Study of Radium-223 Dichloride in Combination With Exemestane and Everolimus Versus Placebo in Combination With Exemestane and Everolimus in Subjects With Bone Predominant HER2 Negative Hormone Receptor Positive Metastatic Breast Cancer

Time from date of randomization to occurrence of one of the following, whichever happened earlier: 1) an on study SSE, which was defined as the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms, the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral), the occurrence of spinal cord compression, a tumor related orthopedic surgical intervention; or 2) death from any cause. Per Protocol Amendment 10, following primary analysis completion, further assessments were focused on safety, and only limited efficacy data including SSE and survival were collected and not designed to support reconsideration of the primary analysis efficacy conclusions. Accordingly, no formal statistical analyses were performed for primary and secondary efficacy outcomes in the final analysis. All primary and secondary efficacy outcome measures presented in this document came from the primary completion analysis.

Time frame: Up to 55 months

Population: Intent to treat analysis set: all randomized participants

Time frame: From first dosing up to 30 days after the last administration of study treatments, up to 72.6 months

Population: Safety analysis set with at least one hematology lab assessment: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus), and who in addition had at least one hematology lab assessment. Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.

Time frame: From first dosing till end of study, up to 72.6 months

Population: Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.

According to protocol amendment 10, all participants who completed the EOT visit will be transferred to a separate extended safety follow-up study for their remaining follow-up. Thus, no further post-treatment data were collected after protocol amendment 10.

Time frame: From post-treatment till end of study, up to 45.8 months

Population: Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.

An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a patient or clinical investigation participant after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they started or worsened after first application of study intervention up to 30 days after end of treatment with study intervention. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly; another medical important serious event as judged by the investigator and an occurrence of any additional malignancies, including acute myelocytic leukemia or hematological conditions.

Time frame: From first dosing up to 30 days after the last administration of study treatments, up to 72.6 months

Population: Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.

The time from the date of randomization to the date of death due to any cause. Per Protocol Amendment 10, following primary analysis completion, further assessments were focused on safety, and only limited efficacy data including SSE and survival were collected and not designed to support reconsideration of the primary analysis efficacy conclusions. Accordingly, no formal statistical analyses were performed for primary and secondary efficacy outcomes in the final analysis. All primary and secondary efficacy outcome measures presented in this document came from the primary completion analysis.

Time frame: Up to 55 months

Population: Intent to treat analysis set: all randomized participants

In the percentage of participants with confirmed pain improvement. Confirmed pain improvement is defined a 2-point decrease or more in BPI-SF WPS from baseline over 2 consecutive measurements conducted at least 4 weeks apart, without an increase in pain management (IPM). An IPM is defined as the initiation of any opioid in participants not taking opioids at baseline, the initiation of a strong opioid in participants taking a weak opioid at baseline, or the initiation of an additional strong opioid in participants taking a strong opioid at baseline.

Time frame: Up to 55 months

Population: Safety analysis set with baseline WPS \>= 2: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo exemestane, or everolimus), and who in addition had baseline BPI-SF WPS \>= 2. Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.

Time from the date of randomization to the date of confirmed radiological progression in either soft tissue, viscera or bone, or death (if death occurs before progression). Progression is defined using the modified RECIST 1.1 criteria (the modification refers to bone lesions assessment). Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or an unequivocal increase in non-target lesions, or the appearance of new lesions. All bone lesions are considered non-measurable and new bone lesions identified by bone scan should be confirmed by further imaging (CT/MRI). If a new bone lesion or unequivocal increase in size of bone lesions is only visible on a CT/MRI and not visible on a technetium-99m bone scan, progression should be declared without further confirmation.

Time frame: Up to 55 months

Population: ITT analysis set: included all randomized participants

Time from the date of randomization to the date of the first cytotoxic chemotherapy

Time frame: Up to 55 months

Population: ITT analysis set: included all randomized participants

Interval from the date of randomization to the date of opiate use

Time frame: Up to 55 months

Population: Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.

Time from randomization to the first date a participant experienced pain progression based on WPS. Pain progression was defined as an increase of 2 or more points in the BPI-SF Worst pain in 24 hours score from baseline observed at 2 consecutive evaluations ≥4 weeks apart or an increase in pain management (IPM) with respect to baseline, whichever occurred first. An IPM is defined as the initiation of any opioid in participants not taking opioids at baseline, the initiation of a strong opioid in participants taking a weak opioid at baseline, or the initiation of an additional strong opioid in participants taking a strong opioid at baseline.

Time frame: Up to 55 months

Population: Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.

Time frame: From first dosing till primary analysis cutoff date, up to 55 months

Population: Safety analysis set with at least one hematology lab assessment: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus), and who in addition had at least one hematology lab assessment. Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.

Time frame: From first dosing till primary analysis cutoff date, up to 55 months

Population: Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.

Time frame: From post-treatment till primary analysis cutoff date, up to 55 months

Population: Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.

An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a patient or clinical investigation participant after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they started or worsened after first application of study intervention up to 30 days after end of treatment with study intervention. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly; another medical important serious event as judged by the investigator and an occurrence of any additional malignancies, including acute myelocytic leukemia or hematological conditions.

Time frame: From first dosing till primary analysis cutoff date, up to 55 months

Population: Safety analysis set: all randomized participants who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Participants were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.