Universität zu Köln

Smith, Matthew, Parker, Chris, Saad, Fred, Miller, Kurt, Tombal, Bertrand, Ng, Quan Sing, Boegemann, Martin, Matveev, Vsevolod, Piulats, Josep Maria, Zucca, Luis Eduardo, Karyakin, Oleg, Kimura, Go ORCID: 0000-0003-0088-9324, Matsubara, Nobuaki, Nahas, William Carlos, Nole, Franco, Rosenbaum, Eli, Heidenreich, Axel, Kakehi, Yoshiyuki, Zhang, Amity, Krissel, Heiko, Teufel, Michael, Shen, Junwu, Wagner, Volker and Higano, Celestia (2019). 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. Lancet Oncol., 20 (3). S. 408 - 420. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1474-5488

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Abstract

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. Copyright (c) 2019 Elsevier Ltd. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Smith, Matthew UNSPECIFIED UNSPECIFIED UNSPECIFIED Parker, Chris UNSPECIFIED UNSPECIFIED UNSPECIFIED Saad, Fred UNSPECIFIED UNSPECIFIED UNSPECIFIED Miller, Kurt UNSPECIFIED UNSPECIFIED UNSPECIFIED Tombal, Bertrand UNSPECIFIED UNSPECIFIED UNSPECIFIED Ng, Quan Sing UNSPECIFIED UNSPECIFIED UNSPECIFIED Boegemann, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Matveev, Vsevolod UNSPECIFIED UNSPECIFIED UNSPECIFIED Piulats, Josep Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Zucca, Luis Eduardo UNSPECIFIED UNSPECIFIED UNSPECIFIED Karyakin, Oleg UNSPECIFIED UNSPECIFIED UNSPECIFIED Kimura, Go UNSPECIFIED orcid.org/0000-0003-0088-9324 UNSPECIFIED Matsubara, Nobuaki UNSPECIFIED UNSPECIFIED UNSPECIFIED Nahas, William Carlos UNSPECIFIED UNSPECIFIED UNSPECIFIED Nole, Franco UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosenbaum, Eli UNSPECIFIED UNSPECIFIED UNSPECIFIED Heidenreich, Axel UNSPECIFIED UNSPECIFIED UNSPECIFIED Kakehi, Yoshiyuki UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Amity UNSPECIFIED UNSPECIFIED UNSPECIFIED Krissel, Heiko UNSPECIFIED UNSPECIFIED UNSPECIFIED Teufel, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Shen, Junwu UNSPECIFIED UNSPECIFIED UNSPECIFIED Wagner, Volker UNSPECIFIED UNSPECIFIED UNSPECIFIED Higano, Celestia UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-155682
DOI:	10.1016/S1470-2045(18)30860-X
Journal or Publication Title:	Lancet Oncol.
Volume:	20
Number:	3
Page Range:	S. 408 - 420
Date:	2019
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1474-5488
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ANDROGEN DEPRIVATION THERAPY; DICHLORIDE; FRACTURE; EFFICACY; SAFETY; RISK; MEN Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15568