractures and deaths were observed in the AAP + radium-223 arm. Importantly, all patients had completed the study-specified radium-223/placebo treatment prior to this unblinding.
The median SSE-FS was reported at 22.3 months with AAP + radium-223 as compared to 26.0 months with AAP + placebo (HR[95%CI]: 1.122[0.917−1.374]; p= 0.2636). Also the OS did not differ significantly between the two treatment groups with a median OS of 30.7 months with AAP + radium-223 and 33.3 months with AAP + placebo (HR[95%CI]: 1.195[0.950−1.505; p=0.1280). Looking at the secondary efficacy endpoints, no differences were seen between both arms. However, a striking difference was observed in the rate of pathological fractures. In fact, AAP + radium-223 was found to be associated with a 29% fracture rate, which was much higher than the 11% fracture rate seen with AAP and placebo. The incidence of grade 3/4 fractures with AAP + radium-223 was 9.3% as compared to 3% with AAP and placebo. This difference in fracture rate in favour of the control arm was seen in both patients without BHA use at baseline as in patients who did use these agents. However, the incidence of fractures was much lower in the subgroup of patients who did use BHAs at baseline (Fracture rates with AAP + radium-223 vs. AAP + placebo in non-BHA patients: 37% vs. 15%. Fracture rates with AAP + radium-223 vs. AAP + placebo in BHA patients 15% vs. 7%).
In summary, concurrent AAP + radium-223 did not improve the SSE-FS or OS and led to a higher fracture rate. As such, these data do not support the combination of AAP and radium-223 as first-line treatment for mCRPC patients with bone metastases. In addition, this trial underlines the fact that bone health needs more attention in the management of mCRPC patients. This is clearly illustrated by the substantially lower fracture rates in patients who were using BHAs at baseline, irrespective of the treatment regimen that was used.
Smith M, Parker C, Saad F, et al. A phase 3 trial of radium-223 (Ra-223) in combination with abiraterone acetate and prednisone/prednisolone for the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients (pts) with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). Presented at ESMO 2018; Abstract LBA30.