Clinical trial NCT02043678: Radium-223 Dichloride and Abiraterone Acetate Compared to Placebo and Abiraterone Acetate for Men With Cancer of the Prostate When Medical or Surgical Castration Does Not Work and When the Cancer Has Spread to the Bone, Has Not Been Treated With Chemotherapy and is Causing no or Only Mild Symptoms
Official title: A Phase III Randomized, Double-blind, Placebo-controlled Trial of Radium-223 Dichloride in Combination With Abiraterone Acetate and Prednisone/Prednisolone in the Treatment of Asymptomatic or Mildly Symptomatic Chemotherapy-naïve Subjects With Bone Predominant Metastatic Castration-resistant Prostate Cancer(CRPC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Prostatic Neoplasms
Keywords: Phase III
Radium-223 dichloride
Abiraterone acetate
Combination therapy
Chemotherapy-naive
Bone metastasis
Castration-resistant prostate cancer (CRPC)
Lead sponsor: Bayer
Sponsor class: INDUSTRY
Collaborators: name: Janssen Research & Development, LLC
First posted: 2014-01-23
Enrollment: 806
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To determine if the addition of radium-223 dichloride to standard treatment is able to prolong life and to delay events specific for prostate cancer which has spread to the bone, such as painful fractures or bone pain which needs to be treated with an X-ray machine.

Detailed description: This study is a phase III multinational, multicenter,randomized, double blind, placebo controlled, study with a randomization allocation ratio of 1:1 (radium-223 dichloride plus abiraterone acetate plus prednisone/prednisolone: placebo plus abiraterone acetate plus prednisone/prednisolone). Until the final overall survival (OS) analysis, the study period consisted of screening / randomization, treatment, active follow-up with clinic visits, active follow-up without clinic visits, and longterm follow-up phases. Up until this point, subjects received study treatment (radium-223 dichloride or placebo in addition to abiraterone acetate plus prednisone / prednisolone for the first 6 cycles followed by abiraterone acetate plus prednisone / prednisolone thereafter) until an on-study SSE occurred (or other withdrawal criteria were met). After the final OS analysis (after implementation of Amendment 7), in order to reduce the burden to study subjects, evaluation of efficacy and exploratory endpoints will be discontinued, except for symptomatic skeletal event (SSE) and OS. Subjects who are discontinued from study treatment will initiate the long-term follow-up period; therefore, active follow-up periods will no longer be applicable. Subjects who are in active follow-up at the time of Amendment 7 is implemented should have the end of active follow-up completed (protocol driven decision) and should be directly transitioned into the extended safety follow-up study. Long term follow-up will continue until the subject dies, is lost to follow-up, withdraws informed consent, actively objects to collection of further data , or is transitioned to the extended safety follow-up study. Subjects will be followed for safety for up to 7 years, which eventually will be completed in this study or in the extended safety follow-up study.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed adenocarcinoma of the prostate
* Male subjects of age ≥ 18 years
* Prostate cancer progression documented by prostate specific antigen (PSA) according to the Prostate Cancer Working Group 2 (PCWG2) criteria or radiological progression according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1
* Two or more bone metastases on bone scan within 4 weeks prior to randomization with no lung, liver, other visceral and/or brain metastasis
* Asymptomatic or mildly symptomatic prostate cancer
* Subjects who received combined androgen blockade with an anti-androgen must have shown PSA progression after discontinuing the anti-androgen prior to enrollment
* Maintenance of medical castration or surgical castration with testosterone less than 50 ng/dL (1.7nmol/L)
* Eastern Cooperative Oncology Group performance status (ECOG PS) score 0 or 1

Exclusion Criteria:

* Prior cytotoxic chemotherapy for the treatment of CRPC, including taxanes, mitoxantrone and estramustine
* Any chronic medical condition requiring a higher dose of corticosteroid than 5 mg prednisone/prednisolone twice daily
* Pathological finding consistent with small cell carcinoma of the prostate
* History of visceral metastasis, or presence of visceral metastasis detected by screening imaging examinations
* History of or known brain metastasis
* Malignant lymphadenopathy exceeding 3 cm in short-axis diameter
* Blood transfusion or erythropoietin stimulating agents prior 4 weeks of screening and during the whole screening period before randomization
* Imminent spinal cord compression based on clinical findings and/or magnetic resonance imaging (MRI). Subjects with history of spinal cord compression should have completely recovered
* Use of opiate analgesics for cancer-related pain, including codeine and dextropropoxyphene, currently or anytime during the 4- week period prior to randomization.

Primary outcomes:
measure: Symptomatic Skeletal Event Free Survival (SSE-FS)
timeFrame: From randomization until first onset of on-study symptomatic skeletal event (SSE) or death, up to 47 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From randomization until death from any cause, up to 67 months
measure: Radiological Progression Free Survival (rPFS)
timeFrame: From randomization until the date of confirmed radiological progression or death, up to 47 months
measure: Time to Pain Progression
timeFrame: From randomization until the date of pain progression based on pain score, up to 47 months
measure: Time to Cytotoxic Chemotherapy
timeFrame: From randomization until the date of first cytotoxic chemotherapy, up to 47 months
measure: Time to Opiate Use for Cancer Pain
timeFrame: From randomization until the date of opiate use, up to 47 months
measure: Number of Participants With Treatment-emergent Adverse Events
timeFrame: From start of study treatment until the end of the treatment period, up to 110 months
measure: Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity
timeFrame: From start of study treatment until the end of the treatment period, up to 110 months
measure: Number of Participants With Any Treatment-emergent Additional Primary Malignancies
timeFrame: From start of study treatment until the end of the treatment period, up to 110 months
measure: Number of Participants With Treatment-emergent Bone Fractures
timeFrame: From start of study treatment until the end of the treatment period, up to 110 months
measure: Number of Participants With Post-treatment Adverse Events
timeFrame: After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up
measure: Number of Participants With Any Study Drug-related Post-treatment Adverse Events Per Maximum Intensity
timeFrame: After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up
measure: Number of Participants With Post-treatment Additional Primary Malignancies
timeFrame: After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up
measure: Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders
timeFrame: After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up
measure: Number of Participants With Post-treatment Bone Fractures
timeFrame: After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up
Other outcomes:
Locations:
city: Anchorage
country: United States
state: Alaska
city: Tucson
country: United States
state: Arizona
city: Oceanside
country: United States
state: California
city: Denver
country: United States
state: Colorado
city: Washington
country: United States
state: District of Columbia
city: Fort Myers
country: United States
state: Florida
city: Atlanta
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state: Georgia
city: Jeffersonville
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state: Indiana
city: New Orleans
country: United States
state: Louisiana
city: Baltimore
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state: Maryland
city: Rockville
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state: Maryland
city: Towson
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state: Maryland
city: Boston
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state: Massachusetts
city: Burlington
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state: Massachusetts
city: Detroit
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state: Michigan
city: Traverse City
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state: Michigan
city: Saint Louis
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state: Missouri
city: Omaha
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state: Nebraska
city: Las Vegas
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state: Nevada
city: Hackensack
country: United States
state: New Jersey
city: Poughkeepsie
country: United States
state: New York
city: Syracuse
country: United States
state: New York
city: Bala-Cynwyd
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Pittsburgh
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state: Pennsylvania
city: Norfolk
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state: Virginia
city: Seattle
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state: Washington
city: Spokane
country: United States
state: Washington
city: Wheeling
country: United States
state: West Virginia
city: St Leonards
country: Australia
state: New South Wales
city: Sydney
country: Australia
state: New South Wales
city: Adelaide
country: Australia
state: South Australia
city: East Bentleigh
country: Australia
state: Victoria
city: Fitzroy
country: Australia
state: Victoria
city: Heidelberg
country: Australia
state: Victoria
city: East Melbourne
country: Australia
city: Randwick
country: Australia
city: Bruxelles - Brussel
country: Belgium
city: Bruxelles
country: Belgium
city: Edegem
country: Belgium
city: Gent
country: Belgium
city: Belo Horizonte
country: Brazil
state: Minas Gerais
city: Porto Alegre
country: Brazil
state: Rio Grande Do Sul
city: Barretos/SP
country: Brazil
state: Sao Paulo
city: São Paulo
country: Brazil
state: Sao Paulo
city: Sao Paulo
country: Brazil
city: Calgary
country: Canada
state: Alberta
city: Vancouver
country: Canada
state: British Columbia
city: Winnipeg
country: Canada
state: Manitoba
city: Hamilton
country: Canada
state: Ontario
city: Ottawa
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Montreal
country: Canada
state: Quebec
city: Québec
country: Canada
state: Quebec
city: Helsinki
country: Finland
city: Kuopio
country: Finland
city: Seinäjoki
country: Finland
city: Tampere
country: Finland
city: Besancon
country: France
city: Bordeaux Cedex
country: France
city: Paris
country: France
city: Paris
country: France
city: Poitiers
country: France
city: Saint-Herblain
country: France
city: Toulouse Cedex 9
country: France
city: Ulm
country: Germany
state: Baden-Württemberg
city: München
country: Germany
state: Bayern
city: Marburg
country: Germany
state: Hessen
city: Münster
country: Germany
state: Nordrhein-Westfalen
city: Dresden
country: Germany
state: Sachsen
city: Jena
country: Germany
state: Thüringen
city: Berlin
country: Germany
city: Afula
country: Israel
city: Beer Sheva
country: Israel
city: Haifa
country: Israel
city: Jerusalem
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city: Kfar Saba
country: Israel
city: Petach Tikva
country: Israel
city: Ramat Gan
country: Israel
city: Tel Aviv
country: Israel
city: Zerifin
country: Israel
city: Modena
country: Italy
state: Emilia-Romagna
city: Roma
country: Italy
state: Lazio
city: Roma
country: Italy
state: Lazio
city: Genova
country: Italy
state: Liguria
city: Milano
country: Italy
state: Lombardia
city: Milano
country: Italy
state: Lombardia
city: Cagliari
country: Italy
state: Sardegna
city: Cortona
country: Italy
state: Toscana
city: Trento
country: Italy
state: Trentino-Alto Adige
city: Nagoya
country: Japan
state: Aichi
city: Hirosaki
country: Japan
state: Aomori
city: Chiba-shi
country: Japan
state: Chiba
city: Kashiwa
country: Japan
state: Chiba
city: Matsuyama
country: Japan
state: Ehime
city: Sapporo
country: Japan
state: Hokkaido
city: Kobe
country: Japan
state: Hyogo
city: Tsukuba
country: Japan
state: Ibaraki
city: Kanazawa
country: Japan
state: Ishikawa
city: Kita-gun
country: Japan
state: Kagawa
city: Yokohama
country: Japan
state: Kanagawa
city: Yokohama
country: Japan
state: Kanagawa
city: Sendai
country: Japan
state: Miyagi
city: Matsumoto
country: Japan
state: Nagano
city: Kurashiki
country: Japan
state: Okayama
city: Okayama-city
country: Japan
state: Okayama
city: Sayama
country: Japan
state: Osaka
city: Hamamatsu
country: Japan
state: Shizuoka
city: Bunkyo-Ku
country: Japan
state: Tokyo
city: Bunkyo-ku
country: Japan
state: Tokyo
city: Koto-ku
country: Japan
state: Tokyo
city: Shinjuku-ku
country: Japan
state: Tokyo
city: Ube
country: Japan
state: Yamaguchi
city: Chiba
country: Japan
city: Fukuoka
country: Japan
city: Fukuoka
country: Japan
city: Kumamoto
country: Japan
city: Miyazaki
country: Japan
city: Nagasaki
country: Japan
city: Amsterdam
country: Netherlands
city: Nijmegen
country: Netherlands
city: Zwolle
country: Netherlands
city: Bodø
country: Norway
city: Lørenskog
country: Norway
city: Oslo
country: Norway
city: Gdansk
country: Poland
city: Gdynia
country: Poland
city: Gliwice
country: Poland
city: Poznan
country: Poland
city: Moscow
country: Russian Federation
city: Obninsk
country: Russian Federation
city: Singapore
country: Singapore
city: Singapore
country: Singapore
city: Singapore
country: Singapore
city: Oviedo
country: Spain
state: Asturias
city: Badalona
country: Spain
state: Barcelona
city: Hospitalet de Llobregat
country: Spain
state: Barcelona
city: Malaga
country: Spain
state: Málaga
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Pamplona
country: Spain
city: Sevilla
country: Spain
city: Linköping
country: Sweden
city: Stockholm
country: Sweden
city: Sundsvall
country: Sweden
city: Umea
country: Sweden
city: Växjö
country: Sweden
city: Edinburgh
country: United Kingdom
state: Lothian
city: Bebington
country: United Kingdom
state: Merseyside
city: Northwood
country: United Kingdom
state: Middlesex
city: Guildford
country: United Kingdom
state: Surrey
city: Sutton
country: United Kingdom
state: Surrey
city: Newcastle Upon Tyne
country: United Kingdom
state: Tyne And Wear
city: Coventry
country: United Kingdom
state: West Midlands
city: Belfast
country: United Kingdom
city: Leeds
country: United Kingdom
city: London
country: United Kingdom
city: Romford
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: Smith M, Parker C, Saad F, Miller K, Tombal B, Ng QS, Boegemann M, Matveev V, Piulats JM, Zucca LE, Karyakin O, Kimura G, Matsubara N, Nahas WC, Nole F, Rosenbaum E, Heidenreich A, Kakehi Y, Zhang A, Krissel H, Teufel M, Shen J, Wagner V, Higano C. 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. 2019 Mar;20(3):408-419. doi: 10.1016/S1470-2045(18)30860-X. Epub 2019 Feb 6.
citation: Shore N, Higano CS, George DJ, Sternberg CN, Saad F, Tombal B, Miller K, Kalinovsky J, Jiao X, Tangirala K, Sartor O. Concurrent or layered treatment with radium-223 and enzalutamide or abiraterone/prednisone: real-world clinical outcomes in patients with metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2020 Dec;23(4):680-688. doi: 10.1038/s41391-020-0236-0. Epub 2020 May 13.
citation: Matsubara N, Kimura G, Uemura H, Uemura H, Nakamura M, Nagamori S, Mizokami A, Kikukawa H, Hosono M, Kinuya S, Krissel H, Siegel J, Kakehi Y. A randomized, double-blind, comparison of radium-223 and placebo, in combination with abiraterone acetate and prednisolone, in castration-resistant metastatic prostate cancer: subgroup analysis of Japanese patients in the ERA 223 study. Int J Clin Oncol. 2020 Apr;25(4):720-731. doi: 10.1007/s10147-019-01589-6. Epub 2019 Dec 10.