Trial Outcomes & Findings for EMD 525797 in Subjects With Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer (NCT NCT01360840)

Last Updated: 2015-12-14

Results Overview

PFS was defined as time from randomization until the first documented sign of objective radiographic disease progression (ORDP) or death from any cause. Death was considered as an event only if it was reported within 12 weeks after last tumor assessment without progression. ORDP was defined as: Bone lesion progression (2 or more new bone lesions compared to baseline) assessed with bone scintigraphy. Assessment was based on Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v1.0) modified as per Prostate Cancer Working Group 2 (PCWG-2); Soft-tissue lesion progression assessed with CT scans according to RECIST v1.0 modified as per PCWG-2; Presence of skeletal events defined as cord compression/fracture documented via a scheduled or unscheduled radiographic assessment triggered by increased pain or other signs and/or symptoms, based on the investigator's discretion; Non-radiological events, including emergency bone irradiation and surgery, were not investigated.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

180 participants

Primary outcome timeframe

Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years

Results posted on

2015-12-14

Participant Flow

First/Last subject (informed consent): April 2011/December 2012. Study completion date: July 2014. Clinical data cut-off: 30 April 2013. Subjects were recruited in 11 countries (Australia, Belgium, Canada, France, Germany, Netherlands, Poland, Russia, South Africa, Spain, and USA) across the globe in 65 centers.

Enrolled: 283 screened for eligibility; 103 were excluded (mainly non-fulfillment of inclusion or exclusion criteria). 180 subjects were assigned to the treatment groups. Two subjects did not receive study drug administration.

Participant milestones

Participant milestones
Measure	Placebo + SoC Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the standard of care (SoC) consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Overall Study STARTED	60	60	60
Overall Study COMPLETED	50	50	51
Overall Study NOT COMPLETED	10	10	9

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo + SoC Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the standard of care (SoC) consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Overall Study Ongoing at data cut-off	10	10	9

Baseline Characteristics

EMD 525797 in Subjects With Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo + SoC n=60 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	Total n=180 Participants Total of all reporting groups
Age, Continuous	69.9 years STANDARD_DEVIATION 8.43 • n=5 Participants	69.0 years STANDARD_DEVIATION 7.31 • n=7 Participants	70.0 years STANDARD_DEVIATION 8.88 • n=5 Participants	69.6 years STANDARD_DEVIATION 8.20 • n=4 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Sex: Female, Male Male	60 Participants n=5 Participants	60 Participants n=7 Participants	60 Participants n=5 Participants	180 Participants n=4 Participants

PRIMARY outcome

Timeframe: Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years

Population: Intention-to-treat (ITT) analysis set included all the subjects who were randomized in the study.

Outcome measures

Outcome measures
Measure	Placebo + SoC n=60 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Progression Free Survival (PFS) Time	3.3 months Interval 2.8 to 4.8	3.4 months Interval 2.8 to 5.6	4.3 months Interval 2.8 to 6.6

SECONDARY outcome

Timeframe: Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years

Population: ITT analysis set included all the subjects who were randomized in the study.

Overall Survival was defined as the time from the date of randomization to the date of death from any cause.

Outcome measures

Outcome measures
Measure	Placebo + SoC n=60 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Overall Survival	NA months Interval 14.8 to The value was not estimable due to lack of events	NA months Interval 12.9 to The value was not estimable due to lack of events	NA months Interval 14.4 to The value was not estimable due to lack of events

SECONDARY outcome

Timeframe: Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years

Population: ITT analysis set included all the subjects who were randomized in the study.

Time to tumor progression was defined as the time from the date of randomization to the date of ORDP. ORDP was defined as: Bone lesion progression (2 or more new bone lesions compared to baseline) assessed with bone scintigraphy, which had to be confirmed by bone scintigraphy 6 weeks later if subjects remained asymptomatic or mildly symptomatic. Assessments were to be based on RECIST v1.0 modified according to PCWG-2; Soft-tissue lesion progression assessed with CT scans according to RECIST v1.0 modified as per PCWG-2; Presence of skeletal events defined as cord compression or fracture documented via a scheduled or unscheduled radiographic assessment triggered by increased pain or other signs and/or symptoms, based on the investigator's discretion; Non-radiological events, including emergency bone irradiation and surgery, were not investigated.

Outcome measures

Outcome measures
Measure	Placebo + SoC n=60 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Time to Tumor Progression	3.3 months Interval 2.8 to 5.4	3.4 months Interval 2.8 to 5.6	4.6 months Interval 2.8 to 6.9

SECONDARY outcome

Timeframe: Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years

Population: ITT analysis set included all the subjects who were randomized in the study. "N" signifies the total number of subjects evaluable for this outcome measure.

Presence of tumor response in soft tissue lesions was defined as the presence of at least 1 confirmed complete response (CR) or confirmed partial response (PR) in soft tissue lesions, documented by computed tomography (CT) scans. Presence of DC in soft tissue lesions was defined as the presence of at least 1 confirmed CR or confirmed PR or stable disease (SD) lasting at least 12 weeks after randomization. Tumor response assessments were based on RECIST v1.0 modified according to the PCWG-2. The response was evaluated for subjects with measurable disease at baseline. According to RECIST v1.0, CR=disappearance of all target and non-target lesions; PR=at least 30% decrease in the sum of the longest diameter of target lesions and non-complete response/non-progressive disease in non-target lesions.

Outcome measures

Outcome measures
Measure	Placebo + SoC n=28 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=22 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC n=24 Participants Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Number of Subjects With Presence of Tumor Response and Disease Control (DC) in Soft Tissue Lesions Disease control	2 Subjects	3 Subjects	4 Subjects
Number of Subjects With Presence of Tumor Response and Disease Control (DC) in Soft Tissue Lesions Tumor response	1 Subjects	0 Subjects	1 Subjects

SECONDARY outcome

Timeframe: Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years

Population: ITT analysis set included all the subjects randomized in the study. "N" signifies the total number of subjects evaluable for this outcome measure.

New bone lesions were evaluated by bone scintigraphy for subjects with bone lesions at baseline.

Outcome measures

Outcome measures
Measure	Placebo + SoC n=57 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=57 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC n=57 Participants Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Number of Subjects With New Bone Lesions Compared to Baseline	40 Subjects	34 Subjects	34 Subjects

SECONDARY outcome

Timeframe: At Weeks 13, 19 and 25

Population: ITT analysis set included all the subjects randomized in the study.

Presence of DC in bone lesions was defined as the appearance of less than 2 new bone lesions, documented by bone scintigraphy.

Outcome measures

Outcome measures
Measure	Placebo + SoC n=60 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Number of Subjects With Presence of DC in Bone Lesions Week 25	2 Subjects	4 Subjects	3 Subjects
Number of Subjects With Presence of DC in Bone Lesions Week 13	4 Subjects	7 Subjects	7 Subjects
Number of Subjects With Presence of DC in Bone Lesions Week 19	2 Subjects	7 Subjects	6 Subjects

SECONDARY outcome

Timeframe: Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years

Population: ITT analysis set included all the subjects who were randomized in the study.

Bone and soft tissue lesions composite tumor response was defined as the presence of both a confirmed CR or PR, documented by CT scans, and a DC in bone lesions, documented by bone scintigraphy. CR was defined as disappearance of all target and non-target lesions and PR was defined as at least 30% decrease in the sum of the longest diameter of target lesions and non-complete response/non-progressive disease in non-target lesions. Presence of DC in bone lesions was defined as the appearance of less than 2 new bone lesions.

Outcome measures

Outcome measures
Measure	Placebo + SoC n=60 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Bone and Soft Tissue Lesions Composite Tumor Response	0 Subjects	0 Subjects	0 Subjects

SECONDARY outcome

Timeframe: Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years

Population: ITT analysis set included all the subjects who were randomized in the study.

Presence of skeletal related events was defined as cord compression or fracture documented via a scheduled or unscheduled radiographic assessment triggered by increased pain or other signs and/or symptoms at the investigator discretion. Non-radiological events, including emergency bone irradiation and surgery, were not investigated.

Outcome measures

Outcome measures
Measure	Placebo + SoC n=60 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Number of Subjects With Presence of Skeletal Related Events	2 Subjects	8 Subjects	3 Subjects

SECONDARY outcome

Timeframe: Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years

Population: ITT analysis set included all the subjects who were randomized in the study. "N" signifies the total number of subjects evaluable for this outcome measure.

PSA response was defined as a decrease greater than 50 percent (%) in PSA value from baseline for 2 consecutive evaluations greater than or equal to (\>=) 3 Weeks apart.

Outcome measures

Outcome measures
Measure	Placebo + SoC n=60 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=58 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Number of Subjects With Presence of Prostate Specific Antigen (PSA) Response	3 Subjects	6 Subjects	5 Subjects

SECONDARY outcome

Timeframe: Baseline, up to data cut-off date (30 April 2013), assessed up to 2 years

Population: ITT analysis set included all the subjects who were randomized in the study. "N" signifies the total number of subjects evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Placebo + SoC n=58 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=57 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Minimum Percentage Change From Baseline in PSA Serum Concentration	24.00 Percent change Standard Deviation 86.156	35.65 Percent change Standard Deviation 127.677	14.70 Percent change Standard Deviation 50.841

SECONDARY outcome

Timeframe: Time from randomization until data cut-off date (30 April 2013), assessed up to 2 years

Population: ITT analysis set included all the subjects who were randomized in the study. "N" signifies the total number of subjects evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Placebo + SoC n=29 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=27 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC n=22 Participants Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Minimum Percentage Change From Baseline in the Number of Circulating Tumor Cells (CTCs)	49.02 Percent change Standard Deviation 127.643	354.74 Percent change Standard Deviation 1038.195	280.58 Percent change Standard Deviation 482.653

SECONDARY outcome

Timeframe: Cycle 1, Day 1 (Week 1): pre-dose, Cycle 3, Day 1 (Week 7): pre-dose, and Cycle 5, Day 1 (Week 13): pre-dose

Population: ITT analysis set included all the subjects who were randomized in the study. "N" signifies the total number of subjects evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Placebo + SoC n=36 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=34 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC n=30 Participants Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Overall Minimum Percentage Change From Previous Time Point in Circulating Tumor Cells (CTC)	9.54 Percent change Standard Deviation 103.225	223.97 Percent change Standard Deviation 868.941	179.11 Percent change Standard Deviation 446.428

SECONDARY outcome

Timeframe: From the first dose of study drug administration until 50 days after the last dose of study drug administration or until cut-off date (30 April 2013), assessed up to 2 years

Population: The Safety analysis set included all the randomized subjects who received at least 1 dose of planned trial treatment and had at least one safety assessment following the trial treatment.

An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs were defined as those AEs that started between first dose of study drug and up to 50 days after last dose.

Outcome measures

Outcome measures
Measure	Placebo + SoC n=60 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=58 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC n=60 Participants Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Number of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation TEAEs leading to death	2 Subjects	2 Subjects	3 Subjects
Number of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation TEAEs Leading to Permanent Discontinuation	5 Subjects	11 Subjects	8 Subjects
Number of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation TEAEs	55 Subjects	49 Subjects	53 Subjects
Number of Subjects With Any Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation Serious TEAEs	16 Subjects	13 Subjects	14 Subjects

SECONDARY outcome

Timeframe: Cycle 1 (Week 1) and cycle 5 (Week 13): Day 1: pre-dose, End of Infusion (EOI), 4, 8, 24, 48, 96, 168, 336, and 504 hours after start of infusion; Cycles 3 and 4 (Weeks 7 and 10), Day 1: pre-dose; Cycle 7 (Week 19), Day 1: pre-dose and EOI

Population: Pharmacokinetic Analysis Set (PKA) included all the randomized subjects who received at least the first dose of the trial drug and provided sufficient data for a concentration time profile for EMD 525797. "n" signifies the number of subjects evaluable for each category in the evaluated group, respectively.

The apparent total body clearance of drug following intravenous administration (CL); The apparent total body clearance of drug at steady state following intravenous administration (CLss).

Outcome measures

Outcome measures
Measure	Placebo + SoC n=4 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=6 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Pharmacokinetic Parameter: Clearance of Intravenously Administered EMD 525797 After First Dose (CL) and Clearance in Steady State of EMD52597 After Fifth Dose (CLss) First dose: CL (n=4, 6)	0.017 Liter per hour Standard Deviation 0.007	0.013 Liter per hour Standard Deviation 0.003	—
Pharmacokinetic Parameter: Clearance of Intravenously Administered EMD 525797 After First Dose (CL) and Clearance in Steady State of EMD52597 After Fifth Dose (CLss) Fifth dose: CLss (n=2, 4)	0.017 Liter per hour Standard Deviation 0.002	0.010 Liter per hour Standard Deviation 0.001	—

SECONDARY outcome

Population: PKA included all the randomized subjects who received at least the first dose of the trial drug and provided sufficient data for a concentration time profile for EMD 525797. "n" signifies the number of subjects evaluable for each category in the evaluated group, respectively.

The apparent volume of distribution during the terminal phase following intravenous administration (V). The estimate of the apparent volume of distribution at steady state following intravenous administration (Vss).

Outcome measures

Outcome measures
Measure	Placebo + SoC n=4 Participants Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 750 mg + SoC n=6 Participants Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.	EMD 525797 1500 mg + SoC Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
Pharmacokinetic Parameter: Volume of Distribution of EMD 525797 After the First Dose (V) and in Steady State After the Fifth Dose (Vss) of Intravenous Infusion First dose (n=4, 6)	4.55 liter Standard Deviation 1.02	4.60 liter Standard Deviation 0.74	—
Pharmacokinetic Parameter: Volume of Distribution of EMD 525797 After the First Dose (V) and in Steady State After the Fifth Dose (Vss) of Intravenous Infusion Fifth dose (n=2, 4)	4.81 liter Standard Deviation NA The sample size of n=2 was inappropriate for Vss parameter to calculate standard deviation. Hence, it was not calculated.	5.18 liter Standard Deviation 0.56	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From the date of randomization up to data cut-off date (30 April 2013), assessed up to 2 years

Population: Data for this outcome measure was presented graphically as per planned analysis but not statistically summarized.

Outcome measures

Outcome data not reported

Adverse Events

Placebo + SoC

Serious events: 16 serious events

Other events: 53 other events

Deaths: 0 deaths

EMD 525797 750 mg + SoC

Serious events: 13 serious events

Other events: 47 other events

Deaths: 0 deaths

EMD 525797 1500 mg + SoC

Serious events: 14 serious events

Other events: 53 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Merck KGaA Communication Center

Merck Serono, a division of Merck KGaA

Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER