A Phase III Study of Radium-223 Dichloride in Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases

Bone Metastases Clinical Trial

— ALSYMPCA  

Official title:

A Double-blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00699751
• Other study ID #: 15245
• Secondary ID: BC1-062007-00619
• Status: Completed
• Phase: Phase 3
• First received: June 17, 2008
• Last updated: October 26, 2015
• Start date: June 2008
• Est. completion date: February 2014

Study information

• Verified date: October 2015
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Health authority: Australia: Department of Health and Ageing Therapeutic Goods AdministrationBelgium: Ministry of Social Affairs, Public Health and the EnvironmentBrazil: Ministry of HealthCanada: Canadian Institutes of Health ResearchCzech Republic: State Institute for Drug ControlFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesHong Kong: Department of HealthItaly: Ministry of HealthNetherlands: Medicines Evaluation Board (MEB)Norway: Norwegian Medicines AgencyPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsSingapore: Health Sciences AuthoritySpain: Spanish Agency of MedicinesSlovakia: State Institute for Drug ControlSweden: Medical Products AgencyUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyIsrael: Israeli Health Ministry Pharmaceutical AdministrationUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

ALSYMPCA (ALpharadin in SYMPtomatic Prostate CAncer) is an international Phase III clinical study to evaluate the efficacy and safety of Radium-223 dichloride in patients with hormone refractory prostate cancer and skeletal metastases.

Description:

The aim of the study was to compare, in patients with symptomatic hormone refractory prostate cancer (HRPC) and skeletal metastases, the efficacy of best standard of care plus Radium-223 dichloride versus best standard of care plus placebo, with the primary efficacy endpoint being overall survival (OS).

Patients were randomised in a 2:1 allocation ratio (Radium-223 dichloride:Placebo). The study treatment consisted of 6 intravenous administrations of Radium-223 dichloride or placebo (saline) each separated by an interval of 4 weeks. The patient were followed until 3 years after first study drug administration.

Within the U.S., the trial was conducted under an IND sponsored by Bayer HealthCare Pharmaceuticals.

All patients received BSoC (Best Standard of Care).

This study has the original PCD as 14 October 2010, when a total of 316 deaths had been observed; this resulted in the Independent Data Monitoring Committee's (IDMC's) recommendation to stop the study as the primary efficacy analysis of overall survival had crossed the pre-specified boundary for efficacy. Later an updated analysis of primary endpoint in the first addendum was done with cut-off of 15 July 2011.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 921
• Est. completion date: February 2014
• Est. primary completion date: July 2011
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the prostate

• Known hormone refractory disease

• Multiple skeletal metastases (= 2 hot spots) on bone scintigraphy

• No intention to use cytotoxic chemotherapy within the next 6 months

• Either regular (not occasional) analgesic medication use for cancer related bone pain or treatment with EBRT (External Beam Radiation Therapy) for bone pain

Exclusion Criteria:

• Treatment with an investigational drug within previous 4 weeks, or planned during the treatment period

• Eligible for first course of docetaxel, i.e. patients who are fit enough, willing and where docetaxel is available

• Treatment with cytotoxic chemotherapy within previous 4 weeks, or planned during the treatment period, or failure to recover from adverse events due to cytotoxic chemotherapy administered more than 4 weeks ago

• Systemic radiotherapy with strontium-89, samarium-153, rhenium-186 or rhenium-188 for the treatment of bony metastases within previous 24 weeks

• Other malignancy treated within the last 5 years (except non-melanoma skin cancer or low-grade superficial bladder cancer)

• History of visceral metastasis, or visceral metastases as assessed by abdominal/pelvic CT or chest x-ray within previous 8 weeks

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Bone Metastases
• Hormone Refractory Prostate Cancer
• Neoplasm Metastasis
• Prostatic Neoplasms

Intervention

Drug:
• Radium-223 dichloride (Xofigo, BAY88-8223)
Radium-223 dichloride 50 kBq/kg b.w., 6 IV administrations separated by 4 weeks intervals.
• Placebo
Isotonic saline 6 IV administrations separated by 4 weeks intervals.
• Best standard of care (BSoC)
Best standard of care is regarded as the routine standard of care at each center, for example local EBRT (External Beam Radiation Therapy), corticosteroids, antiandrogens, estrogens (e.g., stilboestrol), estramustine or ketoconazole.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  Czech Republic,  France,  Germany,  Hong Kong,  Israel,  Italy,  Netherlands,  Norway,  Poland,  Singapore,  Slovakia,  Spain,  Sweden,  United Kingdom, 

References & Publications (10)

Delacruz A, Arauz G, Curley T, Lindo A, Jensen T. Nursing management of patients with castration-resistant prostate cancer undergoing radium-223 dichloride treatment. Clin J Oncol Nurs. 2015 Apr;19(2):E31-5. doi: 10.1188/15.CJON.E31-E35. — View Citation

Den RB, Doyle LA, Knudsen KE. Practical guide to the use of radium 223 dichloride. Can J Urol. 2014 Apr;21(2 Supp 1):70-6. Review. — View Citation

Hoskin P, Sartor O, O'Sullivan JM, Johannessen DC, Helle SI, Logue J, Bottomley D, Nilsson S, Vogelzang NJ, Fang F, Wahba M, Aksnes AK, Parker C. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and sympto — View Citation

Humm JL, Sartor O, Parker C, Bruland OS, Macklis R. Radium-223 in the treatment of osteoblastic metastases: a critical clinical review. Int J Radiat Oncol Biol Phys. 2015 Apr 1;91(5):898-906. doi: 10.1016/j.ijrobp.2014.12.061. Review. — View Citation

Joung JY, Ha YS, Kim IY. Radium Ra 223 dichloride in castration-resistant prostate cancer. Drugs Today (Barc). 2013 Aug;49(8):483-90. doi: 10.1358/dot.2013.49.8.1968670. — View Citation

Nilsson S. Alpha-emitter radium-223 in the management of solid tumors: current status and future directions. Am Soc Clin Oncol Educ Book. 2014:e132-9. doi: 10.14694/EdBook_AM.2014.34.e132. Review. — View Citation

Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzén L, Coleman — View Citation

Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Widmark A, Johannessen DC, Hoskin P, James ND, Solberg A, Syndikus I, Vogelzang NJ, O'Bryan-Tear CG, Shan M, Bruland ØS, Parker C. Effect of rad — View Citation

Shirley M, McCormack PL. Radium-223 dichloride: a review of its use in patients with castration-resistant prostate cancer with symptomatic bone metastases. Drugs. 2014 Apr;74(5):579-86. doi: 10.1007/s40265-014-0198-4. Review. — View Citation

Wissing MD, van Leeuwen FW, van der Pluijm G, Gelderblom H. Radium-223 chloride: Extending life in prostate cancer patients by treating bone metastases. Clin Cancer Res. 2013 Nov 1;19(21):5822-7. doi: 10.1158/1078-0432.CCR-13-1896. Epub 2013 Sep 19. Revie — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 0.	ECOG PS was defined as: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work, office work); 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; or 5 = Dead.	Week 0	No
Other	Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 8.	ECOG PS was defined as: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work, office work); 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; or 5 = Dead.	Week 8	No
Other	Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 16.	ECOG PS was defined as: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work, office work); 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; or 5 = Dead.	Week 16	No
Other	Number of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Week 24.	ECOG PS was defined as: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light house work, office work); 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; or 5 = Dead.	Week 24	No
Other	Absolute Scores for Functional Assessment of Cancer Therapy - Prostate (FACT-P) Trial Outcome Index (TOI)	The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. It was supplemented by 12 questions relating to prostate cancer. The absolute score for the FACT-P TOI domain (physical and social well-being and prostate specific score) was calculated for each visit. Prostate Cancer Trial Outcome Index (TOI): Physical Well-being (PWB) + Functional Well-being (FWB) + Prostate Cancer (PCS). Score ranges from 0 (worst) to 104 (best).	Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)	No
Other	Changes From Baseline for FACT-P Trial Outcome Index (TOI) at Week 16, Week 24, and Follow-up Visit 2 (Week 42)	The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. It was supplemented by 12 questions relating to prostate cancer. The absolute score for the FACT-P TOI domain (physical and social well-being and prostate specific score) was calculated for each visit. Possible scores were 0 to 104; the higher the score, the better the quality of life. The changes from baseline (range -104 to 104) in the domain FACT-P TOI were summarized using descriptive statistics at Week 16, Week 24, and Follow-up Visit 2.	Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)	No
Other	Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 16	The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being and was supplemented by 12 questions relating to prostate cancer. Possible scores for each subscale were 0 to 28; 0 to 28; 0 to 24; 0 to 28; and 0 to 48, respectively. All FACT-P items are scored on a scale of 0-4 representing the extent to which the item reflects the experience of the individual completing the instrument (0 - Not at all; 4 - Very much). Higher scores indicate better quality of life. The absolute score of the FACT-P total score was calculated at Week 16.	At Week 16	No
Other	Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Week 24	The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being and was supplemented by 12 questions relating to prostate cancer. Possible scores for each subscale were 0 to 28; 0 to 28; 0 to 24; 0 to 28; and 0 to 48, respectively. All FACT-P items are scored on a scale of 0-4 representing the extent to which the item reflects the experience of the individual completing the instrument (0 - Not at all; 4 - Very much). Higher scores indicate better quality of life. The absolute score of the FACT-P total score was calculated at Week 24.	At Week 24	No
Other	Absolute Scores for Physical Well Being, Social/Family Well Being, Emotional Well Being, Functional Well Being, and the Prostate Cancer Subscale at Follow-up Visit 2 (Week 42)	The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being and was supplemented by 12 questions relating to prostate cancer. Possible scores for each subscale were 0 to 28; 0 to 28; 0 to 24; 0 to 28; and 0 to 48, respectively. All FACT-P items are scored on a scale of 0-4 representing the extent to which the item reflects the experience of the individual completing the instrument (0 - Not at all; 4 - Very much). Higher scores indicate better quality of life. The absolute score of the FACT-P total score was calculated at Follow-up Visit 2.	At Follow-up Visit 2 (Week 42)	No
Other	Absolute Scores for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)	The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. It was supplemented by 12 questions relating to prostate cancer. The absolute score of the FACT-P total score (physical, social/family, emotional, and functional well-being and prostate specific score) was calculated at Week 16, Week 24, and Follow-up Visit 2.FACT-P Total Score: Physical Well-being (PWB) + Social/Family Well-being (SWB) + Emotional Well-being (EWB) + Functional Well-being (FWB) + Prostate Cancer (PCS). Score ranges from 0 (worst) to 156 (best).	At Week 16, Week 24, and Follow-up Visit 2 (Week 42)	No
Other	Change From Baseline for FACT-P Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)	The FACT-P was 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. It was supplemented by 12 questions relating to prostate cancer. Total possible score was 156; a higher score indicates a better quality of life. The changes from baseline in the FACT-P total score (physical, social/family, emotional, and functional well-being and prostate specific score) were calculated at Week 16, Week 24, and Follow-up Visit 2. Possible range was -156 to 156.	Baseline, Week 16, Week 24, and Follow-up Visit 2 (week 42)	No
Other	Absolute Scores for Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)	The FACT-G instrument consisted of 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. The FACT-G absolute total score (physical, social/family, emotional, and functional well-being) was calculated at Week 16, Week 24, and Follow-up Visit 2. FACT-G Total Score: Physical Well-being (PWB) + Social/Family Well-being (SWB) + Emotional Well-being (EWB) + Functional Well-being (FWB). Score ranges from 0 (worst) to 108 (best).	At Week 16, Week 24, and Follow-up Visit 2 (Week 42)	No
Other	Change From Baseline for FACT-G Total Score at Week 16, Week 24, and Follow-up Visit 2 (Week 42)	The FACT-G instrument consisted of 27 questions relating to 4 domains: physical, social/family, emotional, and functional well-being. Total possible score was 108; a higher score indicates a better quality of life. The changes from baseline in the FACT-G total score (physical, social/family, emotional, and functional well-being) were calculated at Week 16, Week 24, and Follow-up Visit 2. Possible range was -108 to 108.	Baseline, Week 16, Week 24, and Follow-up Visit 2 (Week 42)	No
Other	Number of Participants in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 16	The EQ-5D questionnaire was given to the subject at each visit. The EQ-5D questionnaire consisted of 5 ordinal categorical responses (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Number of participants with EQ-5D at Week 16, as measured by this questionnaire, was counted. The scores for the EQ-5D dimensions are assigned according to the level of problems reported (1 'no problems'; 2 'some problems'; 3 'extreme problems').	Week 16	No
Other	Number of Participants in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Week 24	The EQ-5D questionnaire was given to the subject at each visit. The EQ-5D questionnaire consisted of 5 ordinal categorical responses (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Number of participants with EQ-5D at Week 24, as measured by this questionnaire, was counted. The scores for the EQ-5D dimensions are assigned according to the level of problems reported (1 'no problems'; 2 'some problems'; 3 'extreme problems').	Week 24	No
Other	Number of Participants in the Euro Quality of Life (EQ-5D) Components for Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression at Follow-up Visit 8 (Week 139)	The EQ-5D questionnaire was given to the subject at each visit. The EQ-5D questionnaire consisted of 5 ordinal categorical responses (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Number of participants with EQ-5D at follow-up visit 8, as measured by this questionnaire, was counted. The scores for the EQ-5D dimensions are assigned according to the level of problems reported (1 'no problems'; 2 'some problems'; 3 'extreme problems').	Follow-up Visit 8 (Week 139)	No
Primary	Overall Survival	Overall survival was defined as the time from date of randomization to the date of death.	From randomization to death due to any cause until approximately 3 years after start of enrollment, the data was collected up to the second data analysis date (15 JUL 2011)	No
Secondary	Time to Total Alkaline Phosphatase (ALP) Progression	The time from the first study drug administration to when ALP progression was observed, defined as: 1) In subjects with no ALP decline from baseline; a greater than or equal to 25% increase from baseline value and an increase in absolute value of greater than or equal to 2 ng/mL, at least 12 weeks from baseline; 2) In subjects with initial ALP decline from baseline; the time from start of treatment to first ALP increase that is greater than or equal to 25% increase and at least 2 ng/mL above the nadir value, which was confirmed by a second value obtained 3 or more weeks later	From randomization to first ALP progression until approximately 3 years after start of enrollment	No
Secondary	Percentage of Participants With Total ALP Response at Week 12	ALP levels were measured in participants' blood at Week 12 and compared to baseline values. A confirmed total ALP response (either >/= 30% or 50% reduction from baseline) was confirmed by a second total ALP value approximately 4 weeks later.	At Baseline and Week 12	No
Secondary	Percentage of Participants With Total ALP Response at End of Treatment (EOT; Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase)	ALP levels were measured in participants' blood at EOT (Week 24) and compared to baseline values. A confirmed total ALP response (>/=50% reduction from baseline) was confirmed by a second total ALP value approximately 4 weeks later.	At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)	No
Secondary	Percentage of Participants With Total ALP Normalization at Week 12	The return of total ALP value to within normal range at 12 weeks in 2 consecutive measurements (at least 2 weeks apart) after start of treatment in subjects who had ALP above the upper limit of normal (ULN) at baseline.	At Baseline and Week 12	No
Secondary	Percentage Change From Baseline in Total ALP at Week 12	ALP level was measured in subject's blood at Week 12 and the percent change from the baseline value was calculated (ALP level at week 12 minus ALP level at baseline)/(ALP level at baseline)*100	At Baseline and Week 12	No
Secondary	Maximum Percentage Decrease From Baseline in Total ALP up to Week 12	ALP level was measured in participant's blood up to week 12 and the maximum percent decrease from the baseline up to Week 12 value was calculated as the minimum value of [(ALP level up to week 12 minus ALP level at baseline)/(ALP level at baseline)*100] by participant, and set to zero if no decrease from baseline.	From baseline to Week 12	No
Secondary	Percentage Change From Baseline in Total ALP at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase)	ALP level was measured in subject's blood at EOT (Week 24) and the percent change from the baseline value was calculated (ALP level at EOT minus ALP level at baseline)/(ALP level at baseline)*100	At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)	No
Secondary	Maximum Percentage Decrease From Baseline in Total ALP During the 24 Week Treatment	ALP level was measured in participant's blood during the 24 week treatment (up to EOT) and the maximum percent decrease from baseline during the 24 week treatment value was calculated as the minimum value of [(ALP level up to week 24 minus ALP level at baseline)/(ALP level at baseline)*100] by participant, and set to zero if no decrease from baseline.	From baseline During the 24 Week Treatment	No
Secondary	Time to Prostate Specific Antigen (PSA) Progression	The time from the first study drug administration to when PSA progression was observed, defined as: 1) In subjects with no PSA decline from baseline; a greater than or equal to 25% increase from baseline value and an increase in absolute value of greater than or equal to 2 ng/mL, at least 12 weeks from baseline; 2) In subjects with initial PSA decline from baseline; the time from start of treatment to first PSA increase that is greater than or equal to 25% increase and at least 2 ng/mL above the nadir value, which was confirmed by a second value obtained 3 or more weeks later	From randomization to first PSA progression until approximately 3 years after start of enrollment	No
Secondary	Percentage of Participants With PSA Response at Week 12	PSA levels were measured in participants' blood at Week 12 and compared to baseline values. A confirmed PSA response (>/=50% reduction from baseline) was confirmed by a second PSA value approximately 4 weeks later.	At Baseline and Week 12	No
Secondary	Percentage of Participants With PSA Response at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase)	PSA levels were measured in participants' blood at EOT (Week 24) and compared to baseline values. A confirmed PSA response (>/=50% reduction from baseline) was confirmed by a second PSA value approximately 4 weeks later.	At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)	No
Secondary	Percentage Change From Baseline in PSA at Week 12	PSA level was measured in subject's blood at Week 12 and the percent change from the baseline value was calculated (PSA level at week 12 minus PSA level at baseline)/(PSA level at baseline)*100	At Baseline and Week 12	No
Secondary	Maximum Percentage Decrease From Baseline in PSA up to Week 12	PSA level was measured in participant's blood up to Week 12 and the maximum percent decrease from the baseline up to week 12 value was calculated as the minimum value of [(PSA level up to week 12 minus PSA level at baseline)/(PSA level at baseline)*100] by participant, and set to zero if no decrease from baseline.	From baseline up to Week 12	No
Secondary	Percentage Change From Baseline in PSA at EOT (Week 24 or at the Time the Patient Dies or Discontinues Treatment Phase)	PSA level was measured in subject's blood at EOT (Week 24) and the percent change from the baseline value was calculated (PSA level at EOT minus PSA level at baseline)/(PSA level at baseline)*100	At Baseline and End of Treatment (Week 24 or at the time the patient dies or discontinues treatment phase)	No
Secondary	Maximum Percentage Decrease From Baseline in PSA Response During the 24 Week Treatment Period	PSA level was measured in participant's blood during the 24 week treatment (up to EOT) and the maximum percent decrease from baseline during the 24 Week treatment value was calculated as the minimum value of [(PSA level up to week 24 minus PSA level at baseline)/(PSA level at baseline)*100] by participant, and set to zero if no decrease from baseline.	From baseline to End of Treatment (Week 24; 4 weeks post last injection)	No
Secondary	Time to First Skeletal Related Event (SRE)	A skeletal related event is the use of external beam radiotherapy to relieve skeletal symptoms or the occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral) or the occurrence of spinal cord compression or a tumour related orthopaedic surgical intervention. For all other events, the start date of the event/medication/therapy was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.	From randomization to first first SRE until approximately 3 years after start of enrollment	No
Secondary	Time to Occurrence of First Use of External Beam Radiation Therapy (EBRT) to Relieve Skeletal Symptoms	The start date of therapy was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.	From randomization to first EBRT until approximately 3 years after start of enrollment	No
Secondary	Time to Occurrence of First Use of Radioisotopes to Relieve Skeletal Symptoms	The start date of the radioisotopes was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.	From randomization to first use of radioisotopes until approximately 3 years after start of enrollment	No
Secondary	Time to Occurrence of First New Symptomatic Pathological Bone Fractures, Vertebral and Non-vertebral	The start date of the event was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.	From randomization to occurrence of first new symptomatic pathological bone fractures until approximately 3 years after start of enrollment	No
Secondary	Time to Occurrence of First Tumor Related Orthopedic Surgical Intervention	The start date of the intervention was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.	From randomization to occurrence of first tumor related orthopedic surgical intervention until approximately 3 years after start of enrollment	No
Secondary	Time to Occurrence of First Spinal Cord Compression	The start date of the compression was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.	From randomization to first spinal cord compression until approximately 3 years after start of enrollment	No
Secondary	Time to Occurrence of First Start of Any Other Anti-cancer Treatment	The start date of the treatment was used as the time of the event. If an event has not occurred at the time of the analysis or the patient has been lost to follow-up, the time-to-event variables will be censored at the last disease assessment date.	From randomization to first start of any other anti-cancer treatment until approximately 3 years after start of enrollment	No
Secondary	Time to Occurrence of First Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least 2 Points From Baseline	ECOG scores were: 0 = fully active; 1 = restricted in physically strenuous activity; 2 = ambulatory and capable of all self-care but unable to work; 3 = capable of only limited self-care; 4 = completely disabled; 5 = death. The visit at which a 2-point or more deterioration in PS was observed was the time of the event. ECOG was assessed at every visit. If a marked deterioration in PS has not occurred at the time of the analysis or the participant was lost to follow-up, the time-to-event variables were censored at the last assessment date.	From randomization to first deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) until approximately 3 years after start of enrollment	No

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