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)

• ClinicalTrials.gov Identifier: NCT02043678
• Recruitment Status: Completed
• First Posted: January 23, 2014
• Results First Posted: March 5, 2019
• Last Update Posted: February 26, 2024
• Sponsor: Bayer
• Collaborator: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: January 21, 2014
• First Posted Date: January 23, 2014
• Results First Submitted Date: February 12, 2019
• Results First Posted Date: March 5, 2019
• Last Update Posted Date: February 26, 2024
• Actual Study Start Date: March 30, 2014
• Actual Primary Completion Date: February 15, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 12, 2019)

Symptomatic Skeletal Event Free Survival (SSE-FS) [ Time Frame: From randomization until first onset of on-study symptomatic skeletal event (SSE) or death, up to 47 months ]

SSE-FS was defined as time (months) from randomization to the earliest of onset date of skeletal symptoms treated with external beam radiotherapy (EBRT), onset date of pathological bone fracture, onset date of spinal cord compression, procedure date of tumor-related orthopedic surgery, or death from any cause. Subjects who died without prior SSE and ≥ 13 weeks after the last SSE assessment are censored at the last SSE assessment date. Subjects alive at the survival cut-off date are censored at the last date known to be alive. Subjects with multiple events are only counted for the category in which the first event occurred. If multiple SSE (component events) occur on the same date for 1 subject, the subject is only counted into 1 category in the order of: spinal cord compression > bone fracture > orthopedic surgery > EBRT.

• Original Primary Outcome Measures (submitted: January 21, 2014): Symptomatic skeletal event free survival (SSE-FS) [ Time Frame: At 3 years ]

Current Secondary Outcome Measures (submitted: February 3, 2021)

• Overall Survival (OS) [ Time Frame: From randomization until death from any cause, up to 67 months ]
  OS was defined as the time (months) from the date of randomization to the date of death due to any cause. Subjects alive at the survival cut-off date were censored at the last date known to be alive.
• Radiological Progression Free Survival (rPFS) [ Time Frame: From randomization until the date of confirmed radiological progression or death, up to 47 months ]
  rPFS was defined as the time (months) from the date of randomization to the date of confirmed radiological progression or death (if death occurred before progression) based on independent assessment.
• Time to Pain Progression [ Time Frame: From randomization until the date of pain progression based on pain score, up to 47 months ]
  Time to pain progression was defined as the interval from randomization to the first date a subject experienced pain progression, assessed by BPI-SF (see Baseline Characteristics) and defined as: an increase of 2 or more points in the average worst pain score (WPS) from baseline observed at 2 consecutive evaluations >= 4 weeks apart or initiation of short- or long-acting opioid use for pain for subjects with WPS 0 at baseline; an increase of 2 or more points in the average WPS from baseline observed at 2 consecutive evaluations ≥ 4 weeks apart and an average WPS of ≥ 4 OR initiation of short- or long-acting opioid use for pain for subjects with WPS 1 to 3 at baseline. Subjects without pain progression at the end of study are censored at the last date known to have not progressed: the last evaluation date for pain scores or last visit when recorded opiate use, whichever is last. Subjects with no on-study assessment or no baseline assessment are censored at the date of randomization.
• Time to Cytotoxic Chemotherapy [ Time Frame: From randomization until the date of first cytotoxic chemotherapy, up to 47 months ]
  Time to cytotoxic chemotherapy is time (months) from randomization to the earliest date of the first cytotoxic chemotherapy. Participants who have not started cytotoxic chemotherapy during the study were censored at the last assessment date.
• Time to Opiate Use for Cancer Pain [ Time Frame: From randomization until the date of opiate use, up to 47 months ]
  Time to opiate use for cancer pain was defined as the interval from the date of randomization to the date of opiate use.
• Number of Participants With Treatment-emergent Adverse Events [ Time Frame: From start of study treatment until the end of the treatment period, up to 65 months ]
  An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a participant in the study. A serious adverse event (SAE) was any untoward medical occurrence that at any dose was resulting in death, was lifethreatening, requires hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity. AEs or SAEs occurring after start of study treatment until the end of the treatment period were defined as treatment-emergent AEs (TEAEs) or serious TEAEs. Drug-related TEAEs or serious TEAEs were those with "reasonable causal relationship" to the study treatment decided by the investigators.
• Number of Subjects With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity [ Time Frame: From start of study treatment until the end of the treatment period, up to 65 months ]
  An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a participant in the study. A serious adverse event (SAE) was any untoward medical occurrence that at any dose was resulting in death, was lifethreatening, requires hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity. AEs or SAEs occurring after start of study treatment until the end of the treatment period were defined as treatment-emergent AEs (TEAEs) or serious TEAEs. Radium-223/placebo-related TEAEs or serious TEAEs were those with "reasonable causal relationship" to radium-223 or placebo decided by the investigators.
• Number of Participants With Any Treatment-emergent Additional Primary Malignancies [ Time Frame: From start of study treatment until 4 weeks after last study treatment, up to 65 months ]
  Treatment-emergent additional primary malignancies were adverse events identified as additional primary malignancies that occurred after start of study treatment until the end of the treatment period.
• Number of Participants With Treatment-emergent Bone Fractures [ Time Frame: From start of study treatment until 4 weeks after last study treatment, up to 65 months ]
  Treatment-emergent fractures were adverse events identified as fractures that occurred after start of study treatment until the end of the treatment period. All bone fractures and bone-associated events (e.g., osteoporosis) were reported as either AEs, or SAEs if the criteria of SAE were met, regardless of the investigator's causality assessment.
• Number of Participants With Post-treatment Adverse Events [ Time Frame: After the treatment period, up to 46 months ]
  An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a participant in the study. Any bleeding event occurring during the study was not documented as an AE because this event was planned to be captured in the assessment of efficacy. AEs that started after the treatment period were defined as post-treatment AEs. Drug-related AEs were those with "reasonable causal relationship" to the study treatment decided by the investigators.
• Number of Participants With Any Study Drug-related Post-treatment Adverse Events Per Maximum Intensity [ Time Frame: After the treatment period, up to 46 months ]
  An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a participant in the study. Any bleeding event occurring during the study was not documented as an AE because this event was planned to be captured in the assessment of efficacy. AEs that started after the treatment period were defined as post-treatment AEs. Drug-related AEs were those with "reasonable causal relationship" to the study treatment decided by the investigators.
• Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders [ Time Frame: After the treatment period, up to 46 months ]
  Post-treatment blood and lymphatic system disorders were adverse events identified as blood and lymphatic system disorders that occurred after the end of the treatment period until participant died, was lost to follow-up, withdrew informed consent, actively objected to collection of further data, or was transitioned to the extended safety follow-up study.
• Number of Participants With Post-treatment Bone Fractures [ Time Frame: After the treatment period, up to 46 months ]
  Post-treatment fractures were adverse events identified as fractures that occured after the end of the treatment period until participant died, was lost to follow-up, withdrew informed consent, actively objected to collection of further data, or was transitioned to the extended safety follow-up study. All bone fractures and bone-associated events (e.g., osteoporosis), were reported as either AEs, or SAEs if the criteria of SAE were met, regardless of the investigator's causality assessment.

Original Secondary Outcome Measures (submitted: January 21, 2014)

• Overall Survival [ Time Frame: At 3 years for interim and at 6 years for final ]
• Time to opiate use for cancer pain [ Time Frame: At 3 years ]
• Time to pain progression [ Time Frame: At 3 years ]
• Time to cytotoxic chemotherapy [ Time Frame: At 3 years ]
• Radiological progression free survival (rPFS) [ Time Frame: At 3 years ]
• Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: Up to 3 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Prostatic Neoplasms

Intervention

• Drug: 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
• Drug: Matching placebo (normal saline)
  Intravenous injection ( IV-slow bolus), every 4 weeks for 6 cycles
• Drug: Abiraterone
  1000 mg once daily, oral, with best supportive care
• Drug: Prednisone/Prednisolone
  5 mg twice daily, oral, with best supportive care

Study Arms

• Experimental: 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)
  Interventions:

  • Drug: Radium-223 dichloride (Xofigo, BAY88-8223)
  • Drug: Abiraterone
  • Drug: Prednisone/Prednisolone
• Placebo Comparator: 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)
  Interventions:

  • Drug: Matching placebo (normal saline)
  • Drug: Abiraterone
  • Drug: Prednisone/Prednisolone

Publications *

• 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. Erratum In: Lancet Oncol. 2019 Oct;20(10):e559.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 22, 2016): 806
• Original Estimated Enrollment (submitted: January 21, 2014): 800
• Actual Study Completion Date: February 8, 2024
• Actual Primary Completion Date: February 15, 2018 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Brazil, Canada, Finland, France, Germany, Israel, Italy, Japan, Netherlands, Norway, Poland, Russian Federation, Singapore, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT02043678
• Other Study ID Numbers: 15396; 2013-003438-33 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

Plan Description

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

• Current Responsible Party: Bayer
• Original Responsible Party: Same as current
• Current Study Sponsor: Bayer
• Original Study Sponsor: Same as current
• Collaborators: Janssen Research & Development, LLC

Investigators

• Study Director: Bayer Study Director; Bayer

• PRS Account: Bayer
• Verification Date: February 2024