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 (ERA 223)

Bayer

Status and phase: Completed; Phase 3

Conditions: Prostatic Neoplasms

Treatments: Drug: Prednisone/Prednisolone; Drug: Matching placebo (normal saline); Drug: Radium-223 dichloride (Xofigo, BAY88-8223); Drug: Abiraterone

Study type: Interventional

Funder types: Industry

Identifiers

NCT02043678

15396

2013-003438-33 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 806 patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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806 participants in 2 patient groups, including a placebo group

Radium-223 dichloride + Abi/Pred

Experimental group

Description:

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)

Treatment:

Drug: Abiraterone

Drug: Radium-223 dichloride (Xofigo, BAY88-8223)

Drug: Prednisone/Prednisolone

Placebo + Abi/Pred

Placebo Comparator group

Description:

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)

Treatment:

Drug: Abiraterone

Drug: Matching placebo (normal saline)

Drug: Prednisone/Prednisolone