Prostatic Neoplasms
Conditions
Keywords
Phase III, Radium-223 dichloride, Abiraterone acetate, Combination therapy, Chemotherapy-naive, Bone metastasis, 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.
Interventions
DRUGRadium-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
DRUGMatching placebo (normal saline)
Intravenous injection ( IV-slow bolus), every 4 weeks for 6 cycles
DRUGAbiraterone
1000 mg once daily, oral, with best supportive care
5 mg twice daily, oral, with best supportive care
Sponsors
Janssen Research & Development, LLC
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Symptomatic Skeletal Event Free Survival (SSE-FS) | 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. Participants who died without prior SSE and ≥ 13 weeks after the last SSE assessment are censored at the last SSE assessment date. Participants alive at the survival cut-off date are censored at the last date known to be alive. Participants 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 participant, the participant is only counted into 1 category in the order of: spinal cord compression \> bone fracture \> orthopedic surgery \> EBRT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Radiological Progression Free Survival (rPFS) | 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 | 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 participant experienced pain progression assessed by Brief Pain Inventory-Short Form 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 participants 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 participants with WPS 1 to 3 at baseline. Participants without pain progression at end of study are censored at the last date known to have not progressed: last evaluation date for pain scores or last visit when recorded opiate use, whichever is last. Participants with no on-study assessment or no baseline assessment are censored at the date of randomization. |
| Time to Cytotoxic Chemotherapy | 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 | 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 | From start of study treatment until the end of the treatment period, up to 110 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 life-threatening, requires hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity. A treatment-emergent AEs (TEAEs) or serious TEAEs was defined as any event that started on or after the first dose of the study treatment and during the treatment period and was not a continuation of a pretreatment event or started before the first dose and worsened after the first dose or the treatment period. Drug-related TEAEs or serious TEAEs were those with reasonable causal relationship to the study treatment decided by the investigators. |
| Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | From start of study treatment until the end of the treatment period, up to 110 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. A treatment-emergent AEs (TEAEs) or serious TEAEs was defined as any event that started on or after the first dose of the study treatment and during the treatment period and was not a continuation of a pretreatment event or started before the first dose and worsened after the first dose or the treatment period. Radium-223/placebo-related TEAEs or serious TEAEs were those with reasonable causal relationship to radium-223 or placebo decided by the investigators. |
| Overall Survival (OS) | 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. Participants alive at the survival cut-off date were censored at the last date known to be alive. |
| Number of Participants With Treatment-emergent Bone Fractures | From start of study treatment until the end of the treatment period, up to 110 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 | After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up | 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 | After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up | 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 Additional Primary Malignancies | After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up | Post-treatment additional primary malignancies were adverse events identified as additional primary malignancies that started after the treatment period. |
| Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up | 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 | After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up | 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. |
| Number of Participants With Any Treatment-emergent Additional Primary Malignancies | From start of study treatment until the end of the treatment period, up to 110 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. |
Countries
Australia, Belgium, Brazil, Canada, Finland, France, Germany, Israel, Italy, Japan, Netherlands, Norway, Poland, Russia, Singapore, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Study was conducted at multiple centers in 19 countries between 30 March 2014 (first participant first visit) and 08 February 2024 (last participant last visit).
Pre-assignment details
Overall, 1144 participants were screened. Of them, 338 participants did not complete screening, 806 participants were randomized to treatment and 786 participants received study treatment. 2 participants randomized to the placebo treatment group unintentionally received 1 radium-223 dichloride dose during the treatment period.
Participants by arm
| Arm | Count |
|---|---|
| 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). | 401 |
| 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). | 405 |
| Total | 806 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | AE with clinical progressive disease(PD) | 20 | 19 |
| Overall Study | AE without clinical PD | 54 | 36 |
| Overall Study | Clinical PD | 114 | 148 |
| Overall Study | Deterioration of general conditions | 1 | 1 |
| Overall Study | Logistical difficulties | 2 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Missing | 1 | 0 |
| Overall Study | Never treated | 11 | 9 |
| Overall Study | Non-compliance with study drug | 3 | 1 |
| Overall Study | Ongoing with commercial abiraterone/prednisone outside study | 1 | 1 |
| Overall Study | Other | 10 | 14 |
| Overall Study | Physician Decision | 4 | 3 |
| Overall Study | Protocol-driven decision point | 59 | 58 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Radiological PD | 100 | 90 |
| Overall Study | Subject decision | 0 | 1 |
| Overall Study | Switching to other therapy | 3 | 2 |
| Overall Study | Withdrawal by Subject | 16 | 20 |
Baseline characteristics
| Characteristic | Radium-223 Dichloride + Abi/Pred | Total | Placebo + Abi/Pred |
|---|---|---|---|
| Age, Continuous | 70.9 Years STANDARD_DEVIATION 8.5 | 71.1 Years STANDARD_DEVIATION 8.5 | 71.4 Years STANDARD_DEVIATION 8.4 |
| Cancer pain assessment by Brief Pain Inventory-Short Form (BPI-SF) Asymptomatic (Worst pain score = 0) | 195 Participants | 393 Participants | 198 Participants |
| Cancer pain assessment by Brief Pain Inventory-Short Form (BPI-SF) Mildly Symptomatic (Worst pain score 1 - 3) | 181 Participants | 355 Participants | 174 Participants |
| Cancer pain assessment by Brief Pain Inventory-Short Form (BPI-SF) Missing | 25 Participants | 58 Participants | 33 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 262 Participants | 543 Participants | 281 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 137 Participants | 258 Participants | 121 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Missing | 2 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 40 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 361 Participants | 716 Participants | 355 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 23 Participants | 50 Participants | 27 Participants |
| Extent of Disease >20 lesions but not a superscan | 71 Participants | 141 Participants | 70 Participants |
| Extent of Disease 6-20 metastases | 175 Participants | 356 Participants | 181 Participants |
| Extent of Disease < 6 metastases | 134 Participants | 275 Participants | 141 Participants |
| Extent of Disease Normal or abnormal because of benign bone disease | 2 Participants | 2 Participants | 0 Participants |
| Extent of Disease Superscan | 19 Participants | 32 Participants | 13 Participants |
| Gleason score at diagnosis Greater than or equal to (>=) 8 | 246 Participants | 479 Participants | 233 Participants |
| Gleason score at diagnosis Less than (<) 8 | 140 Participants | 294 Participants | 154 Participants |
| Gleason score at diagnosis Missing | 15 Participants | 33 Participants | 18 Participants |
| Prostate-specific antigen | 92.39 Micrograms per liter (ug/L) STANDARD_DEVIATION 191.62 | 92.36 Micrograms per liter (ug/L) STANDARD_DEVIATION 268.85 | 92.33 Micrograms per liter (ug/L) STANDARD_DEVIATION 328 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 79 Participants | 157 Participants | 78 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 26 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 26 Participants | 52 Participants | 26 Participants |
| Race (NIH/OMB) White | 285 Participants | 569 Participants | 284 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 401 Participants | 806 Participants | 405 Participants |
| Stage of prostate cancer at diagnosis (Tumor Node Metastasis [TNM] Classification) Missing | 19 Participants | 43 Participants | 24 Participants |
| Stage of prostate cancer at diagnosis (Tumor Node Metastasis [TNM] Classification) Stage I | 27 Participants | 45 Participants | 18 Participants |
| Stage of prostate cancer at diagnosis (Tumor Node Metastasis [TNM] Classification) Stage IIA | 22 Participants | 42 Participants | 20 Participants |
| Stage of prostate cancer at diagnosis (Tumor Node Metastasis [TNM] Classification) Stage IIB | 34 Participants | 83 Participants | 49 Participants |
| Stage of prostate cancer at diagnosis (Tumor Node Metastasis [TNM] Classification) Stage III | 102 Participants | 190 Participants | 88 Participants |
| Stage of prostate cancer at diagnosis (Tumor Node Metastasis [TNM] Classification) Stage IV | 197 Participants | 403 Participants | 206 Participants |
| Weight | 82.19 Kilograms (kg) STANDARD_DEVIATION 16.75 | 82.30 Kilograms (kg) STANDARD_DEVIATION 16.37 | 82.40 Kilograms (kg) STANDARD_DEVIATION 16.01 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 287 / 392 | 290 / 394 |
| other Total, other adverse events | 368 / 392 | 376 / 394 |
| serious Total, serious adverse events | 193 / 392 | 191 / 394 |
Outcome results
Primary
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. Participants who died without prior SSE and ≥ 13 weeks after the last SSE assessment are censored at the last SSE assessment date. Participants alive at the survival cut-off date are censored at the last date known to be alive. Participants 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 participant, the participant is only counted into 1 category in the order of: spinal cord compression \> bone fracture \> orthopedic surgery \> EBRT.
Time frame: From randomization until first onset of on-study symptomatic skeletal event (SSE) or death, up to 47 months
Population: Intent-to-Treat (ITT) analysis set (included all randomized participants)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Symptomatic Skeletal Event Free Survival (SSE-FS) | 22.3 Months |
| Placebo + Abi/Pred | Symptomatic Skeletal Event Free Survival (SSE-FS) | 26.0 Months |
p-value: 0.263695% CI: [0.917, 1.374]Cox Proportional Hazards Model
Secondary
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.
Time frame: After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up
Population: Safety analysis set (SAF): included all randomized participants who received at least one dose of any study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Any Study Drug-related Post-treatment Adverse Events Per Maximum Intensity | Grade 1 | 34 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Any Study Drug-related Post-treatment Adverse Events Per Maximum Intensity | Grade 2 | 9 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Any Study Drug-related Post-treatment Adverse Events Per Maximum Intensity | Grade 3 | 6 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Any Study Drug-related Post-treatment Adverse Events Per Maximum Intensity | Grade 4 | 1 Participants |
| Placebo + Abi/Pred | Number of Participants With Any Study Drug-related Post-treatment Adverse Events Per Maximum Intensity | Grade 4 | 0 Participants |
| Placebo + Abi/Pred | Number of Participants With Any Study Drug-related Post-treatment Adverse Events Per Maximum Intensity | Grade 1 | 4 Participants |
| Placebo + Abi/Pred | Number of Participants With Any Study Drug-related Post-treatment Adverse Events Per Maximum Intensity | Grade 3 | 3 Participants |
| Placebo + Abi/Pred | Number of Participants With Any Study Drug-related Post-treatment Adverse Events Per Maximum Intensity | Grade 2 | 3 Participants |
Secondary
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.
Time frame: From start of study treatment until the end of the treatment period, up to 110 months
Population: Safety analysis set (SAF): included all randomized participants who received at least one dose of any study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Any Treatment-emergent Additional Primary Malignancies | 32 Participants |
| Placebo + Abi/Pred | Number of Participants With Any Treatment-emergent Additional Primary Malignancies | 30 Participants |
Secondary
Number of Participants With Post-treatment Additional Primary Malignancies
Post-treatment additional primary malignancies were adverse events identified as additional primary malignancies that started after the treatment period.
Time frame: After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up
Population: Safety analysis set (SAF): included all randomized participants who received at least one dose of any study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Additional Primary Malignancies | 7 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Additional Primary Malignancies | 7 Participants |
Secondary
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.
Time frame: After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up
Population: Safety analysis set (SAF): included all randomized participants who received at least one dose of any study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Adverse Events | Any events | 148 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Adverse Events | Any drug-related events | 20 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Adverse Events | Any chemotherapy-related events | 31 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Adverse Events | Any events | 138 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Adverse Events | Any drug-related events | 10 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Adverse Events | Any chemotherapy-related events | 34 Participants |
Secondary
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.
Time frame: After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up
Population: Safety analysis set (SAF): included all randomized participants who received at least one dose of any study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Ankle fracture | 0 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Craniofacial fracture | 1 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Femur fracture | 1 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Fibula fracture | 0 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Foot fracture | 1 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Jaw fracture | 1 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Patella fracture | 1 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Radius fracture | 1 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Rib fracture | 0 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Spinal compression fracture | 0 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Thoracic vertebral fracture | 0 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Traumatic fracture | 0 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Osteoporotic fracture | 6 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Pathological fracture | 14 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Thoracic vertebral fracture | 1 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Ankle fracture | 1 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Radius fracture | 0 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Craniofacial fracture | 0 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Osteoporotic fracture | 0 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Femur fracture | 0 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Rib fracture | 1 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Fibula fracture | 1 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Traumatic fracture | 1 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Foot fracture | 0 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Spinal compression fracture | 2 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Jaw fracture | 0 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Pathological fracture | 14 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Bone Fractures | Patella fracture | 0 Participants |
Secondary
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.
Time frame: After the treatment period, up to 48.5 months in active follow-up and 74.9 months in long-term follow-up
Population: Safety analysis set (SAF): included all randomized participants who received at least one dose of any study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | Febrile neutropenia | 5 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | Neutropenia | 8 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | Myelosuppression | 1 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | Pancytopenia | 0 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | Leukopenia | 1 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | Thrombocytopenia | 2 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | Anaemia | 5 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | Thrombocytopenia | 2 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | Anaemia | 4 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | Myelosuppression | 0 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | Febrile neutropenia | 8 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | Leukopenia | 0 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | Neutropenia | 3 Participants |
| Placebo + Abi/Pred | Number of Participants With Post-treatment Chemotherapy-related Blood and Lymphatic System Disorders | Pancytopenia | 1 Participants |
Secondary
Number of Participants 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. A treatment-emergent AEs (TEAEs) or serious TEAEs was defined as any event that started on or after the first dose of the study treatment and during the treatment period and was not a continuation of a pretreatment event or started before the first dose and worsened after the first dose or the treatment period. Radium-223/placebo-related TEAEs or serious TEAEs were those with reasonable causal relationship to radium-223 or placebo decided by the investigators.
Time frame: From start of study treatment until the end of the treatment period, up to 110 months
Population: Safety analysis set (SAF): included all randomized participants who received at least one dose of any study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | TEAE - Grade 3 | 20 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | Serious TEAE - Grade 2 | 3 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | TEAE - Grade 2 | 28 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | Serious TEAE - Grade 3 | 9 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | TEAE - Grade 4 | 1 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | Serious TEAE - Grade 4 | 0 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | TEAE - Grade 1 | 43 Participants |
| Placebo + Abi/Pred | Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | Serious TEAE - Grade 4 | 2 Participants |
| Placebo + Abi/Pred | Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | TEAE - Grade 1 | 53 Participants |
| Placebo + Abi/Pred | Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | TEAE - Grade 2 | 23 Participants |
| Placebo + Abi/Pred | Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | TEAE - Grade 3 | 13 Participants |
| Placebo + Abi/Pred | Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | TEAE - Grade 4 | 2 Participants |
| Placebo + Abi/Pred | Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | Serious TEAE - Grade 2 | 0 Participants |
| Placebo + Abi/Pred | Number of Participants With Radium-223/Placebo-related Treatment-emergent Adverse Events Per Maximum Intensity | Serious TEAE - Grade 3 | 5 Participants |
Secondary
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 life-threatening, requires hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity. A treatment-emergent AEs (TEAEs) or serious TEAEs was defined as any event that started on or after the first dose of the study treatment and during the treatment period and was not a continuation of a pretreatment event or started before the first dose and worsened after the first dose or the treatment period. Drug-related TEAEs or serious TEAEs were those with reasonable causal relationship to the study treatment decided by the investigators.
Time frame: From start of study treatment until the end of the treatment period, up to 110 months
Population: Safety analysis set (SAF): included all randomized participants who received at least one dose of any study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 382 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Treatment-emergent Adverse Events | Any drug-related TEAE | 265 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Treatment-emergent Adverse Events | Radium-223/Placebo-related TEAE | 92 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Treatment-emergent Adverse Events | Any serious TEAE | 178 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Treatment-emergent Adverse Events | Any drug-related serious TEAE | 32 Participants |
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Treatment-emergent Adverse Events | Radium-223/Placebo-related serious TEAE | 12 Participants |
| Placebo + Abi/Pred | Number of Participants With Treatment-emergent Adverse Events | Any drug-related serious TEAE | 30 Participants |
| Placebo + Abi/Pred | Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 387 Participants |
| Placebo + Abi/Pred | Number of Participants With Treatment-emergent Adverse Events | Any serious TEAE | 178 Participants |
| Placebo + Abi/Pred | Number of Participants With Treatment-emergent Adverse Events | Any drug-related TEAE | 273 Participants |
| Placebo + Abi/Pred | Number of Participants With Treatment-emergent Adverse Events | Radium-223/Placebo-related serious TEAE | 7 Participants |
| Placebo + Abi/Pred | Number of Participants With Treatment-emergent Adverse Events | Radium-223/Placebo-related TEAE | 91 Participants |
Secondary
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.
Time frame: From start of study treatment until the end of the treatment period, up to 110 months
Population: Safety analysis set (SAF): included all randomized participants who received at least one dose of any study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Number of Participants With Treatment-emergent Bone Fractures | 110 Participants |
| Placebo + Abi/Pred | Number of Participants With Treatment-emergent Bone Fractures | 51 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time (months) from the date of randomization to the date of death due to any cause. Participants alive at the survival cut-off date were censored at the last date known to be alive.
Time frame: From randomization until death from any cause, up to 67 months
Population: ITT analysis set (included all randomized participants)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Overall Survival (OS) | 30.1 Months |
| Placebo + Abi/Pred | Overall Survival (OS) | 34.8 Months |
p-value: 0.119495% CI: [0.964, 1.374]Cox Proportional Hazards model
Secondary
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.
Time frame: From randomization until the date of confirmed radiological progression or death, up to 47 months
Population: ITT analysis set (included all randomized participants)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Radiological Progression Free Survival (rPFS) | 11.2 Months |
| Placebo + Abi/Pred | Radiological Progression Free Survival (rPFS) | 12.4 Months |
p-value: 0.128395% CI: [0.96, 1.383]Cox Proportional Hazards Model
Secondary
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.
Time frame: From randomization until the date of first cytotoxic chemotherapy, up to 47 months
Population: ITT analysis set (included all randomized participants)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Time to Cytotoxic Chemotherapy | 29.5 Months |
| Placebo + Abi/Pred | Time to Cytotoxic Chemotherapy | 28.5 Months |
p-value: 0.787195% CI: [0.816, 1.308]Cox Proportional Hazards Model
Secondary
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.
Time frame: From randomization until the date of opiate use, up to 47 months
Population: ITT analysis set excluding participants who had opiate use at baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Time to Opiate Use for Cancer Pain | 19.0 Months |
| Placebo + Abi/Pred | Time to Opiate Use for Cancer Pain | 22.6 Months |
p-value: 0.246795% CI: [0.921, 1.378]Cox Proportional Hazards Model
Secondary
Time to Pain Progression
Time to pain progression was defined as the interval from randomization to the first date a participant experienced pain progression assessed by Brief Pain Inventory-Short Form 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 participants 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 participants with WPS 1 to 3 at baseline. Participants without pain progression at end of study are censored at the last date known to have not progressed: last evaluation date for pain scores or last visit when recorded opiate use, whichever is last. Participants with no on-study assessment or no baseline assessment are censored at the date of randomization.
Time frame: From randomization until the date of pain progression based on pain score, up to 47 months
Population: ITT analysis set (included all randomized participants)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radium-223 Dichloride + Abi/Pred | Time to Pain Progression | 14.4 Months |
| Placebo + Abi/Pred | Time to Pain Progression | 18.7 Months |
p-value: 0.166995% CI: [0.945, 1.389]Cox Proportional Hazards Model