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

NCT ID: NCT02043678

Last Updated: 2025-02-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 806 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-03-30
• Study Completion Date: 2024-02-08

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.

Conditions

Prostatic Neoplasms

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Radium-223 dichloride + Abi/Pred

Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology \[NIST\] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met)

Group Type: EXPERIMENTAL

Radium-223 dichloride (Xofigo, BAY88-8223)

Intervention Type: DRUG

50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of NIST update) body weight, intravenous injection (IV-slow bolus), every 4 weeks for 6 cycles

Abiraterone

Intervention Type: DRUG

1000 mg once daily, oral, with best supportive care

Prednisone/Prednisolone

Intervention Type: DRUG

5 mg twice daily, oral, with best supportive care

Placebo + Abi/Pred

Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met)

Group Type: PLACEBO_COMPARATOR

Matching placebo (normal saline)

Intervention Type: DRUG

Intravenous injection ( IV-slow bolus), every 4 weeks for 6 cycles

Abiraterone

Intervention Type: DRUG

1000 mg once daily, oral, with best supportive care

Prednisone/Prednisolone

Intervention Type: DRUG

5 mg twice daily, oral, with best supportive care

Interventions

Radium-223 dichloride (Xofigo, BAY88-8223)

50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of NIST update) body weight, intravenous injection (IV-slow bolus), every 4 weeks for 6 cycles

Intervention Type: DRUG

Matching placebo (normal saline)

Intravenous injection ( IV-slow bolus), every 4 weeks for 6 cycles

Intervention Type: DRUG

Abiraterone

1000 mg once daily, oral, with best supportive care

Intervention Type: DRUG

Prednisone/Prednisolone

5 mg twice daily, oral, with best supportive care

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Janssen Research & Development, LLC

INDUSTRY

Sponsor Role: collaborator

Bayer

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bayer Study Director

Role: STUDY_DIRECTOR

Bayer

Locations

Anchorage, Alaska, United States

Tucson, Arizona, United States

Oceanside, California, United States

Denver, Colorado, United States

Washington D.C., District of Columbia, United States

Fort Myers, Florida, United States

Atlanta, Georgia, United States

Jeffersonville, Indiana, United States

New Orleans, Louisiana, United States

Baltimore, Maryland, United States

Rockville, Maryland, United States

Towson, Maryland, United States

Boston, Massachusetts, United States

Burlington, Massachusetts, United States

Detroit, Michigan, United States

Traverse City, Michigan, United States

St Louis, Missouri, United States

Omaha, Nebraska, United States

Las Vegas, Nevada, United States

Hackensack, New Jersey, United States

Poughkeepsie, New York, United States

Syracuse, New York, United States

Bala-Cynwyd, Pennsylvania, United States

Pittsburgh, Pennsylvania, United States

Pittsburgh, Pennsylvania, United States

Norfolk, Virginia, United States

Seattle, Washington, United States

Spokane, Washington, United States

Wheeling, West Virginia, United States

St Leonards, New South Wales, Australia

Sydney, New South Wales, Australia

Adelaide, South Australia, Australia

East Bentleigh, Victoria, Australia

Fitzroy, Victoria, Australia

Heidelberg, Victoria, Australia

East Melbourne, , Australia

Randwick, , Australia

Brussels, , Belgium

Bruxelles - Brussel, , Belgium

Edegem, , Belgium

Ghent, , Belgium

Belo Horizonte, Minas Gerais, Brazil

Porto Alegre, Rio Grande do Sul, Brazil

Barretos/SP, São Paulo, Brazil

São Paulo, São Paulo, Brazil

São Paulo, , Brazil

Calgary, Alberta, Canada

Vancouver, British Columbia, Canada

Winnipeg, Manitoba, Canada

Hamilton, Ontario, Canada

Ottawa, Ontario, Canada

Toronto, Ontario, Canada

Montreal, Quebec, Canada

Québec, Quebec, Canada

Helsinki, , Finland

Kuopio, , Finland

Seinäjoki, , Finland

Tampere, , Finland

Besançon, , France

Bordeaux, , France

Paris, , France

Paris, , France

Poitiers, , France

Saint-Herblain, , France

Toulouse, , France

Ulm, Baden-Wurttemberg, Germany

München, Bavaria, Germany

Marburg, Hesse, Germany

Münster, North Rhine-Westphalia, Germany

Dresden, Saxony, Germany

Jena, Thuringia, Germany

Berlin, , Germany

Afula, , Israel

Beersheba, , Israel

Haifa, , Israel

Jerusalem, , Israel

Kfar Saba, , Israel

Petah Tikva, , Israel

Ramat Gan, , Israel

Tel Aviv, , Israel

Ẕerifin, , Israel

Modena, Emilia-Romagna, Italy

Rome, Lazio, Italy

Rome, Lazio, Italy

Genoa, Liguria, Italy

Milan, Lombardy, Italy

Milan, Lombardy, Italy

Cagliari, Sardinia, Italy

Trento, Trentino-Alto Adige, Italy

Cortona, Tuscany, Italy

Nagoya, Aichi-ken, Japan

Hirosaki, Aomori, Japan

Chiba, Chiba, Japan

Kashiwa, Chiba, Japan

Matsuyama, Ehime, Japan

Sapporo, Hokkaido, Japan

Kobe, Hyōgo, Japan

Tsukuba, Ibaraki, Japan

Kanazawa, Ishikawa-ken, Japan

Kita-gun, Kagawa-ken, Japan

Yokohama, Kanagawa, Japan

Yokohama, Kanagawa, Japan

Sendai, Miyagi, Japan

Matsumoto, Nagano, Japan

Kurashiki, Okayama-ken, Japan

Okayama, Okayama-ken, Japan

Sayama, Osaka, Japan

Hamamatsu, Shizuoka, Japan

Bunkyo-Ku, Tokyo, Japan

Bunkyo-ku, Tokyo, Japan

Koto-ku, Tokyo, Japan

Shinjuku-ku, Tokyo, Japan

Ube, Yamaguchi, Japan

Chiba, , Japan

Fukuoka, , Japan

Fukuoka, , Japan

Kumamoto, , Japan

Miyazaki, , Japan

Nagasaki, , Japan

Amsterdam, , Netherlands

Nijmegen, , Netherlands

Zwolle, , Netherlands

Bodø, , Norway

Lørenskog, , Norway

Oslo, , Norway

Gdansk, , Poland

Gdynia, , Poland

Gliwice, , Poland

Poznan, , Poland

Moscow, , Russia

Obninsk, , Russia

Singapore, , Singapore

Singapore, , Singapore

Singapore, , Singapore

Badalona, Barcelona, Spain

L'Hospitalet de Llobregat, Barcelona, Spain

Málaga, Málaga, Spain

Oviedo, Principality of Asturias, Spain

Barcelona, , Spain

Barcelona, , Spain

Madrid, , Spain

Madrid, , Spain

Madrid, , Spain

Madrid, , Spain

Madrid, , Spain

Pamplona, , Spain

Seville, , Spain

Linköping, , Sweden

Stockholm, , Sweden

Sundsvall, , Sweden

Umeå, , Sweden

Vaxjo, , Sweden

Edinburgh, Lothian, United Kingdom

Bebington, Merseyside, United Kingdom

Northwood, Middlesex, United Kingdom

Guildford, Surrey, United Kingdom

Sutton, Surrey, United Kingdom

Newcastle upon Tyne, Tyne and Wear, United Kingdom

Coventry, West Midlands, United Kingdom

Belfast, , United Kingdom

Leeds, , United Kingdom

London, , United Kingdom

Romford, , United Kingdom

Countries

United States; Australia; Belgium; Brazil; Canada; Finland; France; Germany; Israel; Italy; Japan; Netherlands; Norway; Poland; Russia; Singapore; Spain; Sweden; United Kingdom

References

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.

Reference Type: RESULT

PMID: 30738780 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32404868 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31823152 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

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Other Identifiers

2013-003438-33

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

15396

Identifier Type: -

Identifier Source: org_study_id