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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Prostatic Neoplasms

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


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radium-223 dichloride + Abi/Pred<br>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) | Drug: Radium-223 dichloride (Xofigo, BAY88-8223)<br>* 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<br>Drug: Abiraterone<br>* 1000 mg once daily, oral, with best supportive care<br>Drug: Prednisone/Prednisolone<br>* 5 mg twice daily, oral, with best supportive care<br>|
| Placebo Comparator: Placebo + Abi/Pred<br>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) | Drug: Matching placebo (normal saline)<br>* Intravenous injection ( IV-slow bolus), every 4 weeks for 6 cycles<br>Drug: Abiraterone<br>* 1000 mg once daily, oral, with best supportive care<br>Drug: Prednisone/Prednisolone<br>* 5 mg twice daily, oral, with best supportive care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic Skeletal Event Free Survival (SSE-FS) | 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. | From randomization until first onset of on-study symptomatic skeletal event (SSE) or death, up to 47 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | 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. | From randomization until death from any cause, up to 67 months | 
| Radiological Progression Free Survival (rPFS) | 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. | From randomization until the date of confirmed radiological progression or death, up to 47 months | 
| Time to Pain Progression | 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. | From randomization until the date of pain progression based on pain score, up to 47 months | 
| Time to Cytotoxic Chemotherapy | 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. | From randomization until the date of first cytotoxic chemotherapy, up to 47 months | 
| Time to Opiate Use for Cancer Pain | Time to opiate use for cancer pain was defined as the interval from the date of randomization to the date of opiate use. | From randomization until the date of opiate use, up to 47 months | 
| Number of Participants With Treatment-emergent Adverse Events | 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. | From start of study treatment until the end of the treatment period, up to 65 months | 
| Number of Subjects With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | 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. | From start of study treatment until the end of the treatment period, up to 65 months | 
| Number of Participants With Any Treatment-emergent Additional Primary Malignancies | 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. | From start of study treatment until 4 weeks after last study treatment, up to 65 months | 
| Number of Participants With Treatment-emergent Bone Fractures | 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. | From start of study treatment until 4 weeks after last study treatment, up to 65 months | 
| Number of Participants With Post-treatment Adverse Events | 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. | After the treatment period, up to 46 months | 
| Number of Participants With Any Study Drug-related Post-treatment Adverse Events Per Maximum Intensity | 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. | After the treatment period, up to 46 months | 
| Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | 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. | After the treatment period, up to 46 months | 
| Number of Participants With Post-treatment Bone Fractures | 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. | After the treatment period, up to 46 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase III, Radium-223 dichloride, Abiraterone acetate, Combination therapy, Chemotherapy-naive, Bone metastasis, Castration-resistant prostate cancer (CRPC)