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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 - 03/03/19

Doi : 10.1016/S1470-2045(18)30860-X 
Matthew Smith, ProfMD a, , Chris Parker, ProfMD b, Fred Saad, ProfMD c, Kurt Miller, ProfMD d, Bertrand Tombal, ProfMD e, Quan Sing Ng, MD f, Martin Boegemann, ProfMD g, Vsevolod Matveev, ProfDmedSc h, Josep Maria Piulats, MD i, Luis Eduardo Zucca, MD j, Oleg Karyakin, ProfMD k, Go Kimura, MD l, Nobuaki Matsubara, MD m, William Carlos Nahas, ProfMD n, Franco Nolè, MD o, Eli Rosenbaum, MD p, Axel Heidenreich, ProfMD q, Yoshiyuki Kakehi, ProfMD r, Amily Zhang, MD s, Heiko Krissel, MD t, Michael Teufel, PhD s, Junwu Shen, PhD s, Volker Wagner, MD u, Celestia Higano, ProfMD v
a Massachusetts General Hospital Cancer Center, Boston, MA, USA 
b Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, UK 
c University of Montreal Hospital Center, Montreal, QC, Canada 
d Charité Berlin, Berlin, Germany 
e Cliniques Universitaires Saint-Luc, Brussels, Belgium 
f National Cancer Centre Singapore, Singapore 
g University of Muenster Medical Center, Muenster, Germany 
h N N Blokhin Cancer Research Center, Moscow, Russia 
i Catalan Cancer Institute, IDIBELL, CIBERONC, Barcelona, Spain 
j Barretos Cancer Hospital, Barretos, Brazil 
k Medical Radiological Research Center, Kaluga, Russia 
l Nippon Medical School Hospital, Tokyo, Japan 
m National Cancer Center Hospital East, Chiba, Japan 
n Instituto Do Cancer Do Estado De Sao Paulo, Sao Paulo, Brazil 
o IEO, Istituto Europeo di Oncologia, IRCCS, Milan, Italy 
p Rabin Medical Center Davidoff Center, Petach-Tikva, Israel 
q University Hospital Cologne, Cologne, Germany 
r Kagawa University, Kagawa, Japan 
s Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA 
t Bayer, Berlin, Germany 
u Bayer Consumer Care, Basel, Switzerland 
v University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, USA 

* Correspondence to: Prof Matthew Smith, Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA Massachusetts General Hospital Cancer Center Boston MA 02114 USA

Summary

Background

Abiraterone acetate plus prednisone or prednisolone improves progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. Radium-223 improves overall survival and delays the onset of symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases. We assessed concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 in such patients.

Methods

We did a randomised, double-blind, placebo-controlled, phase 3 trial at 165 oncology and urology centres in 19 countries. Eligible patients were aged 18 years or older, and had histologically confirmed, progressive, chemotherapy-naive, asymptomatic or mildly symptomatic castration-resistant prostate cancer and bone metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 6 months, and adequate haematological, renal, and liver function. Participants were randomly assigned (1:1) according to a permuted block design (block size 4) via interactive response technology to receive up to six intravenous injections of radium-223 (55 kBq/kg) or matching placebo once every 4 weeks. All patients were also scheduled to receive oral abiraterone acetate 1000 mg once daily plus oral prednisone or prednisolone 5 mg twice daily during and after radium-223 or placebo treatment. The primary endpoint was symptomatic skeletal event-free survival, which was assessed in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov, number NCT02043678. Enrolment has been completed, and follow-up is ongoing.

Findings

Between March 30, 2014, and Aug 12, 2016, 806 patients were randomly assigned to receive radium-223 (n=401) or placebo (n=405) in addition to abiraterone acetate plus prednisone or prednisolone. The study was unblinded prematurely, on Nov 17, 2017, after more fractures and deaths were noted in the radium-223 group than in the placebo group (in an unplanned ad-hoc analysis), but all patients had completed radium-223 or placebo before this date. At the primary analysis (data cutoff Feb 15, 2018), 196 (49%) of 401 patients in radium-223 group had had at least one symptomatic skeletal event or died, compared with 190 (47%) of 405 patients in the placebo group (median follow-up 21·2 months [IQR 17·0–25·8]). Median symptomatic skeletal event-free survival was 22·3 months (95% CI 20·4–24·8) in the radium-223 group and 26·0 months (21·8–28·3) in the placebo group (hazard ratio 1·122 [95% CI 0·917–1·374]; p=0·2636). Fractures (any grade) occurred in 112 (29%) of 392 patients in the radium-223 group and 45 (11%) of 394 patients in the placebo group. The most common grade 3–4 treatment-emergent adverse events were hypertension (43 [11%] patients in the radium-223 group vs 52 [13%] patients in the placebo group), fractures (36 [9%] vs 12 [3%]) and increased alanine aminotransferase concentrations (34 [9%] vs 28 [7%]). Serious treatment-emergent adverse events occurred in 160 (41%) patients in the radium-223 group and 155 (39%) in the placebo group. Treatment-related deaths occurred in two (1%) patients in the radium-223 group (acute myocardial infarction and interstitial lung disease) and one (<1%) in the placebo group (arrhythmia).

Interpretation

The addition of radium-223 to abiraterone acetate plus prednisone or prednisolone did not improve symptomatic skeletal event-free survival in patients with castration-resistant prostate cancer and bone metastases, and was associated with an increased frequency of bone fractures compared with placebo. Thus, we do not recommend use of this combination.

Funding

Bayer.

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Vol 20 - N° 3

P. 408-419 - mars 2019 Retour au numéro
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