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

Imagem de Miniatura
Arquivos
art_SMITH_Addition_of_radium223_to_abiraterone_acetate_and_prednisone_2019.PDF (844.64 KB)
Citações na Scopus
280
Tipo de produção
article
Data de publicação
2019
Editora
ELSEVIER SCIENCE INC
DOI
Indexadores
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Autores
SMITH, Matthew
PARKER, Chris
SAAD, Fred
MILLER, Kurt
TOMBAL, Bertrand
NG, Quan Sing
BOEGEMANN, Martin
MATVEEV, Vsevolod
PIULATS, Josep Maria
ZUCCA, Luis Eduardo
Autor de Grupo de pesquisa
Editores
Coordenadores
Organizadores
Citação
LANCET ONCOLOGY, v.20, n.3, p.408-419, 2019
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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.
Palavras-chave
URI
https://observatorio.fm.usp.br/handle/OPI/31071
Referências
  1. Beebe-Dimmer JL, 2012, PHARMACOEPIDEM DR S, V21, P70, DOI 10.1002/pds.2258
  2. Bliuc D, 2009, JAMA-J AM MED ASSOC, V301, P513, DOI 10.1001/jama.2009.50
  3. Carlin Bruce I., 2000, Cancer, V88, P2989, DOI 10.1002/1097-0142(20000615)88:12+<2989::AID-CNCR14>3.3.CO;2-H
  4. Coleman RE, 1997, CANCER, V80, P1588, DOI 10.1002/(SICI)1097-0142(19971015)80:8+<1588::AID-CNCR9>3.0.CO;2-G
  5. Cornford P, 2017, EUR UROL, V71, P630, DOI 10.1016/j.eururo.2016.08.002
  6. Cosman F, 2014, OSTEOPOROSIS INT, V25, P2359, DOI 10.1007/s00198-014-2794-2
  7. Eisenhauer EA, 2009, EUR J CANCER, V45, P228, DOI 10.1016/j.ejca.2008.10.026
  8. Fine JP, 1999, J AM STAT ASSOC, V94, P496, DOI 10.2307/2670170
  9. Hoskin P, 2014, LANCET ONCOL, V15, P1397, DOI 10.1016/S1470-2045(14)70474-7
  10. Mohler JL, 2018, PROSTATE CANC VERSIO
  11. Morote J, 2007, UROLOGY, V69, P500, DOI 10.1016/j.urology.2006.11.002
  12. Nilsson S, 2016, ANN ONCOL, V27, P868, DOI 10.1093/annonc/mdw065
  13. Parker C, 2013, NEW ENGL J MED, V369, P213, DOI 10.1056/NEJMoa1213755
  14. Parker C, 2016, EUR UROL, V70, P875, DOI 10.1016/j.eururo.2016.06.002
  15. Parker CC, 2018, EUR UROL, V73, P427, DOI 10.1016/j.eururo.2017.06.021
  16. Rachner TD, 2018, LANCET DIABETES ENDO, V6, P901, DOI 10.1016/S2213-8587(18)30047-0
  17. Ryan CJ, 2013, NEW ENGL J MED, V368, P138, DOI 10.1056/NEJMoa1209096
  18. Saad F, 2016, LANCET ONCOL, V17, P1306, DOI 10.1016/S1470-2045(16)30173-5
  19. Saad F, 2008, J CLIN ONCOL, V26, P5465, DOI 10.1200/JCO.2008.18.4184
  20. Scher HI, 2008, J CLIN ONCOL, V26, P1148, DOI 10.1200/JCO.2007.12.4487
  21. Stein MN, 2014, ASIAN J ANDROL, V16, P387, DOI 10.4103/1008-682X.129133
  22. Suominen MI, 2017, CLIN CANCER RES, V23, P4335, DOI 10.1158/1078-0432.CCR-16-2955
  23. Unnanuntana A, 2010, J BONE JOINT SURG AM, V92A, P743, DOI [10.2106/JBJS.I.00919, 10.2106/J8JS.I.00919]

Coleções
Artigos e Materiais de Revistas Científicas - FM/MCG
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/55
Artigos e Materiais de Revistas Científicas - ODS/03