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

• Sponsor: Bayer (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02258451
• Collaborator: (none)
• Enrollment: 283
• Locations: 94
• Arms: 2
• Anticipated Duration (Months): 87.9
• Patients Per Site: 3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The objective of this study is to assess efficacy and safety of radium 223 dichloride in subjects with human epidermal growth factor receptor 2 (HER2) negative hormone receptor positive breast cancer with bone metastases treated with exemestane and everolimus

After implementation of CSP Amendment 10, only a limited number of subjects will remain in this study, in order to reduce the burden to study subjects, collection of data will be reduced and will focus mainly on acute safety, SSE, and OS. Once subjects are rolled over, the long-term safety will be collected and assessed entirely in the separate extended safety follow-up study.

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms	Drug: Radium-223 dichloride (Xofigo, BAY88-8223); Drug: Placebo (saline); Drug: Exemestane; Drug: Everolimus	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 283 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II Randomized, Double-blind, Placebo-controlled Trial of Radium-223 Dichloride in Combination With Exemestane and Everolimus Versus Placebo in Combination With Exemestane and Everolimus When Administered to Metastatic HER2 Negative Hormone Receptor Positive Breast Cancer Subjects With Bone Metastases
• Actual Study Start Date: Jun 4, 2015
• Actual Primary Completion Date: Jan 22, 2020
• Anticipated Study Completion Date: Sep 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Radium-223 dichloride + exemestane/everolimus Up to 6 cycles of radium-223 dichloride 50kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) (randomized). Participants will also receive exemestane, 25-mg tablet once daily (after a meal), and everolimus, 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.	Drug: Radium-223 dichloride (Xofigo, BAY88-8223); Up to 6 cycles of radium-223 dichloride 50kBq/kg body (55 kBq/kg after implementation of NIST update); Drug: Exemestane; One 25 mg tablet once daily after a meal.; Drug: Everolimus; The recommended dose of everolimus administered in the study is 10 mg once daily with or without food. Starting dose, dose modifications, and administration of exemestane and everolimus must be in compliance with the local labels in each of the participating countries and/or in line with local standard of practice.
Placebo Comparator: Placebo + exemestane/everolimus Up to 6 cycles of saline injection (placebo) (randomized). Participants will also receive exemestane, 25-mg tablet once daily (after a meal), and everolimus, 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.	Drug: Placebo (saline); Up to 6 cycles of saline injection; Drug: Exemestane; One 25 mg tablet once daily after a meal.; Drug: Everolimus; The recommended dose of everolimus administered in the study is 10 mg once daily with or without food. Starting dose, dose modifications, and administration of exemestane and everolimus must be in compliance with the local labels in each of the participating countries and/or in line with local standard of practice.

Outcome Measures

Primary Outcome Measures

1. Symptomatic Skeletal Event-free Survival (SSE-FS) [Up to 55 months]

   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

Secondary Outcome Measures

1. Overall Survival [Up to 55 months]

   The time from the date of randomization to the date of death due to any cause.

2. Time to Opiate Use for Cancer Pain [Up to 55 months]

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

3. Time to Pain Progression [Up to 55 months]

   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.

4. Time to Cytotoxic Chemotherapy [Up to 55 months]

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

5. Radiological Progression-free Survival (rPFS) [Up to 55 months]

   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.

6. Percentage of Participants With Pain Improvement [Up to 55 months]

   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.

7. Number of Participants With Treatmemt-emergent Adverse Events (TEAEs) [From first dosing up to 30 days after the last administration of study treatments, up to 93 months]

   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 subject 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.

8. Number of Participants With Post-treatment Chemotherapy Related Adverse Events [From post-treatment till end of study, up to 93 months]

9. Number of Participants With Hematological Oxicities: Worst Grade Under Treatment [From first dosing up to 30 days after the last administration of study treatments, up to 93 months]

10. Number of Participants With New Primary Malignancies [From first dosing till end of study, up to 93 months]

Other Outcome Measures

1. Number of Participants With Treatmemt-emergent Adverse Events (TEAEs) [From first dosing till primary analysis cutoff date, up to 55 months]

   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 subject 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.

2. Number of Participants With Post-treatment Chemotherapy Related Adverse Events [From post-treatment till primary analysis cutoff date, up to 55 months]

3. Number of Participants With Hematological Toxicities: Worst Grade Under Treatment [From first dosing till primary analysis cutoff date, up to 55 months]

4. Number of Participants With New Primary Malignancies During Study Treatment or Follow-up Period [From first dosing till primary analysis cutoff date, up to 55 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Women (≥18 years of age) with metastatic breast cancer not amenable to curative treatment by surgery or radiotherapy.

• Documentation of histological or cytological confirmation of estrogen receptor positive (ER+) and HER2 negative adenocarcinoma of the breast must be available.

• Documentation of menopausal status: postmenopausal subjects or pre-menopausal subjects with ovarian radiation or concomitant therapy with a luteinizing hormone-releasing hormone (LH-RH) agonist/antagonist are eligible.

• Subjects with bone dominant disease with at least 2 skeletal metastases identified at baseline by bone scintigraphy and confirmed by computed tomography (CT)/magnetic resonance imaging (MRI).

• Subjects must have received at least one line of hormonal therapy in the metastatic setting.

• Subjects who are eligible as per the Investigator's assessment and according to the local label for treatment with exemestane and everolimus as a second line or greater of hormone therapy in a metastatic setting.

• Subjects must have experienced recurrent/progressive disease following treatment with a non-steroidal aromatase inhibitor (letrozole or anastrozole) in an adjuvant or metastatic setting

• Subjects must have experienced no more than two skeletal-related events (SREs) prior to study entry defined as: need for external beam radiotherapy (EBRT) to bone pain, pathological bone fracture (excluding major trauma), spinal cord compression and/or orthopedic surgical procedure. Subjects with no prior SREs are not permitted.

• Subjects must be on therapy with bisphosphonates or denosumab for at least 1 month before start of study treatment.

• Adequate hematological, liver and kidney function.

Exclusion Criteria:

• Subjects with Inflammatory breast cancer.

• Patients with immediately life-threatening visceral disease for whom chemotherapy is preferred treatment option.

• Subjects who have either received chemotherapy for metastatic disease or are considered by the treating investigator to be appropriate candidates for chemotherapy as current treatment for metastatic breast cancer are excluded. Chemotherapy administered for adjuvant/neo adjuvant disease is acceptable provided it was administered at least 1 year prior to study entry.

• Subjects who received prior treatment or are already receiving everolimus treatment prior to study entry are not eligible.

• Subjects with known or history of brain metastases or leptomeningeal disease: subjects with neurological symptoms must undergo a contrast CT scan or MRI of the brain within 28 days prior to randomization to exclude active brain metastasis. Imaging of the central nervous system (CNS) is otherwise not required.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Yuma	Arizona	United States	85364
2		La Jolla	California	United States	92093
3		Long Beach	California	United States	90813
4		Los Angeles	California	United States	90033
5		New Haven	Connecticut	United States	06510
6		Hollywood	Florida	United States	33021
7		Ashland	Kentucky	United States	41101
8		Rockville	Maryland	United States	20850
9		Ann Arbor	Michigan	United States	48109
10		Detroit	Michigan	United States	48202
11		Pontiac	Michigan	United States	48341
12		Rochester	Minnesota	United States	55905
13		Saint Louis	Missouri	United States	63110
14		Newark	New Jersey	United States	07103
15		Jamaica	New York	United States	11432
16		Watertown	South Dakota	United States	57201
17		Spokane	Washington	United States	99208-1129
18		Innsbruck		Austria	6020
19		Anderlecht		Belgium	1070
20		Edegem		Belgium	2650
21		Kortrijk		Belgium	8500
22		Leuven		Belgium	3000
23		Angers Cedex		France	49055
24		Nantes		France	44805
25		NIMES Cedex 9		France	30029
26		Saint Cloud		France	92210
27		Tours		France	37044
28		Herne	Nordrhein-Westfalen	Germany	44625
29		Chai Wan		Hong Kong
30		Hong Kong		Hong Kong
31		Kowloon		Hong Kong
32		Afula		Israel	1834111
33		Beer Sheva		Israel	8410101
34		Haifa		Israel	3109601
35		Holon		Israel	5822012
36		Jerusalem		Israel	9103102
37		Jerusalem		Israel	9112001
38		Ramat Gan		Israel	5262000
39		Tel Aviv		Israel	64239
40		Zrifin		Israel	7030000
41		Bologna	Emilia-Romagna	Italy	40138
42		Forlì Cesena	Emilia-Romagna	Italy	47014
43		Modena	Emilia-Romagna	Italy	41124
44		Roma	Lazio	Italy	00149
45		Roma	Lazio	Italy	00161
46		Genova	Liguria	Italy	16128
47		Cremona	Lombardia	Italy	26100
48		Milano	Lombardia	Italy	20132
49		Bari	Puglia	Italy	70124
50		Pisa	Toscana	Italy	56126
51		Nagoya	Aichi	Japan	464-8681
52		Sapporo	Hokkaido	Japan	060-8648
53		Osakasayama	Osaka	Japan	589-8511
54		Hidaka	Saitama	Japan	350-1298
55		Kita-Adachigun	Saitama	Japan	362-0806
56		Koto-ku	Tokyo	Japan	135-8550
57		Kagoshima		Japan	892-0833
58		Osaka		Japan	540-0006
59		Suwon-si	Gyeonggido	Korea, Republic of	442-723
60		Seoul	Seoul Teugbyeolsi	Korea, Republic of	03080
61		Busan		Korea, Republic of	49241
62		Daegu		Korea, Republic of	42601
63		Incheon		Korea, Republic of
64		Seoul		Korea, Republic of	05505
65		Oslo		Norway	0424
66		Bialystok		Poland	15-027
67		Gdansk		Poland	80-952
68		Gdynia		Poland	81-519
69		Poznan		Poland	61-485
70		Warszawa		Poland	02-781
71		Singapore		Singapore	119074
72		Singapore		Singapore	169610
73		Singapore		Singapore	258499
74		Palma de Mallorca	Illes Baleares	Spain	07120
75		Barcelona		Spain	08035
76		Barcelona		Spain	08036
77		Barcelona		Spain	08041
78		Madrid		Spain	28033
79		Madrid		Spain	28041
80		Madrid		Spain	28046
81		Madrid		Spain	28050
82		Pamplona		Spain	31008
83		Sevilla		Spain	41013
84		Sevilla		Spain	41071
85		Aarau	Aargau	Switzerland	5001
86		Kaoshiung		Taiwan	81346
87		Taichung		Taiwan	40705
88		Taipei		Taiwan
89		Truro	Cornwall	United Kingdom	TR1 3LJ
90		Plymouth	Devon	United Kingdom	PL6 8DH
91		Nottingham	Nottinghamshire	United Kingdom	NG5 1PB
92		Taunton	Somerset	United Kingdom	TA1 5DA
93		Bristol		United Kingdom	BS2 8ED
94		Merseyside		United Kingdom	CH63 4JY

Sponsors and Collaborators

• Bayer

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

• Study Protocol - Dec 4, 2019
• Statistical Analysis Plan - Jun 24, 2020

More Information

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT02258451
• Other Study ID Numbers: 17096; 2014-002114-23
• First Posted: Oct 7, 2014
• Last Update Posted: Jul 27, 2022
• Last Verified: Jul 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Bayer: Breast Cancer
• Additional relevant MeSH terms: Breast Neoplasms; Everolimus; Exemestane; Radium Ra 223 dichloride

Study Results

Participant Flow

Recruitment Details	The study was conducted at 92 centers in 17 countries with first participant first visit on 04-JUN-2015 and primary completion on 22-JAN-2020. The study is still ongoing.
Pre-assignment Detail	Overall, 389 participants were screened and 283 were assigned to treatment. Of these, 142 in the radium 223 dichloride arm and 141 in the placebo arm.

Arm/Group Title	Radium-223 + EXE/EVE	Placebo + EXE/EVE
Arm/Group Description	Participants randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice	Participants randomized to treatment with placebo, also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice
Period Title: Overall Study
STARTED	142	141
COMPLETED	0	0
NOT COMPLETED	142	141

Baseline Characteristics

Arm/Group Title	Radium-223 + EXE/EVE	Placebo + EXE/EVE	Total
Arm/Group Description	Participants randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice	Participants randomized to treatment with placebo, also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice	Total of all reporting groups
Overall Participants	142	141	283
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.95 (10.40)	59.08 (11.64)	59.52 (11.02)
Sex: Female, Male (Count of Participants)
Female	142 100%	141 100%	283 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 2.1%	5 3.5%	8 2.8%
Not Hispanic or Latino	127 89.4%	125 88.7%	252 89%
Unknown or Not Reported	12 8.5%	11 7.8%	23 8.1%

Outcome Measures

1. Primary Outcome

Title	Symptomatic Skeletal Event-free Survival (SSE-FS)
Description	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
Time Frame	Up to 55 months

Outcome Measure Data

Analysis Population Description

ITT analysis set: included all randomized subjects.

Arm/Group Title	Radium-223 + EXE/EVE	Placebo + EXE/EVE
Arm/Group Description	Participants randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice	Participants randomized to treatment with placebo, also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice
Measure Participants	142	141
Median (95% Confidence Interval) [Months]	21.1	19.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 + EXE/EVE, Placebo + EXE/EVE
	Comments	The 1-sided null hypothesis that treatment with radium-223 dichloride does not result in superior SSE-FS to treatment with placebo in subject population was tested against the 1-sided alternative hypothesis that the treatment with radium-223 dichloride results in superior SSE-FS time to treatment the placebo. H0: SSE-FSRadium-223+Exemestane/Everolimus <= SSE-FS Placebo+Exemestane/Everolimus, versus HA: SSE-FSRadium-223+Exemestane/Everolimus > SSE-FS Placebo+Exemestane/Everolimus
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4843
	Comments	1-sided SSE-FS hypotheses were tested using a log-rank test with a 2-sided alpha of 0.2, stratified by the randomization stratification factors.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.891
	Confidence Interval	(2-Sided) 80%; 0.720 to 1.102
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (radium-223 dichloride / placebo) for SSE-FS was calculated using Cox Proportional Hazards Model, stratified by the same stratification factors as randomization.

2. Secondary Outcome

Title	Overall Survival
Description	The time from the date of randomization to the date of death due to any cause.
Time Frame	Up to 55 months

Outcome Measure Data

Analysis Population Description

Intent to treat analysis set: all randomized participants

Arm/Group Title	Radium-223 + EXE/EVE	Placebo + EXE/EVE
Arm/Group Description	Participants randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice	Participants randomized to treatment with placebo, also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice
Measure Participants	142	141
Median (95% Confidence Interval) [Months]	25.0	26.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 + EXE/EVE, Placebo + EXE/EVE
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8438
	Comments	P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.968
	Confidence Interval	(2-Sided) 95%; 0.697 to 1.343
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (radium-223 dichloride / placebo) was calculated using Cox Proportional Hazards Model , stratified by the same stratification factors as randomization.

3. Secondary Outcome

Title	Time to Opiate Use for Cancer Pain
Description	Interval from the date of randomization to the date of opiate use
Time Frame	Up to 55 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Radium-223 + EXE/EVE	Placebo + EXE/EVE
Arm/Group Description	Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice	Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice
Measure Participants	139	139
Median (95% Confidence Interval) [Months]	21.4	18.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 + EXE/EVE, Placebo + EXE/EVE
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8811
	Comments	P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.962
	Confidence Interval	(2-Sided) 95%; 0.577 to 1.604
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (radium-223 dichloride / placebo) was calculated using Cox Proportional Hazards Model , stratified by the same stratification factors as randomization.

4. Secondary Outcome

Title	Time to Pain Progression
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Radium-223 + EXE/EVE	Placebo + EXE/EVE
Arm/Group Description	Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice	Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice
Measure Participants	139	139
Median (95% Confidence Interval) [Months]	7.6	5.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 + EXE/EVE, Placebo + EXE/EVE
	Comments	Participants with baseline WPS > 8 were included in the analysis population but censored at Day 1.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6537
	Comments	P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.928
	Confidence Interval	(2-Sided) 95%; 0.667 to 1.289
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (radium-223 dichloride / placebo) was calculated using Cox Proportional Hazards Model , stratified by the same stratification factors as randomization.

5. Secondary Outcome

Title	Time to Cytotoxic Chemotherapy
Description	Time from the date of randomization to the date of the first cytotoxic chemotherapy
Time Frame	Up to 55 months

Outcome Measure Data

Analysis Population Description

ITT analysis set: included all randomized subjects.

Arm/Group Title	Radium-223 + EXE/EVE	Placebo + EXE/EVE
Arm/Group Description	Participants randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice	Participants randomized to treatment with placebo, also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice
Measure Participants	142	141
Median (95% Confidence Interval) [Months]	13.7	11.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 + EXE/EVE, Placebo + EXE/EVE
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4496
	Comments	P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.884
	Confidence Interval	(2-Sided) 95%; 0.641 to 1.219
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (radium-223 dichloride / placebo) was calculated using Cox Proportional Hazards Model , stratified by the same stratification factors as randomization.

6. Secondary Outcome

Title	Radiological Progression-free Survival (rPFS)
Description	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

Outcome Measure Data

Analysis Population Description

ITT analysis set: included all randomized subjects.

Arm/Group Title	Radium-223 + EXE/EVE	Placebo + EXE/EVE
Arm/Group Description	Participants randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice	Participants randomized to treatment with placebo, also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice
Measure Participants	142	141
Median (95% Confidence Interval) [Months]	7.9	6.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 + EXE/EVE, Placebo + EXE/EVE
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3467
	Comments	P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.874
	Confidence Interval	(2-Sided) 95%; 0.660 to 1.157
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (radium-223 dichloride / placebo) was calculated using Cox Proportional Hazards Model , stratified by the same stratification factors as randomization.

7. Secondary Outcome

Title	Percentage of Participants With Pain Improvement
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Radium-223 + EXE/EVE	Placebo + EXE/EVE
Arm/Group Description	Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice	Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice
Measure Participants	91	96
Number (95% Confidence Interval) [percentage of participants]	38.5 27.1%	34.4 24.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radium-223 + EXE/EVE, Placebo + EXE/EVE
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.556
	Comments	P-value was calculated using a 2-sided Cochran-Mantel-Haenszel test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	4.1
	Confidence Interval	(2-Sided) 95%; -10.2 to 18.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Number of Participants With Treatmemt-emergent Adverse Events (TEAEs)
Description	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 subject 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.
Time Frame	From first dosing up to 30 days after the last administration of study treatments, up to 93 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Number of Participants With Post-treatment Chemotherapy Related Adverse Events
Time Frame	From post-treatment till end of study, up to 93 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Number of Participants With Hematological Oxicities: Worst Grade Under Treatment
Time Frame	From first dosing up to 30 days after the last administration of study treatments, up to 93 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Number of Participants With New Primary Malignancies
Time Frame	From first dosing till end of study, up to 93 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Other Pre-specified Outcome

Title	Number of Participants With Treatmemt-emergent Adverse Events (TEAEs)
Description	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 subject 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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Radium-223 + EXE/EVE	Placebo + EXE/EVE
Arm/Group Description	Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice	Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice
Measure Participants	139	139
Any TEAE	139 97.9%	136 96.5%
Serious TEAE	57 40.1%	53 37.6%
Radium-223/Placebo-related TEAEs	73 51.4%	50 35.5%
Exemestane-related TEAEs	75 52.8%	64 45.4%
Everolimus-related TEAEs	130 91.5%	125 88.7%

13. Other Pre-specified Outcome

Title	Number of Participants With Post-treatment Chemotherapy Related Adverse Events
Time Frame	From post-treatment till primary analysis cutoff date, up to 55 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Radium-223 + EXE/EVE	Placebo + EXE/EVE
Arm/Group Description	Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice	Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice
Measure Participants	139	139
All system organ classes_Any_Grade 3	1 0.7%	0 0%
All system organ classes_Any_Grade 4	1 0.7%	0 0%
Blood and lymphatic system disorders_Any_Grade 3	1 0.7%	0 0%
Blood and lymphatic system disorders_Febrile neutropenia_Grade 3	1 0.7%	0 0%
Investigations_Any_Grade 4	1 0.7%	0 0%
Investigations_Neutrophil count decreased_Grade 4	1 0.7%	0 0%

14. Other Pre-specified Outcome

Title	Number of Participants With Hematological Toxicities: Worst Grade Under Treatment
Time Frame	From first dosing till primary analysis cutoff date, up to 55 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Radium-223 + EXE/EVE	Placebo + EXE/EVE
Arm/Group Description	Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice	Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice
Measure Participants	139	137
Grade 1	61 43%	57 40.4%
Grade 2	43 30.3%	55 39%
Grade 3	21 14.8%	11 7.8%
Grade 4	0 0%	0 0%
Normal	14 9.9%	14 9.9%
Grade 1	0 0%	0 0%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Normal	139 97.9%	137 97.2%
Grade 1	0 0%	0 0%
Grade 2	1 0.7%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Normal	138 97.2%	137 97.2%
Grade 1	20 14.1%	33 23.4%
Grade 2	63 44.4%	45 31.9%
Grade 3	43 30.3%	24 17%
Grade 4	2 1.4%	0 0%
Normal	11 7.7%	35 24.8%
Grade 1	0 0%	0 0%
Grade 2	2 1.4%	2 1.4%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Normal	137 96.5%	135 95.7%
Grade 1	24 16.9%	29 20.6%
Grade 2	47 33.1%	28 19.9%
Grade 3	19 13.4%	0 0%
Grade 4	0 0%	2 1.4%
Normal	49 34.5%	78 55.3%
Grade 1	60 42.3%	61 43.3%
Grade 2	7 4.9%	2 1.4%
Grade 3	7 4.9%	0 0%
Grade 4	1 0.7%	0 0%
Normal	64 45.1%	74 52.5%
Grade 1	37 26.1%	47 33.3%
Grade 2	59 41.5%	36 25.5%
Grade 3	17 12%	3 2.1%
Grade 4	1 0.7%	1 0.7%
Normal	25 17.6%	50 35.5%

15. Other Pre-specified Outcome

Title	Number of Participants With New Primary Malignancies During Study Treatment or Follow-up Period
Time Frame	From first dosing till primary analysis cutoff date, up to 55 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Radium-223 + EXE/EVE	Placebo + EXE/EVE
Arm/Group Description	Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice	Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice
Measure Participants	139	139
Count of Participants [Participants]	1 0.7%	0 0%

Adverse Events

Time Frame	From first dosing till primary analysis cutoff date, up to 55 months
Arm/Group Title	Radium-223 + EXE/EVE		Placebo + EXE/EVE
Arm/Group Description	Participants who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25-mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice		Participants did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25-mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice
All Cause Mortality
	Radium-223 + EXE/EVE		Placebo + EXE/EVE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	72/139 (51.8%)		70/139 (50.4%)
Serious Adverse Events
	Radium-223 + EXE/EVE		Placebo + EXE/EVE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/139 (43.9%)		54/139 (38.8%)
Blood and lymphatic system disorders
Anaemia	3/139 (2.2%)	6	5/139 (3.6%)	12
Febrile neutropenia	2/139 (1.4%)	2	0/139 (0%)	0
Thrombocytopenia	1/139 (0.7%)	2	0/139 (0%)	0
Cardiac disorders
Atrial fibrillation	1/139 (0.7%)	1	0/139 (0%)	0
Atrial flutter	0/139 (0%)	0	2/139 (1.4%)	2
Pericardial effusion	0/139 (0%)	0	1/139 (0.7%)	1
Gastrointestinal disorders
Abdominal pain upper	0/139 (0%)	0	1/139 (0.7%)	1
Colitis	0/139 (0%)	0	1/139 (0.7%)	1
Colitis ischaemic	0/139 (0%)	0	1/139 (0.7%)	1
Diarrhoea	3/139 (2.2%)	6	0/139 (0%)	0
Dysphagia	0/139 (0%)	0	1/139 (0.7%)	1
Enteritis	1/139 (0.7%)	1	0/139 (0%)	0
Gastrointestinal haemorrhage	1/139 (0.7%)	1	0/139 (0%)	0
Nausea	1/139 (0.7%)	1	0/139 (0%)	0
Small intestinal obstruction	0/139 (0%)	0	1/139 (0.7%)	1
Stomatitis	1/139 (0.7%)	1	0/139 (0%)	0
Vomiting	2/139 (1.4%)	3	2/139 (1.4%)	2
Subileus	0/139 (0%)	0	1/139 (0.7%)	2
General disorders
Death	0/139 (0%)	0	2/139 (1.4%)	2
Fatigue	1/139 (0.7%)	1	0/139 (0%)	0
Injection site extravasation	0/139 (0%)	0	1/139 (0.7%)	1
Malaise	1/139 (0.7%)	1	1/139 (0.7%)	2
Oedema peripheral	0/139 (0%)	0	2/139 (1.4%)	2
Pain	1/139 (0.7%)	1	0/139 (0%)	0
Pyrexia	2/139 (1.4%)	2	3/139 (2.2%)	5
Sudden death	1/139 (0.7%)	1	0/139 (0%)	0
Performance status decreased	0/139 (0%)	0	1/139 (0.7%)	2
General physical health deterioration	2/139 (1.4%)	3	3/139 (2.2%)	4
Multiple organ dysfunction syndrome	0/139 (0%)	0	1/139 (0.7%)	2
Hepatobiliary disorders
Cholecystitis	0/139 (0%)	0	1/139 (0.7%)	1
Hepatic failure	1/139 (0.7%)	1	0/139 (0%)	0
Hepatic function abnormal	1/139 (0.7%)	2	0/139 (0%)	0
Hepatic haematoma	1/139 (0.7%)	1	0/139 (0%)	0
Infections and infestations
Appendicitis	1/139 (0.7%)	1	0/139 (0%)	0
Cellulitis	2/139 (1.4%)	3	1/139 (0.7%)	1
Erysipelas	1/139 (0.7%)	1	0/139 (0%)	0
Gastroenteritis	2/139 (1.4%)	2	1/139 (0.7%)	1
Influenza	1/139 (0.7%)	1	0/139 (0%)	0
Labyrinthitis	1/139 (0.7%)	1	0/139 (0%)	0
Lower respiratory tract infection	1/139 (0.7%)	1	0/139 (0%)	0
Pneumonia	5/139 (3.6%)	6	2/139 (1.4%)	2
Pseudomembranous colitis	1/139 (0.7%)	1	0/139 (0%)	0
Pyelonephritis acute	0/139 (0%)	0	1/139 (0.7%)	2
Sepsis	0/139 (0%)	0	1/139 (0.7%)	2
Sinusitis	1/139 (0.7%)	1	0/139 (0%)	0
Skin infection	0/139 (0%)	0	1/139 (0.7%)	1
Upper respiratory tract infection	1/139 (0.7%)	1	0/139 (0%)	0
Urinary tract infection	1/139 (0.7%)	2	2/139 (1.4%)	2
Vestibular neuronitis	1/139 (0.7%)	1	0/139 (0%)	0
Wound infection	0/139 (0%)	0	1/139 (0.7%)	1
Febrile infection	1/139 (0.7%)	1	0/139 (0%)	0
Biliary tract infection	0/139 (0%)	0	1/139 (0.7%)	1
Stoma site infection	0/139 (0%)	0	1/139 (0.7%)	1
Investigations
Biopsy lung	0/139 (0%)	0	1/139 (0.7%)	1
Haemoglobin decreased	0/139 (0%)	0	1/139 (0.7%)	1
Influenza A virus test positive	1/139 (0.7%)	1	0/139 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/139 (0.7%)	1	0/139 (0%)	0
Diabetes mellitus	1/139 (0.7%)	1	0/139 (0%)	0
Hypercalcaemia	0/139 (0%)	0	1/139 (0.7%)	2
Hyperglycaemia	1/139 (0.7%)	2	0/139 (0%)	0
Hypokalaemia	1/139 (0.7%)	1	0/139 (0%)	0
Hyponatraemia	0/139 (0%)	0	1/139 (0.7%)	1
Decreased appetite	0/139 (0%)	0	2/139 (1.4%)	4
Musculoskeletal and connective tissue disorders
Arthralgia	1/139 (0.7%)	1	1/139 (0.7%)	1
Back pain	0/139 (0%)	0	2/139 (1.4%)	3
Bone pain	2/139 (1.4%)	2	1/139 (0.7%)	2
Muscular weakness	0/139 (0%)	0	2/139 (1.4%)	5
Pathological fracture	3/139 (2.2%)	3	4/139 (2.9%)	4
Synovitis	0/139 (0%)	0	1/139 (0.7%)	1
Osteonecrosis of jaw	2/139 (1.4%)	2	0/139 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant pleural effusion	1/139 (0.7%)	1	0/139 (0%)	0
Metastases to ovary	0/139 (0%)	0	1/139 (0.7%)	1
Metastases to meninges	2/139 (1.4%)	4	0/139 (0%)	0
Colon cancer metastatic	1/139 (0.7%)	1	0/139 (0%)	0
Cancer pain	1/139 (0.7%)	1	0/139 (0%)	0
Nervous system disorders
Dizziness	1/139 (0.7%)	1	0/139 (0%)	0
Dysmetria	0/139 (0%)	0	1/139 (0.7%)	1
Facial paralysis	0/139 (0%)	0	2/139 (1.4%)	2
Headache	0/139 (0%)	0	1/139 (0.7%)	1
Paraparesis	1/139 (0.7%)	1	0/139 (0%)	0
Radiculopathy	0/139 (0%)	0	1/139 (0.7%)	1
Spinal cord compression	2/139 (1.4%)	2	1/139 (0.7%)	3
Lumbar radiculopathy	1/139 (0.7%)	1	0/139 (0%)	0
Neurological decompensation	1/139 (0.7%)	1	0/139 (0%)	0
Psychiatric disorders
Hallucination	0/139 (0%)	0	1/139 (0.7%)	1
Renal and urinary disorders
Hydronephrosis	1/139 (0.7%)	1	1/139 (0.7%)	1
Urinary bladder polyp	0/139 (0%)	0	1/139 (0.7%)	1
Urinary tract obstruction	0/139 (0%)	0	1/139 (0.7%)	1
Acute kidney injury	1/139 (0.7%)	3	3/139 (2.2%)	3
Respiratory, thoracic and mediastinal disorders
Asthma	1/139 (0.7%)	1	0/139 (0%)	0
Chronic obstructive pulmonary disease	0/139 (0%)	0	1/139 (0.7%)	1
Dyspnoea	1/139 (0.7%)	1	4/139 (2.9%)	7
Epistaxis	1/139 (0.7%)	2	0/139 (0%)	0
Interstitial lung disease	1/139 (0.7%)	2	0/139 (0%)	0
Pleural effusion	0/139 (0%)	0	1/139 (0.7%)	3
Pneumonitis	7/139 (5%)	11	2/139 (1.4%)	2
Pulmonary embolism	2/139 (1.4%)	3	0/139 (0%)	0
Respiratory failure	1/139 (0.7%)	1	0/139 (0%)	0
Skin and subcutaneous tissue disorders
Urticaria	0/139 (0%)	0	1/139 (0.7%)	2
Other (Not Including Serious) Adverse Events
	Radium-223 + EXE/EVE		Placebo + EXE/EVE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	139/139 (100%)		135/139 (97.1%)
Blood and lymphatic system disorders
Anaemia	54/139 (38.8%)	189	40/139 (28.8%)	142
Leukopenia	12/139 (8.6%)	49	2/139 (1.4%)	3
Neutropenia	29/139 (20.9%)	73	11/139 (7.9%)	11
Thrombocytopenia	22/139 (15.8%)	58	9/139 (6.5%)	19
Ear and labyrinth disorders
Vertigo	7/139 (5%)	8	1/139 (0.7%)	1
Gastrointestinal disorders
Abdominal pain	7/139 (5%)	7	10/139 (7.2%)	12
Abdominal pain upper	14/139 (10.1%)	17	7/139 (5%)	8
Constipation	6/139 (4.3%)	7	20/139 (14.4%)	23
Diarrhoea	42/139 (30.2%)	66	31/139 (22.3%)	52
Dry mouth	10/139 (7.2%)	13	9/139 (6.5%)	9
Dyspepsia	7/139 (5%)	8	7/139 (5%)	8
Mouth ulceration	3/139 (2.2%)	3	10/139 (7.2%)	19
Nausea	41/139 (29.5%)	55	30/139 (21.6%)	41
Stomatitis	66/139 (47.5%)	144	69/139 (49.6%)	165
Vomiting	25/139 (18%)	32	22/139 (15.8%)	31
General disorders
Asthenia	29/139 (20.9%)	48	25/139 (18%)	49
Chest pain	4/139 (2.9%)	4	7/139 (5%)	7
Fatigue	38/139 (27.3%)	66	41/139 (29.5%)	60
Oedema peripheral	26/139 (18.7%)	37	25/139 (18%)	32
Pyrexia	20/139 (14.4%)	27	13/139 (9.4%)	16
Peripheral swelling	8/139 (5.8%)	8	9/139 (6.5%)	16
Infections and infestations
Conjunctivitis	8/139 (5.8%)	8	3/139 (2.2%)	3
Cystitis	4/139 (2.9%)	4	7/139 (5%)	8
Nasopharyngitis	7/139 (5%)	7	5/139 (3.6%)	6
Upper respiratory tract infection	15/139 (10.8%)	22	20/139 (14.4%)	38
Urinary tract infection	12/139 (8.6%)	16	12/139 (8.6%)	14
Investigations
Alanine aminotransferase increased	21/139 (15.1%)	51	23/139 (16.5%)	50
Aspartate aminotransferase increased	19/139 (13.7%)	44	21/139 (15.1%)	40
Blood cholesterol increased	15/139 (10.8%)	21	10/139 (7.2%)	22
Blood creatinine increased	11/139 (7.9%)	26	9/139 (6.5%)	21
Lymphocyte count decreased	8/139 (5.8%)	36	7/139 (5%)	14
Neutrophil count decreased	14/139 (10.1%)	43	6/139 (4.3%)	9
Platelet count decreased	12/139 (8.6%)	42	12/139 (8.6%)	26
Weight decreased	28/139 (20.1%)	37	22/139 (15.8%)	30
White blood cell count decreased	13/139 (9.4%)	43	12/139 (8.6%)	29
Metabolism and nutrition disorders
Hypercholesterolaemia	12/139 (8.6%)	28	5/139 (3.6%)	6
Hyperglycaemia	17/139 (12.2%)	36	17/139 (12.2%)	40
Hypertriglyceridaemia	12/139 (8.6%)	28	10/139 (7.2%)	36
Hypocalcaemia	4/139 (2.9%)	4	8/139 (5.8%)	14
Hypokalaemia	19/139 (13.7%)	29	14/139 (10.1%)	27
Hypophosphataemia	11/139 (7.9%)	16	8/139 (5.8%)	37
Decreased appetite	48/139 (34.5%)	68	35/139 (25.2%)	43
Musculoskeletal and connective tissue disorders
Arthralgia	27/139 (19.4%)	41	35/139 (25.2%)	59
Back pain	17/139 (12.2%)	19	27/139 (19.4%)	37
Bone pain	16/139 (11.5%)	31	24/139 (17.3%)	34
Musculoskeletal pain	11/139 (7.9%)	14	17/139 (12.2%)	22
Myalgia	9/139 (6.5%)	10	7/139 (5%)	8
Pain in extremity	21/139 (15.1%)	28	22/139 (15.8%)	32
Pathological fracture	16/139 (11.5%)	22	15/139 (10.8%)	22
Musculoskeletal chest pain	6/139 (4.3%)	7	11/139 (7.9%)	14
Osteonecrosis of jaw	9/139 (6.5%)	12	2/139 (1.4%)	4
Spinal pain	7/139 (5%)	10	9/139 (6.5%)	13
Nervous system disorders
Dizziness	9/139 (6.5%)	11	9/139 (6.5%)	12
Dysgeusia	17/139 (12.2%)	26	13/139 (9.4%)	14
Headache	25/139 (18%)	35	30/139 (21.6%)	41
Psychiatric disorders
Insomnia	15/139 (10.8%)	15	12/139 (8.6%)	14
Respiratory, thoracic and mediastinal disorders
Cough	25/139 (18%)	37	26/139 (18.7%)	37
Dyspnoea	16/139 (11.5%)	20	17/139 (12.2%)	23
Epistaxis	9/139 (6.5%)	12	14/139 (10.1%)	15
Pneumonitis	16/139 (11.5%)	20	16/139 (11.5%)	19
Oropharyngeal pain	7/139 (5%)	8	8/139 (5.8%)	10
Skin and subcutaneous tissue disorders
Dermatitis acneiform	7/139 (5%)	11	9/139 (6.5%)	31
Dry skin	8/139 (5.8%)	8	12/139 (8.6%)	12
Pruritus	17/139 (12.2%)	18	14/139 (10.1%)	19
Rash	21/139 (15.1%)	30	30/139 (21.6%)	44
Rash maculo-papular	9/139 (6.5%)	11	7/139 (5%)	14
Vascular disorders
Hypertension	13/139 (9.4%)	22	7/139 (5%)	11

Limitations/Caveats

Due to reassessment of the Primary Completion date (PCD) conditions, PCD was moved back to 22 January 2020. Interim survival data on patients transferring from this study to study 16996 (NCT02312960), as of analysis cutoff, was pooled with this study's data to increase the reliability of efficacy results. This pooling was specified in a supplemental SAP dated 24 Jun 2020. All other primary and secondary analysis details were specified in the main study SAP dated 14 Feb 2020.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Where done for the purpose of filing a patent application, and where deemed necessary, the Sponsor/Bayer may request the PI of the Trial to postpone by 90 days the publication or presentation of a paper. The PI of the Trial may not publish the data yielded by its Site until all the results of the trial (in the case of a multi-center trial) have been published in their entirety or until at least 12 months have passed following completion, discontinuation or early termination of the Trial.