ERA 223: A phase 3 trial of radium-223 (Ra-223) in combination with abiraterone acetate and prednisone/prednisolone for the treatment of asymptomat...

Date 19 October 2018
Event ESMO 2018 Congress
Session Proffered paper session - Genitourinary tumours, prostate
Topics Anticancer Agents
Prostate Cancer
Radiation Oncology
Presenter Matthew Smith
Authors M.R. Smith1, C.C. Parker2, F. Saad3, K. Miller4, B. Tombal5, Q.S. Ng6, M. Bögemann7, V. Matveev8, J.M. Piulats9, L.E. Zucca10, A. Heidenreich11, Y. Kakehi12, A. Zhang13, H. Krissel14, J. Shen15, V. Wagner16, C. Higano17
  • 1Department Of Oncology, Massachusetts General Hospital, 2114 - Boston/US
  • 2Department Of Urology, The Institute of Cancer Research/Royal Marsden NHS Foundation Trust, SM2 5PT - Sutton/GB
  • 3Department Of Urology, University of Montreal Hospital Center (CHUM), H2X 3J4 - Montreal/CA
  • 4Department Of Medical Oncology, Charité Berlin, Berlin/DE
  • 5Department Of Urology, Cliniques Universitaires St. Luc, 1200 - Brussels/BE
  • 6Division Of Medical Oncology, National Cancer Centre Singapore, Singapore/SG
  • 7Department Of Clinical Oncology (urology), University of Muenster Medical Center, Muenster/DE
  • 8Department Of Urology, N.N. Blokhin Cancer Research Center, Moscow/RU
  • 9Department Of Medical Oncology, Catalan Cancer Institute, Barcelona/ES
  • 10Department Of Medical Oncology, Barretos Cancer Hospital, Barretos/BR
  • 11Department Of Urology, University Hospital Cologne, Cologne/DE
  • 12Department Of Urology, Kagawa University, Kagawa/JP
  • 13Oncology, Bayer HealthCare Pharmaceuticals, Whippany/US
  • 14Oncology, Bayer AG, Berlin/DE
  • 15Clinical Statistics, Bayer HealthCare Pharmaceuticals, Whippany/US
  • 16Oncology, Bayer Consumer Care AG, Basel/CH
  • 17Department Of Medical Oncology, University of Washington and Fred Hutchinson Cancer Research Center, Seattle/US

Abstract

Background

Abiraterone acetate and prednisone/prednisolone (AAP) improves progression-free survival and overall survival (OS) in men with mCRPC. Ra-223 increases OS and decreases symptomatic skeletal events (SSEs) in men with mCRPC and bone metastases. We evaluated concurrent treatment with AAP and Ra-223.

Methods

This phase 3, double-blind, placebo (PBO)-controlled trial randomised asymptomatic/mildly symptomatic men with chemotherapy-naïve mCRPC and bone metastases in a 1:1 ratio of AAP + Ra-223 or AAP + PBO. Bone health agents (BHAs [bisphosphonates or denosumab]) were only allowed in pts receiving them at baseline. The primary endpoint was SSE-free survival (SSE-FS).

Results

806 pts were randomised (401 to AAP + Ra-223; 405 to AAP + PBO); 39% and 42% of pts were receiving BHAs at baseline in the AAP + Ra-223 and AAP + PBO arms, respectively. The trial was unblinded early after more fractures and deaths were observed in the AAP + Ra-223 arm. All pts had completed study-specified Ra-223/PBO treatment prior to unblinding. At the primary analysis, median SSE-FS was 22.3 mo (95% CI 20.4−24.8) with AAP + Ra-223 and 26.0 mo (95% CI 21.8−28.3) with AAP + PBO (HR 1.122, 95% CI 0.917−1.374; p=0.2636). Median OS was 30.7 mo (95% CI 25.8−not estimable) with AAP + Ra-223 and 33.3 mo (95% CI 30.2−41.1) with AAP + PBO (HR 1.195, 95% CI 0.950−1.505; p=0.1280). Other secondary/exploratory endpoints are shown in the Table. Fractures occurred in 29% and 11% of pts in the AAP + Ra-223 and AAP + PBO arms, respectively. In pts receiving BHAs, 15% and 7% experienced a fracture in the AAP + Ra-223 and AAP + PBO arms, respectively, vs 37% and 15% without BHAs.

AAP + Ra-223
N=401
AAP + PBO
N=405
HR (95% CI)
Additional secondary endpoints
rPFS (central review), median (95% CI), months 11.2 (9.1–11.8) 12.4 (10.8–14.5) 1.152 (0.960–1.383)
Time to cytotoxic chemotherapy, median (95% CI), months 29.5 (26.5–35.7) 28.5 (23.7–NE) 1.033 (0.816–1.308)
Time to opiate use for cancer pain, median (95% CI), months 19.0 (14.4–23.2) 22.6 (18.0–25.7) 1.126 (0.921–1.378)
Exploratory endpoints
Overall confirmed PSA response, n/N (%) 287/396 (72) 267/401 (67)
Time to PSA progression, median (95% CI), months 9.6 (8.2–10.8) 9.0 (7.9–10.1) 0.937 (0.792–1.108)
Overall confirmed ALP response, n/N (%) 218/398 (55) 104/402 (26)
Time to ALP progression, median (95% CI), months 7.4 (7.1–7.9) 6.8 (5.3–8.4) 1.083 (0.918–1.276)
Time to deterioration in health-related quality of life*,
median (95% CI), months
9.5 (6.9–12.0) 10.5 (8.3–13.0) 1.079 (0.865–1.345)
*As reported in the safety population (AAP + Ra-223 N=392, AAP + PBO N=394) using the NCCN-FACT FPSI-17 physical disease-related symptoms subscale score measured during the treatment period. ALP: alkaline phosphatase; NE: not estimable; PSA: prostate-specific antigen; rPFS: radiological progression-free survival.

Conclusions

Concurrent AAP + Ra-223 treatment did not improve SSE-FS or OS and led to a higher fracture rate. Based on these results, we do not recommend Ra-223 in combination with AAP.

Clinical trial identification

NCT02043678

Editorial Acknowledgement

Medical writing support was provided by Michael Sheldon, PhD, of Scion, London, UK, funded by Bayer