A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA)

• ClinicalTrials.gov Identifier: NCT00567190
• Recruitment Status: Completed
• First Posted: December 4, 2007
• Results First Posted: September 13, 2012
• Last Update Posted: December 13, 2019
• Sponsor: Genentech, Inc.
• Collaborator: Hoffmann-La Roche
• Information provided by (Responsible Party): Genentech, Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Metastatic Breast Cancer
• Interventions: Drug: Pertuzumab; Drug: Placebo; Drug: Trastuzumab; Drug: Docetaxel
• Enrollment: 808

Participant Flow

Recruitment Details
Pre-assignment Details	A total of 1196 patients were screened for the study, of whom a total of 808 participants were randomized to one of the two treatment arms.

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel
Arm/Group Description	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Period Title: Overall Study
Started [1]	402	406
Did Not Receive Any Study Treatment	2	2
Received at Least One Dose of Pertuzumab [2]	399	9 [3]
Received at Least One Dose of Placebo [4]	1 [5]	395
Crossover From Placebo to Pertuzumab	0	50 [6]
Completed [7]	119	73
Not Completed	283	333
Reason Not Completed
Death	235	280
Withdrew Consent or Lost to Follow-up	48	53
[1] Intent-to-Treat (ITT) Population; [2] Safety Population (Pertuzumab); [3] 9 participants randomized to the Placebo arm actually received at least one dose of pertuzumab.; [4] Safety Population (Placebo); [5] 1 participant randomized to the Pertuzumab arm actually received placebo at every treatment cycle.; [6] From July 2012, 50 participants randomized to Placebo arm crossed over to open-label pertuzumab.; [7] Alive and in Survival Follow-up at End of Study

Baseline Characteristics

Arm/Group Title		Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel	Total
Arm/Group Description		Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Total of all reporting groups
Overall Number of Baseline Participants		402	406	808
Baseline Analysis Population Description		ITT population
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	402 participants	406 participants	808 participants
		53.4 (10.94)	53.5 (11.35)	53.5 (11.14)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	402 participants	406 participants	808 participants
	Female	402 100.0%	404 99.5%	806 99.8%
	Male	0 0.0%	2 0.5%	2 0.2%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	402 participants	406 participants	808 participants
	Hispanic or Latino	39 9.7%	44 10.8%	83 10.3%
	Not Hispanic or Latino	362 90.0%	362 89.2%	724 89.6%
	Unknown or Not Reported	1 0.2%	0 0.0%	1 0.1%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	402 participants	406 participants	808 participants
	American Indian or Alaska Native	3 0.7%	4 1.0%	7 0.9%
	Asian	128 31.8%	133 32.8%	261 32.3%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	10 2.5%	20 4.9%	30 3.7%
	White	245 60.9%	235 57.9%	480 59.4%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	16 4.0%	14 3.4%	30 3.7%
Region; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	402 participants	406 participants	808 participants
	Asia	125 31.1%	128 31.5%	253 31.3%
	Europe	154 38.3%	152 37.4%	306 37.9%
	North America	67 16.7%	68 16.7%	135 16.7%
	South America	56 13.9%	58 14.3%	114 14.1%
Prior Treatment Status; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	402 participants	406 participants	808 participants
	Adjuvant or Neo-Adjuvant Therapy	184 45.8%	192 47.3%	376 46.5%
	De Novo	218 54.2%	214 52.7%	432 53.5%
Independent-Review Facility (IRF)-Determined Disease Status at Screening [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	402 participants	406 participants	808 participants
	Measurable Disease	343 85.3%	336 82.8%	679 84.0%
	Non-Measurable Disease	44 10.9%	43 10.6%	87 10.8%
	Not Evaluated	15 3.7%	27 6.7%	42 5.2%
		[1] Measure Description: A participant was deemed to have measurable disease if they had at least 1 target lesion at screening. Target lesions (maximum of 5 per organ and 10 in total) were selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). Any participants with non-target lesions only were deemed to have non-measurable disease. The IRF did not evaluate baseline tumor assessments for any participant without a post-baseline tumor assessment.

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS) Determined by an Independent Review Facility
Description	PFS was defined as the time from randomization to first documented radiographical progressive disease (PD), as determined by an independent review facility (IRF) using RECIST version 1.0, or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first (Kaplan-Meier method). For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of ≥1 new lesion. For non-target lesions, PD was defined as the appearance of ≥1 new lesion or unequivocal progression of existing lesions. Participants without IRF-determined PD or who had not died within 18 weeks of their last IRF-determined, progression-free tumor assessment were censored at the date of the last IRF-reviewed, evaluable tumor assessment; those with no post-baseline tumor assessment and who had not died within 18 weeks of baseline were censored at 1 day.
Time Frame	Tumor assessments every 9 weeks from randomization to IRF-determined PD or death from any cause, whichever occurred first, up to the primary completion date (up to 3 years, 3 months)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: All randomized participants

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel
Arm/Group Description:	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed	402	406
Median (95% Confidence Interval); Unit of Measure: Months
	18.5; (15 to 23)	12.4; (10 to 13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	The null hypothesis (H0) was that the survival distributions of PFS in the two treatments arms (pertuzumab vs. placebo) are the same. The alternative hypothesis (H1) was that the survival distribution of PFS in the experimental arm (pertuzumab) and control arm (placebo) are different.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Tested at two-sided 5% significance level
	Method	Log Rank (stratified)
	Comments	Stratified by prior treatment status and region
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.51 to 0.75
	Estimation Comments	Hazard ratio is comparing Pertuzumab arm with Placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	The null hypothesis (H0) was that the survival distributions of PFS in the two treatments arms (pertuzumab vs. placebo) are the same. The alternative hypothesis (H1) was that the survival distribution of PFS in the experimental arm (pertuzumab) and control arm (placebo) are different.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Tested at two-sided 5% significance level
	Method	Log Rank (unstratified)
	Comments	Unstratified
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.52 to 0.76
	Estimation Comments	Hazard ratio is comparing Pertuzumab arm with Placebo arm.

2. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS) was the time from randomization to death from any cause, using Kaplan-Meier methodology. Survival data was collected every 18 weeks during the post-treatment follow-up period until death, loss to follow-up, or withdrawal of consent. Those who were alive, lost to follow up, or withdrew consent were censored at the latest date they participated in the study; those without post-baseline data were censored at 1 day. OS analyses were planned to take place at the primary completion date (First Interim), after 385 deaths (Event-Driven Final), and at the end of study (End-of-Study). A second interim OS analysis was planned due to a formal request from the European Medicines Agency. Median [range] time in weeks on study at each OS analysis (Pertuzumab vs. Placebo): First: 77.1 [0.7-165.3] vs. 73.1 [0.4-165.3]; Second: 117.1 [0.7-207.9] vs. 105.9 [0.4-207.9]; Event-Driven Final: 189.9 [0.7-304.1] vs. 140.5 [0.4-301.6]; End-of-Study: 201.8 [0.7-520.0] vs. 138.0 [0.4-514.7].
Time Frame	From randomization to death from any cause, up to each respective analysis data cut-off date (see the Description field for the median time on study per treatment arm)

Outcome Measure Data

Analysis Population Description

ITT Population: All randomized participants

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel
Arm/Group Description:	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed	402	406
Median (95% Confidence Interval); Unit of Measure: Months
End-of-Study OS Analysis	57.1; (50 to 72)	40.8; (36 to 48)
Event-Driven Final OS Analysis	56.5 [1]; (49 to NA)	40.8; (36 to 48)
Second Interim OS Analysis	NA [2]; (42 to NA)	37.6 [1]; (34 to NA)
First Interim OS Analysis	NA [3]; (NA to NA)	NA [2]; (30 to NA)

[1]

The upper limit of the 95% CI could not be determined because it was larger than the maximum follow-up time at data cutoff for the analysis.

[2]

The median and upper limit of the 95% CI could not be determined because they were larger than the maximum follow-up time at data cutoff for the analysis.

[3]

The median and lower and upper limits of the 95% CI could not be determined because they were larger than the maximum follow-up time at data cutoff for the analysis.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	End-of-Study OS Analysis: This end-of-study OS analysis is considered exploratory only as the confirmatory OS analysis for statistical interpretation had previously occurred at the second interim OS analysis.
	Type of Statistical Test	Superiority
	Comments	Exploratory
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Exploratory
	Method	Log Rank (stratified)
	Comments	Stratified by prior treatment status and region.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.58 to 0.82
	Estimation Comments	Hazard ratio is comparing Pertuzumab arm with Placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	Event-Driven Final OS Analysis: This final OS analysis was event-driven and planned to take place after a total of 385 deaths had occurred. It is considered exploratory only as the confirmatory OS analysis for statistical interpretation had previously occurred at the second interim OS analysis.
	Type of Statistical Test	Superiority
	Comments	Exploratory
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	Exploratory
	Method	Log Rank (stratified)
	Comments	Stratified by prior treatment status and region.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.56 to 0.84
	Estimation Comments	Hazard ratio is comparing Pertuzumab arm with Placebo arm.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	Second Interim OS Analysis: For this second interim OS analysis, the pre-defined O'Brien-Fleming stopping boundary for the Lan-DeMets α-spending function was: HR≤0.739, p≤0.0138.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0008
	Comments	The threshold for statistical significance was HR≤0.739, p≤0.0138.
	Method	Log Rank (stratified)
	Comments	Stratified by prior treatment status and region.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.52 to 0.84
	Estimation Comments	Hazard ratio (HR) is comparing Pertuzumab arm with Placebo arm.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	First Interim OS Analysis: For this first interim OS analysis, the pre-defined O'Brien-Fleming stopping boundary for the Lan-DeMets α-spending function was: HR≤0.603, p≤0.0012.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0050
	Comments	The threshold for statistical significance was HR≤0.603, p≤0.0012.
	Method	Log Rank (stratified)
	Comments	Stratified by prior treatment status and region.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.47 to 0.88
	Estimation Comments	Hazard ratio (HR) is comparing pertuzumab with placebo arms.

3. Secondary Outcome

Title	Progression-Free Survival (PFS) Determined by the Investigator
Description	PFS was defined as the time from randomization to first documented radiographical progressive disease (PD), as determined by the investigator using RECIST version 1.0, or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first (Kaplan-Meier method). For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of ≥1 new lesion. For non-target lesions, PD was defined as the appearance of ≥1 new lesion or unequivocal progression of existing lesions. Participants without PD or who had not died within 18 weeks of their last investigator-determined, progression-free tumor assessment were censored at the date of the last investigator tumor assessment; those with no post-baseline tumor assessment and who had not died within 18 weeks of baseline were censored at 1 day.
Time Frame	Tumor assessments every 9 weeks from randomization to investigator-determined PD or death from any cause, whichever occurred first (median [range] time on study in pertuzumab vs. placebo arms: 201.8 [0.7-520.0] weeks vs. 138.0 [0.4-514.7] weeks)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients.

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel
Arm/Group Description:	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed	402	406
Median (95% Confidence Interval); Unit of Measure: Months
	18.7; (17 to 22)	12.4; (10 to 14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	PFS by Investigator - Stratified
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank (stratified)
	Comments	Stratified by prior treatment status and region.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.59 to 0.81
	Estimation Comments	Hazard ratio is comparing Pertuzumab arm with Placebo arm.

4. Secondary Outcome

Title	Objective Response Determined by an Independent Review Facility
Description	An objective response was defined as the percentage of participants with confirmed best overall response of complete response (CR) or partial response (PR) determined by an independent review facility (IRF) using RECIST v1.0 on two consecutive occasions ≥4 weeks apart. For target lesions, CR: disappearance of all target lesions; PR: ≥30% decrease in the sum of the longest diameter (LD) of target lesions (baseline sum LD as reference); PD: ≥20% increase in the sum of the LD of target lesions (smallest sum of the LD recorded as reference) or appearance of ≥1 new lesion; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase for PD. For non-target lesions, CR: disappearance of all non-target lesions; Incomplete/SD: persistence of ≥1 non-target lesions; PD: unequivocal progression of existing non-target lesions. 95% confidence intervals (CI) were calculated only for clinical responses using the Pearson-Clopper method.
Time Frame	Tumor assessments every 9 weeks from Baseline until IRF-determined progressive disease (PD), death, or first administration of next line of anti-cancer therapy (whichever occurred first), up to the primary completion date (up to 3 years, 3 months)

Outcome Measure Data

Analysis Population Description

ITT Population: All randomized participants; only participants with IRF-determined measurable disease at baseline (i.e., ≥1 target lesion) were included in the analysis.

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel
Arm/Group Description:	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed	343	336
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of patients
Objective Response (CR + PR)	80.2; (75.6 to 84.3)	69.3; (64.1 to 74.2)
Complete Response (CR)	5.5; (3.4 to 8.5)	4.2; (2.3 to 6.9)
Partial Response (PR)	74.6; (69.7 to 79.2)	65.2; (59.8 to 70.3)
Stable Disease (SD)	14.6; (11.0 to 18.8)	20.8; (16.6 to 25.6)
Progressive Disease (PD)	3.8; (2.0 to 6.4)	8.3; (5.6 to 11.8)
Unable to Assess (UA)	0.6; (0.1 to 2.1)	0.6; (0.1 to 2.1)
Missing (No Assessment)	0.9 [1]; (NA to NA)	0.9 [1]; (NA to NA)

[1]

95% confidence intervals were calculated only for clinical responses.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	Difference in Objective Response (CR + PR) Between Arms
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0011
	Comments	[Not Specified]
	Method	Mantel Haenszel
	Comments	Stratified by prior treatment status and region.
Method of Estimation	Estimation Parameter	Difference in Objective Response Rates
	Estimated Value	10.83
	Confidence Interval	(2-Sided) 95%; 4.2 to 17.5
	Estimation Comments	Difference in the objective response rates between arms is calculated as Pertuzumab arm minus Placebo arm. The 95% CI was calculated using the Hauck-Anderson method.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	Odds Ratio for Objective Response (CR + PR)
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.79
	Confidence Interval	(2-Sided) 95%; 1.26 to 2.54
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Duration of Objective Response Determined by an Independent Review Facility
Description	Duration of objective response (estimated using the Kaplan-Meier method) was defined as the time from the initial confirmed complete response (CR) or partial response (PR), the date of tumor assessment at which the CR/PR was first detected by the independent review facility (IRF) using RECIST version 1.0, until the date of IRF-determined progressive disease (PD), death from any cause within 18 weeks of the last tumor assessment, or first administration of next line of anti-cancer therapy (whichever occurred first). If the visit when the initial CR or PR was observed spanned multiple dates, the latest date was used. Only participants in the ITT analysis population with an IRF-determined objective response (CR or PR), observed prior to IRF-assessed PD, death or next line of anti-cancer therapy, were included in the analysis. Participants who did not progress or die after they had a confirmed response were censored at the date of their last IRF-evaluable tumor measurement.
Time Frame	From initial IRF-confirmed objective response until IRF-determined progressive disease (PD), death, or first administration of next line of anti-cancer therapy (whichever occurred first), up to the primary completion date (up to 3 years, 3 months)

Outcome Measure Data

Analysis Population Description

ITT Population: All randomized participants; only participants with IRF-determined measurable disease at baseline (i.e., ≥1 target lesion) that had an objective response were included in the analysis.

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel
Arm/Group Description:	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed	275	233
Median (95% Confidence Interval); Unit of Measure: Weeks
	87.6; (71 to 106)	54.1; (46 to 64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.51 to 0.85
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Time to Symptom Progression
Description	Time to symptom progression was defined as the time from randomization to the first symptom progression as measured by the Functional Assessment of Cancer Therapy-for patients with Breast Cancer (FACT-B) questionnaire with the Trial Outcomes Index-Physical/Functional/Breast (TOI-PFB) subscale. The FACT-B TOI-PFB subscale contains 24 items from 3 subsections of the FACT-B questionnaire: Physical well-being, functional well-being, and additional concerns for breast cancer patients (breast cancer subscale [BCS]). All items in the questionnaire were rated by the patient on a 5-point scale ranging from 0 ("not at all") to 4 ("very much"). The total score ranged from 0 to 96. A higher score indicates better perceived quality of life. A positive change score from baseline indicates improvement. Symptom progression was defined as a decrease from baseline of 5 points or more.
Time Frame	Every 9 weeks from Baseline until investigator-determined progressive disease, up to the primary completion date (up to 3 years, 3 months)

Outcome Measure Data

Analysis Population Description

ITT population: All randomized participants; only female participants were included in the analysis.

Arm/Group Title	Pertuzumab + Trastuzumab + Docetaxel	Placebo + Trastuzumab + Docetaxel
Arm/Group Description:	Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed	402	404
Median (95% Confidence Interval); Unit of Measure: Weeks
	18.4; (18 to 27)	18.3; (18 to 27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7161
	Comments	Stratified by prior treatment status and region.
	Method	Log Rank (stratified)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.16
	Estimation Comments	Hazard ratio is comparing Pertuzumab arm with Placebo arm.

7. Secondary Outcome

Title	Overall Number of Participants Who Experienced at Least One Adverse Event, Including Serious and Non-Serious Adverse Events, by Most Severe Intensity (According to NCI-CTCAE v3.0) During the Treatment Period
Description	Adverse event (AE) severity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 (NCI-CTCAE v3.0); if the AE was not specifically listed, the following grades of severity were used: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening or disabling; and Grade 5 = death. Severe and serious are not synonymous. Severity refers to the intensity of an AE, whereas a serious AE must meet criteria set out in the protocol; both were independently assessed for each AE. Only the most severe intensity was counted for multiple occurrences of the same AE in one participant. AEs reported prior to first crossover treatment were included in the Placebo arm, and in the Crossover arm after that date, for participants who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame	Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description:	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed	396	408	50
Measure Type: Count of Participants; Unit of Measure: Participants
At Least One Serious AE - All Grades	116 29.3%	160 39.2%	10 20.0%
At Least One Non-Serious AE - All Grades	386 97.5%	400 98.0%	45 90.0%
At Least One AE - All Grades	391 98.7%	408 100.0%	47 94.0%
At Least One AE - Grade 1	368 92.9%	386 94.6%	44 88.0%
At Least One AE - Grade 2	350 88.4%	383 93.9%	34 68.0%
At Least One AE - Grade 3	229 57.8%	264 64.7%	11 22.0%
At Least One AE - Grade 4	158 39.9%	167 40.9%	1 2.0%
At Least One AE - Grade 5	12 3.0%	8 2.0%	1 2.0%

8. Secondary Outcome

Title	Overall Number of Adverse Events by Severity (NCI-CTCAE v3.0 All Grades and Grades 3 to 5) Per 100 Patient-Years of Exposure During the Treatment Period
Description	Adverse event (AE) severity, including serious and non-serious AEs, was assessed according to the NCI-CTCAE version 3.0; if the AE was not specifically listed, the following grades of severity were used: Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe; Grade 4 is life-threatening or disabling; and Grade 5 is death. Multiple occurrences of the same AE in 1 participant were counted multiple times. Only AEs that started during the overall study treatment period were included. The cutoff date for inclusion of events and for calculation of patient-years was the date of the most recent follow-up of the participant, defined as the last available date during the treatment period, excluding pre-treatment and safety follow-up data. Confidence intervals were calculated assuming the number of events followed a Poisson distribution. Data reported prior to the date of first crossover treatment were included under the Placebo arm for participants who crossed over from placebo to pertuzumab.
Time Frame	From Baseline to 42 days after the last dose of study treatment (total patient-years of exposure on study treatment in Placebo vs. Pertuzumab arms: 526.81 vs. 989.88 patient-years)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication.

Arm/Group Title		Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description:		This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed		396	408
Overall Number of Units Analyzed; Type of Units Analyzed: Adverse Events		9062	11908
Measure Type: Number; Number (90% Confidence Interval); Unit of Measure: Events per 100 patient-years
All Grades	Number Analyzed	9062 Adverse Events	11908 Adverse Events
		1720.2; (1690.6 to 1750.2)	1203.0; (1184.9 to 1221.3)
Grades 3 to 5	Number Analyzed	1187 Adverse Events	1304 Adverse Events
		225.3; (214.7 to 236.4)	131.7; (125.8 to 137.9)

9. Secondary Outcome

Title	Cardiac-Related AEs to Monitor: Number of Participants Who Experienced at Least One Symptomatic Left Ventricular Dysfunction (LVD), Any LVD, or Serious AE Suggestive of Congestive Heart Failure by Severity During the Treatment Period
Description	Cardiac-related adverse events (AEs) to monitor during the study included investigator-assessed symptomatic left ventricular dysfunction (LVD), any LVD, or a serious adverse event (SAE) suggestive of congestive heart failure (CHF). All cardiac-related AEs were graded for severity according to NCI-CTCAE v3.0. Asymptomatic (Grades 1-2) and symptomatic (Grades 3-5) left ventricular systolic dysfunction (LVSD) both coded to the MedDRA preferred term LVD. Investigator-assessed events of symptomatic LVD were also graded for severity of symptoms according to Classes I (least severe) to IV (most severe) of the New York Heart Association (NYHA) Classification. SAEs suggestive of CHF were identified as serious events from the Standardized MedDRA Query (SMQ) (Wide) 'Cardiac Failure'. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame	Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description:	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed	396	408	50
Measure Type: Count of Participants; Unit of Measure: Participants
Symptomatic LVD(Investigator)-All NYHA Classes	7 1.8%	6 1.5%	1 2.0%
Symptomatic LVD(Investigator)-NYHA Classes III/IV	4 1.0%	4 1.0%	1 2.0%
Any LVD - All NCI-CTCAE Grades	34 8.6%	32 7.8%	3 6.0%
Any LVD - NCI-CTCAE Grade ≥3	13 3.3%	6 1.5%	2 4.0%
SAE Suggestive of CHF - All NCI-CTCAE Grades	8 2.0%	8 2.0%	1 2.0%
SAE Suggestive of CHF - NCI-CTCAE Grade ≥3	7 1.8%	7 1.7%	1 2.0%

10. Secondary Outcome

Title	Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period
Description	The clinical diagnoses listed in this table, excluding cardiac safety (summarized separately), were also selected as adverse events (AEs) to monitor based on clinical and nonclinical data for pertuzumab and the safety profile established for trastuzumab, monoclonal antibodies in general, and potential effects associated with HER receptor inhibition. Search strategies were defined by single or aggregate MedDRA Preferred Terms (PT) through Standardized MedDRA Queries (SMQ), where possible, or based on Roche AE Group Terms (AEGT). Diarrhoea AEs: High-Level Term (HLT) 'Diarrhoea (excl. infective)' and PT 'Diarrhoea infectious'. Leukopenic and Febrile Neutropenic Infections: AEs from 'Infections & Infestations' with start ≤14 days after start date of Grade ≥3 AEs in SMQ(narrow) 'Leukopenia' or PT 'Febrile neutropenia', respectively. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame	Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description:	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed	396	408	50
Measure Type: Count of Participants; Unit of Measure: Participants
Diarrhoea (HLT+PT) - All Grades	191 48.2%	280 68.6%	25 50.0%
Diarrhoea (HLT+PT) - Grade ≥3	20 5.1%	40 9.8%	1 2.0%
Rash (AEGT) - All Grades	155 39.1%	213 52.2%	18 36.0%
Rash (AEGT) - Grade ≥3	6 1.5%	15 3.7%	0 0.0%
Leukopenia (SMQ-narrow) - All Grades	231 58.3%	257 63.0%	1 2.0%
Leukopenia (SMQ-narrow) - Grade ≥3	211 53.3%	238 58.3%	0 0.0%
Leukopenic Infection (PTs) - All Grades	38 9.6%	53 13.0%	0 0.0%
Leukopenic Infection (PTs) - Grade ≥3	9 2.3%	18 4.4%	0 0.0%
Febrile Neutropenic Infection (PTs) - All Grades	3 0.8%	14 3.4%	0 0.0%
Febrile Neutropenic Infection (PTs) - Grade ≥3	1 0.3%	6 1.5%	0 0.0%
Anaphylaxis and Hypersensitivity (AEGT)-All Grades	37 9.3%	48 11.8%	1 2.0%
Anaphylaxis and Hypersensitivity (AEGT)-Grade ≥3	10 2.5%	9 2.2%	0 0.0%
Interstitial Lung Disease (SMQ-narrow) -All Grades	6 1.5%	10 2.5%	1 2.0%
Interstitial Lung Disease (SMQ-narrow) -Grade ≥3	2 0.5%	3 0.7%	0 0.0%
QT Prolongation (SMQ-wide) - All Grades	5 1.3%	16 3.9%	0 0.0%
QT Prolongation (SMQ-wide) - Grade ≥3	1 0.3%	7 1.7%	0 0.0%
Mucositis (AEGT) - All Grades	154 38.9%	208 51.0%	12 24.0%
Mucositis (AEGT) - Grade ≥3	8 2.0%	14 3.4%	0 0.0%
Drug-Related Hepatic Disorder(SMQ-wide)-All Grades	43 10.9%	47 11.5%	0 0.0%
Drug-Related Hepatic Disorder (SMQ-wide)-Grade ≥3	5 1.3%	8 2.0%	0 0.0%

11. Secondary Outcome

Title	Overall Number of Participants Who Experienced at Least One Adverse Event Leading to Discontinuation of Any or All Study Medication
Description	Participants could continue study treatment with pertuzumab/placebo plus trastuzumab when docetaxel was discontinued due to an adverse event (AE). Discontinuation of pertuzumab/placebo or trastuzumab due to an AE led to discontinuation of all study medication. The number of participants who discontinued any study medication due to an AE includes those who discontinued all study medication and those who discontinued docetaxel only and then continued on targeted therapy (note: some of these participants may have subsequently discontinued all treatment due to a separate AE). Multiple occurrences of the same adverse event in 1 participant was counted only once. AEs reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for those who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame	Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description:	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed	396	408	50
Measure Type: Count of Participants; Unit of Measure: Participants
AE Leading to Discontinuation-Any Study Medication	114 28.8%	131 32.1%	5 10.0%
AE Leading to Discontinuation-All Study Medication	24 6.1%	39 9.6%	4 8.0%

12. Secondary Outcome

Title	Overall Number of Participants Who Experienced at Least One Adverse Event That Resulted in Interruption or Modification of Any Study Medication
Description	Pertuzumab, trastuzumab, and docetaxel administration could have been delayed to assess or treat adverse events (AEs). Docetaxel dose reduction was allowed for myelosuppression, hepatic dysfunction, and other toxicities. No dose reduction was allowed for pertuzumab or trastuzumab. Multiple occurrences of the same adverse event in one participant was counted only once. AEs reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for participants who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks
Time Frame	Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description:	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed	396	408	50
Measure Type: Count of Participants; Unit of Measure: Participants
	217 54.8%	265 65.0%	16 32.0%

13. Secondary Outcome

Title	Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period
Description	The post-treatment period was defined as the period following the treatment discontinuation visit. Only the following new adverse events (AEs) should have been reported during the post-treatment follow-up period: 1. Cardiac events (regardless of causality or seriousness) that started up to 1 year after the last dose, except for symptomatic left ventricular systolic dysfunction (regardless of causality) that started up to 3 years after the last dose; and 2. Treatment-related serious AEs, regardless of start date. AEs are listed by Medical Dictionary for Regulatory Activities, Version 21.1 (MedDRA v21.1) System Organ Class (SOC) and Preferred Term (PT); PTs fall under the SOC that is listed immediately above it in the table. Multiple occurrences of the same AE in one participant was counted only once. AEs reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for participants who crossed over from placebo to pertuzumab.
Time Frame	From Day 43 after discontinuation of all study medication to end of post-treatment follow-up period (up to 3 years)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication.

Arm/Group Title	Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description:	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed	396	408	50
Measure Type: Count of Participants; Unit of Measure: Participants
Total with at Least One AE During Post-Treatment	18 4.5%	17 4.2%	3 6.0%
Cardiac Disorders (SOC)	8 2.0%	9 2.2%	1 2.0%
Left Ventricular Dysfunction (PT)	6 1.5%	5 1.2%	1 2.0%
Cardiac Failure (PT)	0 0.0%	2 0.5%	0 0.0%
Bundle Branch Block Left (PT)	0 0.0%	1 0.2%	0 0.0%
Cardiopulmonary Failure (PT)	1 0.3%	0 0.0%	0 0.0%
Myocardial Ischaemia (PT)	1 0.3%	0 0.0%	0 0.0%
Pericardial Effusion (PT)	0 0.0%	1 0.2%	0 0.0%
Prinzmetal Angina (PT)	1 0.3%	0 0.0%	0 0.0%
General Disorders & Admin. Site Conditions (SOC)	3 0.8%	2 0.5%	0 0.0%
Oedema Peripheral (PT)	2 0.5%	1 0.2%	0 0.0%
Asthenia (PT)	1 0.3%	0 0.0%	0 0.0%
Influenza Like Illness (PT)	0 0.0%	1 0.2%	0 0.0%
Infections & Infestations (SOC)	0 0.0%	0 0.0%	2 4.0%
Influenza (PT)	0 0.0%	0 0.0%	1 2.0%
Viral Infection (PT)	0 0.0%	0 0.0%	1 2.0%
Abscess Limb (PT)	0 0.0%	1 0.2%	0 0.0%
Nasopharyngitis (PT)	1 0.3%	0 0.0%	0 0.0%
Subcutaneous Abscess (PT)	0 0.0%	1 0.2%	0 0.0%
Musculoskeletal & Connective Tissue Disorders(SOC)	0 0.0%	0 0.0%	1 2.0%
Back Pain (PT)	0 0.0%	0 0.0%	1 2.0%
Pain in Extremity (PT)	1 0.3%	0 0.0%	0 0.0%
Nervous System Disorders (SOC)	2 0.5%	2 0.5%	0 0.0%
Neuropathy Peripheral (PT)	1 0.3%	1 0.2%	0 0.0%
Cognitive Disorder (PT)	1 0.3%	0 0.0%	0 0.0%
Dizziness (PT)	0 0.0%	1 0.2%	0 0.0%
Headache (PT)	0 0.0%	1 0.2%	0 0.0%
Respiratory, Thoracic & Mediastinal Disorders(SOC)	2 0.5%	1 0.2%	0 0.0%
Cough (PT)	1 0.3%	0 0.0%	0 0.0%
Dyspnoea (PT)	1 0.3%	0 0.0%	0 0.0%
Rhinitis Allergic (PT)	0 0.0%	1 0.2%	0 0.0%
Skin & Subcutaneous Tissue Disorders (SOC)	1 0.3%	2 0.5%	0 0.0%
Erythema (PT)	0 0.0%	1 0.2%	0 0.0%
Nail Disorder (PT)	1 0.3%	0 0.0%	0 0.0%
Rash Macular (PT)	0 0.0%	1 0.2%	0 0.0%
Blood & Lymphatic System Disorders (SOC)	1 0.3%	1 0.2%	0 0.0%
Febrile Neutropenia (PT)	1 0.3%	0 0.0%	0 0.0%
Leukopenia (PT)	0 0.0%	1 0.2%	0 0.0%
Gastrointestinal Disorders (SOC)	0 0.0%	2 0.5%	0 0.0%
Diarrhoea (PT)	0 0.0%	1 0.2%	0 0.0%
Stomatitis (PT)	0 0.0%	1 0.2%	0 0.0%
Endocrine Disorders (SOC)	1 0.3%	0 0.0%	0 0.0%
Thyroid Mass (PT)	1 0.3%	0 0.0%	0 0.0%
Eye Disorders (SOC)	1 0.3%	0 0.0%	0 0.0%
Retinal Detachment (PT)	1 0.3%	0 0.0%	0 0.0%
Immune System Disorders (SOC)	0 0.0%	1 0.2%	0 0.0%
Iodine Allergy (PT)	0 0.0%	1 0.2%	0 0.0%
Investigations (SOC)	1 0.3%	0 0.0%	0 0.0%
Aspartate Aminotransferase Increased (PT)	1 0.3%	0 0.0%	0 0.0%
Renal & Urinary Disorders (SOC)	0 0.0%	1 0.2%	0 0.0%
Dysuria (PT)	0 0.0%	1 0.2%	0 0.0%
Reproductive System & Breast Disorders (SOC)	0 0.0%	1 0.2%	0 0.0%
Breast Induration (PT)	0 0.0%	1 0.2%	0 0.0%
Vascular Disorders (SOC)	0 0.0%	1 0.2%	0 0.0%
Venous Thrombosis (PT)	0 0.0%	1 0.2%	0 0.0%

14. Secondary Outcome

Title	Number of Participants by Categories for the Maximum Absolute Decrease From Baseline in LVEF Value During the Treatment Period
Description	All participants were required to have an left ventricular ejection fraction (LVEF) ≥50% at baseline, as measured by echocardiogram (preferred) or multiple-gated acquisition (MUGA) scan. The same method of LVEF assessment and the same institution/facility used at baseline was used throughout the study, to the extent possible. The baseline value was defined as the last valid value recorded during the pre-treatment period before or on study Day 1. The maximum absolute decrease in LVEF value was defined as the lowest post-baseline value up to the end of the overall study treatment period. Data reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for participants who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame	Every 9 weeks from the date of randomization until Treatment Discontinuation Visit (see Description for time on study treatment per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication. Only participants with evaluable LVEF assessments during the overall study treatment period were included in the analysis.

Arm/Group Title		Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description:		This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed		396	408	50
Measure Type: Count of Participants; Unit of Measure: Participants
LVEF Increase/No Change/Decrease FromBL <10%Points	Number Analyzed	378 participants	394 participants	49 participants
		252 66.7%	249 63.2%	30 61.2%
LVEF <50% and Decrease From BL ≥10% to <15% Points	Number Analyzed	378 participants	394 participants	49 participants
		9 2.4%	7 1.8%	0 0.0%
LVEF <50% and Decrease From BL ≥15% Points	Number Analyzed	378 participants	394 participants	49 participants
		19 5.0%	21 5.3%	3 6.1%
LVEF ≥50% and Decrease From BL ≥10% Points	Number Analyzed	378 participants	394 participants	49 participants
		95 25.1%	115 29.2%	15 30.6%
No Baseline (BL) LVEF Value	Number Analyzed	378 participants	394 participants	49 participants
		3 0.8%	2 0.5%	1 2.0%

15. Secondary Outcome

Title	Baseline LVEF Value and Change in LVEF From Baseline at Maximum Absolute Decrease Value During the Treatment Period
Description	All participants were required to have a left ventricular ejection fraction (LVEF) ≥50% at baseline, as measured by echocardiogram (preferred) or multiple-gated acquisition (MUGA) scan. The same method of LVEF assessment and the same institution/facility used at baseline was used throughout the study, to the extent possible. The baseline value was defined as the last valid value recorded during the pre-treatment period before or on study Day 1. The maximum absolute decrease in LVEF value was defined as the lowest post-baseline value up to the end of the overall study treatment period. Only data reported prior to the date of first crossover treatment were included for participants who crossed over from placebo to pertuzumab.
Time Frame	Every 9 weeks from the date of randomization until Treatment Discontinuation Visit (median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication. Only participants with evaluable LVEF assessments at baseline (BL) or at BL and post-BL (for change in LVEF from BL at max. decrease) were included in the analyses.

Arm/Group Title		Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description:		This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed		396	408
Mean (Standard Deviation); Unit of Measure: Percentage points of LVEF
Baseline (BL) LVEF Value	Number Analyzed	393 participants	406 participants
		65.6 (6.51)	64.8 (6.71)
Change in LVEF From BL at Maximum Decrease Value	Number Analyzed	375 participants	392 participants
		-7.3 (7.15)	-7.5 (7.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Trastuzumab + Docetaxel, Pertuzumab + Trastuzumab + Docetaxel
	Comments	Wilcoxon Test of Maximum Decrease in LVEF From BL
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7174
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

16. Secondary Outcome

Title	Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period
Description	Clinical laboratory tests for blood biochemistry parameters were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest grade according to NCI-CTCAE v3.0. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks. ALP = alkaline phosphatase; GGT = gamma-glutamyl transferase; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase
Time Frame	On Day 1 of every treatment cycle (1 cycle is 21 days) until Treatment Discontinuation Visit (see Description for time on study treatment per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication. Only participants with at least one valid laboratory value for any given parameter during the overall study treatment period were included in the analysis.

Arm/Group Title		Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description:		This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed		396	408	50
Measure Type: Count of Participants; Unit of Measure: Participants
Albumin (g/L) - Low, Any Grade (Gr.)	Number Analyzed	385 participants	396 participants	49 participants
		163 42.3%	196 49.5%	15 30.6%
Albumin (g/L) - Low, Gr. 1	Number Analyzed	385 participants	396 participants	49 participants
		113 29.4%	132 33.3%	10 20.4%
Albumin (g/L) - Low, Gr. 2	Number Analyzed	385 participants	396 participants	49 participants
		46 11.9%	58 14.6%	4 8.2%
Albumin (g/L) - Low, Gr. 3	Number Analyzed	385 participants	396 participants	49 participants
		4 1.0%	6 1.5%	1 2.0%
Albumin (g/L) - Low, Gr. 4	Number Analyzed	385 participants	396 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%
ALP (U/L) - High, Any Gr.	Number Analyzed	388 participants	400 participants	49 participants
		184 47.4%	210 52.5%	17 34.7%
ALP (U/L) - High, Gr. 1	Number Analyzed	388 participants	400 participants	49 participants
		158 40.7%	177 44.3%	17 34.7%
ALP (U/L) - High, Gr. 2	Number Analyzed	388 participants	400 participants	49 participants
		19 4.9%	24 6.0%	0 0.0%
ALP (U/L) - High, Gr. 3	Number Analyzed	388 participants	400 participants	49 participants
		7 1.8%	9 2.3%	0 0.0%
ALP (U/L) - High, Gr. 4	Number Analyzed	388 participants	400 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%
Calcium (mmol/L) - Low, Any Gr.	Number Analyzed	387 participants	399 participants	49 participants
		156 40.3%	203 50.9%	14 28.6%
Calcium (mmol/L) - Low, Gr. 1	Number Analyzed	387 participants	399 participants	49 participants
		107 27.6%	139 34.8%	11 22.4%
Calcium (mmol/L) - Low, Gr. 2	Number Analyzed	387 participants	399 participants	49 participants
		45 11.6%	49 12.3%	0 0.0%
Calcium (mmol/L) - Low, Gr. 3	Number Analyzed	387 participants	399 participants	49 participants
		3 0.8%	7 1.8%	1 2.0%
Calcium (mmol/L) - Low, Gr. 4	Number Analyzed	387 participants	399 participants	49 participants
		1 0.3%	8 2.0%	2 4.1%
Calcium (mmol/L) - High, Any Gr.	Number Analyzed	387 participants	399 participants	49 participants
		54 14.0%	79 19.8%	12 24.5%
Calcium (mmol/L) - High, Gr. 1	Number Analyzed	387 participants	399 participants	49 participants
		50 12.9%	65 16.3%	7 14.3%
Calcium (mmol/L) - High, Gr. 2	Number Analyzed	387 participants	399 participants	49 participants
		0 0.0%	2 0.5%	1 2.0%
Calcium (mmol/L) - High, Gr. 3	Number Analyzed	387 participants	399 participants	49 participants
		3 0.8%	2 0.5%	0 0.0%
Calcium (mmol/L) - High, Gr. 4	Number Analyzed	387 participants	399 participants	49 participants
		1 0.3%	10 2.5%	4 8.2%
Creatinine (umol/L) - High, Any Gr.	Number Analyzed	390 participants	402 participants	49 participants
		317 81.3%	346 86.1%	38 77.6%
Creatinine (umol/L) - High, Gr. 1	Number Analyzed	390 participants	402 participants	49 participants
		271 69.5%	279 69.4%	27 55.1%
Creatinine (umol/L) - High, Gr. 2	Number Analyzed	390 participants	402 participants	49 participants
		44 11.3%	54 13.4%	9 18.4%
Creatinine (umol/L) - High, Gr. 3	Number Analyzed	390 participants	402 participants	49 participants
		2 0.5%	6 1.5%	0 0.0%
Creatinine (umol/L) - High, Gr. 4	Number Analyzed	390 participants	402 participants	49 participants
		0 0.0%	7 1.7%	2 4.1%
Fasting Glucose (mmol/L) - Low, Any Gr.	Number Analyzed	387 participants	400 participants	49 participants
		42 10.9%	75 18.8%	6 12.2%
Fasting Glucose (mmol/L) - Low, Gr. 1	Number Analyzed	387 participants	400 participants	49 participants
		32 8.3%	61 15.3%	4 8.2%
Fasting Glucose (mmol/L) - Low, Gr. 2	Number Analyzed	387 participants	400 participants	49 participants
		9 2.3%	9 2.3%	0 0.0%
Fasting Glucose (mmol/L) - Low, Gr. 3	Number Analyzed	387 participants	400 participants	49 participants
		1 0.3%	2 0.5%	0 0.0%
Fasting Glucose (mmol/L) - Low, Gr. 4	Number Analyzed	387 participants	400 participants	49 participants
		0 0.0%	3 0.8%	2 4.1%
Fasting Glucose (mmol/L) - High, Any Gr.	Number Analyzed	387 participants	400 participants	49 participants
		271 70.0%	299 74.8%	34 69.4%
Fasting Glucose (mmol/L) - High, Gr. 1	Number Analyzed	387 participants	400 participants	49 participants
		168 43.4%	192 48.0%	26 53.1%
Fasting Glucose (mmol/L) - High, Gr. 2	Number Analyzed	387 participants	400 participants	49 participants
		83 21.4%	78 19.5%	8 16.3%
Fasting Glucose (mmol/L) - High, Gr. 3	Number Analyzed	387 participants	400 participants	49 participants
		20 5.2%	26 6.5%	0 0.0%
Fasting Glucose (mmol/L) - High, Gr. 4	Number Analyzed	387 participants	400 participants	49 participants
		0 0.0%	3 0.8%	0 0.0%
GGT (U/L) - High, Any Gr.	Number Analyzed	375 participants	394 participants	48 participants
		209 55.7%	225 57.1%	14 29.2%
GGT (U/L) - High, Gr. 1	Number Analyzed	375 participants	394 participants	48 participants
		133 35.5%	144 36.5%	9 18.8%
GGT (U/L) - High, Gr. 2	Number Analyzed	375 participants	394 participants	48 participants
		41 10.9%	52 13.2%	4 8.3%
GGT (U/L) - High, Gr. 3	Number Analyzed	375 participants	394 participants	48 participants
		30 8.0%	27 6.9%	1 2.1%
GGT (U/L) - High, Gr. 4	Number Analyzed	375 participants	394 participants	48 participants
		5 1.3%	2 0.5%	0 0.0%
Magnesium (mmol/L) - Low, Any Gr.	Number Analyzed	371 participants	398 participants	49 participants
		79 21.3%	117 29.4%	8 16.3%
Magnesium (mmol/L) - Low, Gr. 1	Number Analyzed	371 participants	398 participants	49 participants
		71 19.1%	98 24.6%	6 12.2%
Magnesium (mmol/L) - Low, Gr. 2	Number Analyzed	371 participants	398 participants	49 participants
		7 1.9%	13 3.3%	0 0.0%
Magnesium (mmol/L) - Low, Gr. 3	Number Analyzed	371 participants	398 participants	49 participants
		1 0.3%	3 0.8%	0 0.0%
Magnesium (mmol/L) - Low, Gr. 4	Number Analyzed	371 participants	398 participants	49 participants
		0 0.0%	3 0.8%	2 4.1%
Magnesium (mmol/L) - High, Any Gr.	Number Analyzed	371 participants	398 participants	49 participants
		76 20.5%	105 26.4%	16 32.7%
Magnesium (mmol/L) - High, Gr. 1	Number Analyzed	371 participants	398 participants	49 participants
		58 15.6%	80 20.1%	11 22.4%
Magnesium (mmol/L) - High, Gr. 2	Number Analyzed	371 participants	398 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%
Magnesium (mmol/L) - High, Gr. 3	Number Analyzed	371 participants	398 participants	49 participants
		18 4.9%	22 5.5%	4 8.2%
Magnesium (mmol/L) - High, Gr. 4	Number Analyzed	371 participants	398 participants	49 participants
		0 0.0%	3 0.8%	1 2.0%
Potassium (mmol/L) - Low, Any Gr.	Number Analyzed	389 participants	401 participants	49 participants
		80 20.6%	144 35.9%	11 22.4%
Potassium (mmol/L) - Low, Gr. 1	Number Analyzed	389 participants	401 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%
Potassium (mmol/L) - Low, Gr. 2	Number Analyzed	389 participants	401 participants	49 participants
		68 17.5%	118 29.4%	8 16.3%
Potassium (mmol/L) - Low, Gr. 3	Number Analyzed	389 participants	401 participants	49 participants
		10 2.6%	18 4.5%	2 4.1%
Potassium (mmol/L) - Low, Gr. 4	Number Analyzed	389 participants	401 participants	49 participants
		2 0.5%	8 2.0%	1 2.0%
Potassium (mmol/L) - High, Any Gr.	Number Analyzed	389 participants	401 participants	49 participants
		67 17.2%	78 19.5%	13 26.5%
Potassium (mmol/L) - High, Gr. 1	Number Analyzed	389 participants	401 participants	49 participants
		49 12.6%	55 13.7%	11 22.4%
Potassium (mmol/L) - High, Gr. 2	Number Analyzed	389 participants	401 participants	49 participants
		15 3.9%	17 4.2%	2 4.1%
Potassium (mmol/L) - High, Gr. 3	Number Analyzed	389 participants	401 participants	49 participants
		3 0.8%	6 1.5%	0 0.0%
Potassium (mmol/L) - High, Gr. 4	Number Analyzed	389 participants	401 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%
SGOT (U/L) - High, Any Gr.	Number Analyzed	389 participants	400 participants	49 participants
		184 47.3%	193 48.3%	17 34.7%
SGOT (U/L) - High, Gr. 1	Number Analyzed	389 participants	400 participants	49 participants
		169 43.4%	170 42.5%	15 30.6%
SGOT (U/L) - High, Gr. 2	Number Analyzed	389 participants	400 participants	49 participants
		11 2.8%	12 3.0%	2 4.1%
SGOT (U/L) - High, Gr. 3	Number Analyzed	389 participants	400 participants	49 participants
		4 1.0%	10 2.5%	0 0.0%
SGOT (U/L) - High, Gr. 4	Number Analyzed	389 participants	400 participants	49 participants
		0 0.0%	1 0.3%	0 0.0%
SGPT (U/L) - High, Any Gr.	Number Analyzed	390 participants	400 participants	49 participants
		195 50.0%	209 52.3%	19 38.8%
SGPT (U/L) - High, Gr. 1	Number Analyzed	390 participants	400 participants	49 participants
		172 44.1%	175 43.8%	17 34.7%
SGPT (U/L) - High, Gr. 2	Number Analyzed	390 participants	400 participants	49 participants
		18 4.6%	19 4.8%	2 4.1%
SGPT (U/L) - High, Gr. 3	Number Analyzed	390 participants	400 participants	49 participants
		5 1.3%	14 3.5%	0 0.0%
SGPT (U/L) - High, Gr. 4	Number Analyzed	390 participants	400 participants	49 participants
		0 0.0%	1 0.3%	0 0.0%
Sodium (mmol/L) - Low, Any Gr.	Number Analyzed	389 participants	402 participants	49 participants
		109 28.0%	135 33.6%	25 51.0%
Sodium (mmol/L) - Low, Gr. 1	Number Analyzed	389 participants	402 participants	49 participants
		87 22.4%	121 30.1%	22 44.9%
Sodium (mmol/L) - Low, Gr. 2	Number Analyzed	389 participants	402 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%
Sodium (mmol/L) - Low, Gr. 3	Number Analyzed	389 participants	402 participants	49 participants
		21 5.4%	12 3.0%	1 2.0%
Sodium (mmol/L) - Low, Gr. 4	Number Analyzed	389 participants	402 participants	49 participants
		1 0.3%	2 0.5%	2 4.1%
Sodium (mmol/L) - High, Any Gr.	Number Analyzed	389 participants	402 participants	49 participants
		76 19.5%	103 25.6%	9 18.4%
Sodium (mmol/L) - High, Gr. 1	Number Analyzed	389 participants	402 participants	49 participants
		71 18.3%	91 22.6%	7 14.3%
Sodium (mmol/L) - High, Gr. 2	Number Analyzed	389 participants	402 participants	49 participants
		4 1.0%	9 2.2%	2 4.1%
Sodium (mmol/L) - High, Gr. 3	Number Analyzed	389 participants	402 participants	49 participants
		1 0.3%	2 0.5%	0 0.0%
Sodium (mmol/L) - High, Gr. 4	Number Analyzed	389 participants	402 participants	49 participants
		0 0.0%	1 0.2%	0 0.0%
Total Bilirubin (umol/L) - High, Any Gr.	Number Analyzed	390 participants	401 participants	49 participants
		35 9.0%	57 14.2%	7 14.3%
Total Bilirubin (umol/L) - High, Gr. 1	Number Analyzed	390 participants	401 participants	49 participants
		26 6.7%	44 11.0%	6 12.2%
Total Bilirubin (umol/L) - High, Gr. 2	Number Analyzed	390 participants	401 participants	49 participants
		7 1.8%	9 2.2%	0 0.0%
Total Bilirubin (umol/L) - High, Gr. 3	Number Analyzed	390 participants	401 participants	49 participants
		2 0.5%	2 0.5%	0 0.0%
Total Bilirubin (umol/L) - High, Gr. 4	Number Analyzed	390 participants	401 participants	49 participants
		0 0.0%	2 0.5%	1 2.0%
Uric Acid (umol/L) - High, Any Gr.	Number Analyzed	370 participants	397 participants	49 participants
		118 31.9%	113 28.5%	15 30.6%
Uric Acid (umol/L) - High, Gr. 1	Number Analyzed	370 participants	397 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%
Uric Acid (umol/L) - High, Gr. 2	Number Analyzed	370 participants	397 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%
Uric Acid (umol/L) - High, Gr. 3	Number Analyzed	370 participants	397 participants	49 participants
		116 31.4%	98 24.7%	10 20.4%
Uric Acid (umol/L) - High, Gr. 4	Number Analyzed	370 participants	397 participants	49 participants
		2 0.5%	15 3.8%	5 10.2%

17. Secondary Outcome

Title	Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period
Description	Clinical laboratory tests for hematology parameters were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest grade according to NCI-CTCAE v3.0. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks. INR = International Normalized Ratio; PTT = partial thromboplastin time; WBC = white blood cell
Time Frame	On Day 1 (and Day 8 for some measures) of every treatment cycle (1 cycle is 21 days) until Treatment Discontinuation Visit (see Description for time on study treatment per arm)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least one dose of any study medication. Only participants with at least one valid laboratory value for any given parameter during the overall study treatment period were included in the analysis.

Arm/Group Title		Placebo + Trastuzumab + Docetaxel	Pertuzumab + Trastuzumab + Docetaxel	Crossover From Placebo to Pertuzumab
Arm/Group Description:		This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.	Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed		396	408	50
Measure Type: Count of Participants; Unit of Measure: Participants
Hemoglobin (g/L) - Low, Any Grade (Gr.)	Number Analyzed	392 participants	404 participants	49 participants
		350 89.3%	372 92.1%	20 40.8%
Hemoglobin (g/L) - Low, Gr. 1	Number Analyzed	392 participants	404 participants	49 participants
		202 51.5%	186 46.0%	9 18.4%
Hemoglobin (g/L) - Low, Gr. 2	Number Analyzed	392 participants	404 participants	49 participants
		127 32.4%	161 39.9%	6 12.2%
Hemoglobin (g/L) - Low, Gr. 3	Number Analyzed	392 participants	404 participants	49 participants
		21 5.4%	25 6.2%	5 10.2%
Hemoglobin (g/L) - Low, Gr. 4	Number Analyzed	392 participants	404 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%
Hemoglobin (g/L) - High, Any Gr.	Number Analyzed	392 participants	404 participants	49 participants
		10 2.6%	23 5.7%	4 8.2%
Hemoglobin (g/L) - High, Gr. 1	Number Analyzed	392 participants	404 participants	49 participants
		9 2.3%	20 5.0%	2 4.1%
Hemoglobin (g/L) - High, Gr. 2	Number Analyzed	392 participants	404 participants	49 participants
		1 0.3%	2 0.5%	0 0.0%
Hemoglobin (g/L) - High, Gr. 3	Number Analyzed	392 participants	404 participants	49 participants
		0 0.0%	1 0.2%	2 4.1%
Hemoglobin (g/L) - High, Gr. 4	Number Analyzed	392 participants	404 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%
Lymphocytes (10^9/L) - Low, Any Gr.	Number Analyzed	391 participants	404 participants	49 participants
		259 66.2%	276 68.3%	8 16.3%
Lymphocytes (10^9/L) - Low, Gr. 1	Number Analyzed	391 participants	404 participants	49 participants
		36 9.2%	39 9.7%	0 0.0%
Lymphocytes (10^9/L) - Low, Gr. 2	Number Analyzed	391 participants	404 participants	49 participants
		128 32.7%	136 33.7%	4 8.2%
Lymphocytes (10^9/L) - Low, Gr. 3	Number Analyzed	391 participants	404 participants	49 participants
		64 16.4%	69 17.1%	3 6.1%
Lymphocytes (10^9/L) - Low, Gr. 4	Number Analyzed	391 participants	404 participants	49 participants
		31 7.9%	32 7.9%	1 2.0%
Lymphocytes (10^9/L)- High, Any Gr.	Number Analyzed	391 participants	404 participants	49 participants
		58 14.8%	72 17.8%	9 18.4%
Lymphocytes (10^9/L)- High, Gr. 1	Number Analyzed	391 participants	404 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%
Lymphocytes (10^9/L)- High, Gr. 2	Number Analyzed	391 participants	404 participants	49 participants
		49 12.5%	57 14.1%	6 12.2%
Lymphocytes (10^9/L)- High, Gr. 3	Number Analyzed	391 participants	404 participants	49 participants
		9 2.3%	15 3.7%	3 6.1%
Lymphocytes (10^9/L)- High, Gr. 4	Number Analyzed	391 participants	404 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%
Neutrophils (10^9/L)- Low, Any Gr.	Number Analyzed	391 participants	404 participants	49 participants
		349 89.3%	371 91.8%	2 4.1%
Neutrophils (10^9/L)- Low, Gr. 1	Number Analyzed	391 participants	404 participants	49 participants
		7 1.8%	4 1.0%	0 0.0%
Neutrophils (10^9/L)- Low, Gr. 2	Number Analyzed	391 participants	404 participants	49 participants
		25 6.4%	34 8.4%	0 0.0%
Neutrophils (10^9/L)- Low, Gr. 3	Number Analyzed	391 participants	404 participants	49 participants
		81 20.7%	99 24.5%	0 0.0%
Neutrophils (10^9/L)- Low, Gr. 4	Number Analyzed	391 participants	404 participants	49 participants
		236 60.4%	234 57.9%	2 4.1%
PTT (sec) - High, Any Gr.	Number Analyzed	28 participants	35 participants	3 participants
		6 21.4%	9 25.7%	1 33.3%
PTT (sec) - High, Gr. 1	Number Analyzed	28 participants	35 participants	3 participants
		5 17.9%	2 5.7%	1 33.3%
PTT (sec) - High, Gr. 2	Number Analyzed	28 participants	35 participants	3 participants
		0 0.0%	4 11.4%	0 0.0%
PTT (sec) - High, Gr. 3	Number Analyzed	28 participants	35 participants	3 participants
		1 3.6%	3 8.6%	0 0.0%
PTT (sec) - High, Gr. 4	Number Analyzed	28 participants	35 participants	3 participants
		0 0.0%	0 0.0%	0 0.0%
Platelets (10^9/L) - Low, Any Gr.	Number Analyzed	392 participants	404 participants	49 participants
		82 20.9%	92 22.8%	13 26.5%
Platelets (10^9/L) - Low, Gr. 1	Number Analyzed	392 participants	404 participants	49 participants
		75 19.1%	78 19.3%	11 22.4%
Platelets (10^9/L) - Low, Gr. 2	Number Analyzed	392 participants	404 participants	49 participants
		5 1.3%	5 1.2%	0 0.0%
Platelets (10^9/L) - Low, Gr. 3	Number Analyzed	392 participants	404 participants	49 participants
		2 0.5%	3 0.7%	0 0.0%
Platelets (10^9/L) - Low, Gr. 4	Number Analyzed	392 participants	404 participants	49 participants
		0 0.0%	6 1.5%	2 4.1%
Prothrombin Time (INR) - High, Any Gr.	Number Analyzed	198 participants	216 participants	14 participants
		135 68.2%	157 72.7%	11 78.6%
Prothrombin Time (INR) - High, Gr. 1	Number Analyzed	198 participants	216 participants	14 participants
		127 64.1%	136 63.0%	9 64.3%
Prothrombin Time (INR) - High, Gr. 2	Number Analyzed	198 participants	216 participants	14 participants
		3 1.5%	6 2.8%	0 0.0%
Prothrombin Time (INR) - High, Gr. 3	Number Analyzed	198 participants	216 participants	14 participants
		5 2.5%	15 6.9%	2 14.3%
Prothrombin Time (INR) - High, Gr. 4	Number Analyzed	198 participants	216 participants	14 participants
		0 0.0%	0 0.0%	0 0.0%
WBC (10^9/L) - Low, Any Gr.	Number Analyzed	392 participants	404 participants	49 participants
		366 93.4%	387 95.8%	5 10.2%
WBC (10^9/L) - Low, Gr. 1	Number Analyzed	392 participants	404 participants	49 participants
		36 9.2%	34 8.4%	1 2.0%
WBC (10^9/L) - Low, Gr. 2	Number Analyzed	392 participants	404 participants	49 participants
		92 23.5%	92 22.8%	3 6.1%
WBC (10^9/L) - Low, Gr. 3	Number Analyzed	392 participants	404 participants	49 participants
		186 47.4%	206 51.0%	0 0.0%
WBC (10^9/L) - Low, Gr. 4	Number Analyzed	392 participants	404 participants	49 participants
		52 13.3%	55 13.6%	1 2.0%
WBC (10^9/L) - High, Any Gr.	Number Analyzed	392 participants	404 participants	49 participants
		0 0.0%	3 0.7%	1 2.0%
WBC (10^9/L) - High, Gr. 1	Number Analyzed	392 participants	404 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%
WBC (10^9/L) - High, Gr. 2	Number Analyzed	392 participants	404 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%
WBC (10^9/L) - High, Gr. 3	Number Analyzed	392 participants	404 participants	49 participants
		0 0.0%	3 0.7%	1 2.0%
WBC (10^9/L) - High, Gr. 4	Number Analyzed	392 participants	404 participants	49 participants
		0 0.0%	0 0.0%	0 0.0%

Adverse Events

Time Frame	From first treatment dose (12-Feb-2008) through to end of study (23-Nov-2018) for a total safety analysis timeframe of 10 years, 9.5 months.
Adverse Event Reporting Description	Of enrolled participants (Pertuzumab [Ptz]: N=402, Placebo [Pla]: N=406), 2 in each arm received no treatment (total of 4), 9 in Pla arm received at least 1 dose of Ptz, and 1 in Ptz arm received Pla at every cycle; resulting in a Safety Population of Ptz: N=408 (402-2+9-1), Pla: N=396 (406-2-9+1), and 50 participants in Pla arm crossed over to Ptz.
Arm/Group Title	Placebo + Trastuzumab + Docetaxel		Pertuzumab + Trastuzumab + Docetaxel		Crossover From Placebo to Pertuzumab
Arm/Group Description	This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.		This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.		Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
All-Cause Mortality
	Placebo + Trastuzumab + Docetaxel		Pertuzumab + Trastuzumab + Docetaxel		Crossover From Placebo to Pertuzumab
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	261/396 (65.91%)		238/408 (58.33%)		14/50 (28.00%)
Serious Adverse Events
	Placebo + Trastuzumab + Docetaxel		Pertuzumab + Trastuzumab + Docetaxel		Crossover From Placebo to Pertuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	116/396 (29.29%)		160/408 (39.22%)		10/50 (20.00%)
Blood and lymphatic system disorders
Anaemia † 1	3/396 (0.76%)	3	3/408 (0.74%)	4	1/50 (2.00%)	1
Febrile neutropenia † 1	20/396 (5.05%)	23	46/408 (11.27%)	48	0/50 (0.00%)	0
Granulocytopenia † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Leukopenia † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Neutropenia † 1	19/396 (4.80%)	20	18/408 (4.41%)	23	0/50 (0.00%)	0
Cardiac disorders
Atrial fibrillation † 1	3/396 (0.76%)	3	0/408 (0.00%)	0	0/50 (0.00%)	0
Cardiac failure congestive † 1	0/396 (0.00%)	0	2/408 (0.49%)	2	0/50 (0.00%)	0
Coronary artery disease † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Left ventricular dysfunction † 1	7/396 (1.77%)	7	6/408 (1.47%)	6	1/50 (2.00%)	1
Myocardial infarction † 1	3/396 (0.76%)	3	0/408 (0.00%)	0	0/50 (0.00%)	0
Myocardial ischaemia † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Ventricular fibrillation † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Ear and labyrinth disorders
Vertigo † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Eye disorders
Cataract † 1	0/396 (0.00%)	0	2/408 (0.49%)	2	1/50 (2.00%)	1
Gastrointestinal disorders
Abdominal pain † 1	1/396 (0.25%)	2	0/408 (0.00%)	0	0/50 (0.00%)	0
Colitis † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Constipation † 1	2/396 (0.51%)	3	0/408 (0.00%)	0	0/50 (0.00%)	0
Diarrhoea † 1	5/396 (1.26%)	5	13/408 (3.19%)	16	1/50 (2.00%)	1
Duodenal ulcer † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Duodenal ulcer haemorrhage † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Enteritis † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Gastrointestinal haemorrhage † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Haemorrhoidal haemorrhage † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Haemorrhoids † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Intestinal ischaemia † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Intestinal obstruction † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Intestinal perforation † 1	2/396 (0.51%)	2	0/408 (0.00%)	0	0/50 (0.00%)	0
Lower gastrointestinal haemorrhage † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Nausea † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Oesophagitis † 1	0/396 (0.00%)	0	2/408 (0.49%)	2	0/50 (0.00%)	0
Rectal haemorrhage † 1	1/396 (0.25%)	1	1/408 (0.25%)	1	0/50 (0.00%)	0
Upper gastrointestinal haemorrhage † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Vomiting † 1	1/396 (0.25%)	1	2/408 (0.49%)	2	0/50 (0.00%)	0
Volvulus † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Small intestinal obstruction † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
General disorders
Drowning † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Asthenia † 1	0/396 (0.00%)	0	2/408 (0.49%)	2	0/50 (0.00%)	0
Chest pain † 1	2/396 (0.51%)	2	1/408 (0.25%)	1	0/50 (0.00%)	0
Death † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	1/50 (2.00%)	1
Fatigue † 1	1/396 (0.25%)	1	2/408 (0.49%)	2	0/50 (0.00%)	0
General physical health deterioration † 1	2/396 (0.51%)	2	0/408 (0.00%)	0	0/50 (0.00%)	0
Influenza like illness † 1	0/396 (0.00%)	0	2/408 (0.49%)	2	0/50 (0.00%)	0
Mucosal inflammation † 1	1/396 (0.25%)	1	1/408 (0.25%)	1	0/50 (0.00%)	0
Pyrexia † 1	3/396 (0.76%)	3	6/408 (1.47%)	6	2/50 (4.00%)	2
Hepatobiliary disorders
Cholecystitis acute † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Cholelithiasis † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Hepatic failure † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Immune system disorders
Anaphylactic reaction † 1	1/396 (0.25%)	1	1/408 (0.25%)	1	0/50 (0.00%)	0
Drug hypersensitivity † 1	3/396 (0.76%)	3	3/408 (0.74%)	3	0/50 (0.00%)	0
Hypersensitivity † 1	0/396 (0.00%)	0	3/408 (0.74%)	3	0/50 (0.00%)	0
Infections and infestations
Acute sinusitis † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Anal abscess † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Appendicitis † 1	0/396 (0.00%)	0	2/408 (0.49%)	2	0/50 (0.00%)	0
Breast abscess † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Breast cellulitis † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Campylobacter gastroenteritis † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Catheter site infection † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Cellulitis † 1	2/396 (0.51%)	2	10/408 (2.45%)	12	0/50 (0.00%)	0
Cellulitis gangrenous † 1	0/396 (0.00%)	0	0/408 (0.00%)	0	1/50 (2.00%)	1
Clostridium difficile colitis † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Coccidioidomycosis † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Vascular device infection † 1	1/396 (0.25%)	1	2/408 (0.49%)	2	0/50 (0.00%)	0
Diarrhoea infectious † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Erysipelas † 1	0/396 (0.00%)	0	2/408 (0.49%)	2	0/50 (0.00%)	0
Gastroenteritis † 1	2/396 (0.51%)	3	2/408 (0.49%)	2	0/50 (0.00%)	0
Gastrointestinal infection † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
H1N1 influenza † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Herpes zoster † 1	3/396 (0.76%)	3	1/408 (0.25%)	1	0/50 (0.00%)	0
Infection † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Lower respiratory tract infection † 1	0/396 (0.00%)	0	4/408 (0.98%)	4	0/50 (0.00%)	0
Lymph node tuberculosis † 1	0/396 (0.00%)	0	0/408 (0.00%)	0	1/50 (2.00%)	1
Neutropenic infection † 1	1/396 (0.25%)	1	4/408 (0.98%)	4	0/50 (0.00%)	0
Neutropenic sepsis † 1	2/396 (0.51%)	2	0/408 (0.00%)	0	0/50 (0.00%)	0
Onychomycosis † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Oral candidiasis † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Osteomyelitis † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Osteomyelitis chronic † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Pharyngitis † 1	0/396 (0.00%)	0	2/408 (0.49%)	2	0/50 (0.00%)	0
Pneumonia † 1	11/396 (2.78%)	11	7/408 (1.72%)	7	1/50 (2.00%)	1
Pneumonia staphylococcal † 1	0/396 (0.00%)		1/408 (0.25%)		0/50 (0.00%)
Postoperative wound infection † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Pyelonephritis acute † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Rash pustular † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Respiratory tract infection † 1	1/396 (0.25%)	1	1/408 (0.25%)	1	0/50 (0.00%)	0
Respiratory tract infection viral † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Sepsis † 1	3/396 (0.76%)	3	1/408 (0.25%)	1	0/50 (0.00%)	0
Sepsis syndrome † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Septic shock † 1	1/396 (0.25%)	1	1/408 (0.25%)	1	0/50 (0.00%)	0
Skin infection † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Soft tissue infection † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Upper respiratory tract infection † 1	0/396 (0.00%)	0	2/408 (0.49%)	2	0/50 (0.00%)	0
Urinary tract infection † 1	1/396 (0.25%)	1	3/408 (0.74%)	3	0/50 (0.00%)	0
Urosepsis † 1	0/396 (0.00%)	0	2/408 (0.49%)	2	0/50 (0.00%)	0
Viral infection † 1	2/396 (0.51%)	2	0/408 (0.00%)	0	0/50 (0.00%)	0
Wound infection † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Wound infection staphylococcal † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Acute hepatitis B † 1	0/396 (0.00%)	0	0/408 (0.00%)	0	1/50 (2.00%)	1
Pyelonephritis † 1	0/396 (0.00%)	0	0/408 (0.00%)	0	1/50 (2.00%)	1
Groin abscess † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Pharyngotonsillitis † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Urinary tract infection bacterial † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Injury, poisoning and procedural complications
Compression fracture † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Contusion † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Femur fracture † 1	1/396 (0.25%)	1	3/408 (0.74%)	3	0/50 (0.00%)	0
Fracture † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Post procedural discomfort † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Scapula fracture † 1	0/396 (0.00%)		1/408 (0.25%)		0/50 (0.00%)	0
Tendon injury † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Thermal burn † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Tibia fracture † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Hip fracture † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Tendon rupture † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Upper limb fracture † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Investigations
Blood electrolytes abnormal † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Blood glucose increased † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Ejection fraction decreased † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Dehydration † 1	2/396 (0.51%)	2	1/408 (0.25%)	1	1/50 (2.00%)	1
Diabetes mellitus † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Fluid retention † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Hyperglycaemia † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Hypoglycaemia † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Musculoskeletal and connective tissue disorders
Back pain † 1	1/396 (0.25%)	1	2/408 (0.49%)	2	0/50 (0.00%)	0
Mobility decreased † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Muscular weakness † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Myalgia † 1	1/396 (0.25%)	1	1/408 (0.25%)	1	0/50 (0.00%)	0
Neck pain † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Osteonecrosis of jaw † 1	0/396 (0.00%)	0	2/408 (0.49%)	2	0/50 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Colon cancer † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Endometrial cancer † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Glioblastoma multiforme † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Ocular neoplasm † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Pituitary tumour benign † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Tumour haemorrhage † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Uterine leiomyoma † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Nervous system disorders
Cerebrovascular accident † 1	1/396 (0.25%)	1	1/408 (0.25%)	1	0/50 (0.00%)	0
Seizure † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Monoparesis † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Peripheral sensorimotor neuropathy † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Somnolence † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Spinal cord compression † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Syncope † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Facial paralysis † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Cerebral haematoma † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Headache † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Loss of consciousness † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Psychiatric disorders
Suicide attempt † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Renal and urinary disorders
Haematuria † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Nephrolithiasis † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Renal failure † 1	1/396 (0.25%)	1	1/408 (0.25%)	1	0/50 (0.00%)	0
Chronic kidney disease † 1	0/396 (0.00%)	0	0/408 (0.00%)	0	1/50 (2.00%)	1
Acute kidney injury † 1	2/396 (0.51%)	2	2/408 (0.49%)	2	0/50 (0.00%)	0
Reproductive system and breast disorders
Breast haemorrhage † 1	1/396 (0.25%)	2	0/408 (0.00%)	0	0/50 (0.00%)	0
Metrorrhagia † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Vaginal haemorrhage † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Asthma † 1	1/396 (0.25%)	6	0/408 (0.00%)	0	0/50 (0.00%)	0
Dyspnoea † 1	2/396 (0.51%)	2	2/408 (0.49%)	2	0/50 (0.00%)	0
Haemoptysis † 1	0/396 (0.00%)	0	1/408 (0.25%)	2	0/50 (0.00%)	0
Interstitial lung disease † 1	0/396 (0.00%)	0	2/408 (0.49%)	2	0/50 (0.00%)	0
Pleural effusion † 1	4/396 (1.01%)	5	2/408 (0.49%)	5	0/50 (0.00%)	0
Pneumonia aspiration † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Pneumonitis † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Pneumothorax † 1	1/396 (0.25%)	1	1/408 (0.25%)	1	0/50 (0.00%)	0
Pulmonary embolism † 1	0/396 (0.00%)	0	6/408 (1.47%)	6	0/50 (0.00%)	0
Respiratory failure † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Hypoxia † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Skin and subcutaneous tissue disorders
Dermatitis allergic † 1	0/396 (0.00%)	0	1/408 (0.25%)	2	0/50 (0.00%)	0
Drug eruption † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Rash maculo-papular † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Surgical and medical procedures
Abortion induced † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Vascular disorders
Aortic stenosis † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Deep vein thrombosis † 1	0/396 (0.00%)	0	3/408 (0.74%)	3	0/50 (0.00%)	0
Vena cava thrombosis † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Hypertension † 1	1/396 (0.25%)	1	1/408 (0.25%)	1	0/50 (0.00%)	0
Hypertensive crisis † 1	1/396 (0.25%)	1	0/408 (0.00%)	0	0/50 (0.00%)	0
Hypotension † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
Venous thrombosis limb † 1	0/396 (0.00%)	0	1/408 (0.25%)	1	0/50 (0.00%)	0
1 Term from vocabulary, MedDRA 21.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo + Trastuzumab + Docetaxel		Pertuzumab + Trastuzumab + Docetaxel		Crossover From Placebo to Pertuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	386/396 (97.47%)		400/408 (98.04%)		45/50 (90.00%)
Blood and lymphatic system disorders
Neutropenia † 1	191/396 (48.23%)	797	209/408 (51.23%)	849	1/50 (2.00%)	1
Anaemia † 1	77/396 (19.44%)	143	100/408 (24.51%)	151	6/50 (12.00%)	15
Leukopenia † 1	82/396 (20.71%)	344	75/408 (18.38%)	288	0/50 (0.00%)	0
Cardiac disorders
Left ventricular dysfunction † 1	27/396 (6.82%)	33	27/408 (6.62%)	43	3/50 (6.00%)	9
Eye disorders
Lacrimation increased † 1	55/396 (13.89%)	63	60/408 (14.71%)	74	0/50 (0.00%)	0
Dry eye † 1	8/396 (2.02%)	8	24/408 (5.88%)	27	2/50 (4.00%)	2
Cataract † 1	1/396 (0.25%)	1	7/408 (1.72%)	8	3/50 (6.00%)	3
Gastrointestinal disorders
Diarrhoea † 1	191/396 (48.23%)	428	277/408 (67.89%)	989	25/50 (50.00%)	155
Nausea † 1	168/396 (42.42%)	359	184/408 (45.10%)	394	4/50 (8.00%)	7
Vomiting † 1	96/396 (24.24%)	150	110/408 (26.96%)	184	5/50 (10.00%)	7
Constipation † 1	100/396 (25.25%)	179	69/408 (16.91%)	135	4/50 (8.00%)	6
Stomatitis † 1	63/396 (15.91%)	138	82/408 (20.10%)	167	6/50 (12.00%)	13
Abdominal pain † 1	50/396 (12.63%)	66	64/408 (15.69%)	86	2/50 (4.00%)	2
Dyspepsia † 1	48/396 (12.12%)	73	55/408 (13.48%)	80	3/50 (6.00%)	8
Abdominal pain upper † 1	43/396 (10.86%)	54	44/408 (10.78%)	69	2/50 (4.00%)	2
Gastritis † 1	7/396 (1.77%)	8	16/408 (3.92%)	20	3/50 (6.00%)	3
General disorders
Fatigue † 1	148/396 (37.37%)	291	156/408 (38.24%)	320	5/50 (10.00%)	16
Asthenia † 1	122/396 (30.81%)	268	114/408 (27.94%)	265	3/50 (6.00%)	3
Oedema peripheral † 1	111/396 (28.03%)	163	102/408 (25.00%)	141	1/50 (2.00%)	1
Mucosal inflammation † 1	78/396 (19.70%)	111	111/408 (27.21%)	185	1/50 (2.00%)	1
Pyrexia † 1	72/396 (18.18%)	94	81/408 (19.85%)	138	3/50 (6.00%)	6
Oedema † 1	49/396 (12.37%)	76	49/408 (12.01%)	84	1/50 (2.00%)	1
Chills † 1	15/396 (3.79%)	18	34/408 (8.33%)	36	1/50 (2.00%)	7
Pain † 1	22/396 (5.56%)	26	26/408 (6.37%)	31	0/50 (0.00%)	0
Chest pain † 1	21/396 (5.30%)	24	15/408 (3.68%)	17	0/50 (0.00%)	0
Influenza like illness † 1	10/396 (2.53%)	12	23/408 (5.64%)	41	2/50 (4.00%)	2
Immune system disorders
Hypersensitivity † 1	21/396 (5.30%)	29	28/408 (6.86%)	33	1/50 (2.00%)	1
Infections and infestations
Upper respiratory tract infection † 1	57/396 (14.39%)	99	90/408 (22.06%)	174	13/50 (26.00%)	32
Nasopharyngitis † 1	60/396 (15.15%)	108	76/408 (18.63%)	161	13/50 (26.00%)	58
Urinary tract infection † 1	29/396 (7.32%)	39	39/408 (9.56%)	65	4/50 (8.00%)	6
Paronychia † 1	16/396 (4.04%)	23	32/408 (7.84%)	45	6/50 (12.00%)	8
Conjunctivitis † 1	19/396 (4.80%)	22	31/408 (7.60%)	45	2/50 (4.00%)	2
Influenza † 1	22/396 (5.56%)	33	30/408 (7.35%)	43	6/50 (12.00%)	10
Rhinitis † 1	22/396 (5.56%)	35	22/408 (5.39%)	50	4/50 (8.00%)	13
Pneumonia † 1	8/396 (2.02%)	8	12/408 (2.94%)	20	4/50 (8.00%)	4
Cystitis † 1	6/396 (1.52%)	7	16/408 (3.92%)	25	5/50 (10.00%)	6
Cellulitis † 1	12/396 (3.03%)	14	16/408 (3.92%)	20	3/50 (6.00%)	6
Bronchitis † 1	15/396 (3.79%)	19	16/408 (3.92%)	29	4/50 (8.00%)	5
Pharyngitis † 1	9/396 (2.27%)	10	22/408 (5.39%)	28	3/50 (6.00%)	6
Investigations
Weight decreased † 1	19/396 (4.80%)	22	37/408 (9.07%)	51	3/50 (6.00%)	3
Weight increased † 1	22/396 (5.56%)	35	17/408 (4.17%)	21	0/50 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite † 1	106/396 (26.77%)	176	120/408 (29.41%)	229	2/50 (4.00%)	3
Hypokalaemia † 1	21/396 (5.30%)	28	37/408 (9.07%)	60	3/50 (6.00%)	3
Hyperglycaemia † 1	11/396 (2.78%)	24	17/408 (4.17%)	19	3/50 (6.00%)	4
Musculoskeletal and connective tissue disorders
Myalgia † 1	98/396 (24.75%)	209	97/408 (23.77%)	202	5/50 (10.00%)	30
Arthralgia † 1	71/396 (17.93%)	130	83/408 (20.34%)	133	5/50 (10.00%)	5
Pain in extremity † 1	52/396 (13.13%)	79	76/408 (18.63%)	116	5/50 (10.00%)	6
Back pain † 1	48/396 (12.12%)	58	66/408 (16.18%)	98	6/50 (12.00%)	17
Bone pain † 1	31/396 (7.83%)	56	37/408 (9.07%)	48	1/50 (2.00%)	1
Musculoskeletal pain † 1	38/396 (9.60%)	57	40/408 (9.80%)	51	2/50 (4.00%)	2
Muscle spasms † 1	20/396 (5.05%)	24	50/408 (12.25%)	94	3/50 (6.00%)	5
Musculoskeletal chest pain † 1	17/396 (4.29%)	22	22/408 (5.39%)	27	1/50 (2.00%)	1
Nervous system disorders
Neuropathy peripheral † 1	79/396 (19.95%)	114	95/408 (23.28%)	138	1/50 (2.00%)	1
Headache † 1	76/396 (19.19%)	128	106/408 (25.98%)	187	7/50 (14.00%)	9
Dysgeusia † 1	62/396 (15.66%)	116	75/408 (18.38%)	95	1/50 (2.00%)	30
Peripheral sensory neuropathy † 1	59/396 (14.90%)	82	52/408 (12.75%)	93	2/50 (4.00%)	2
Dizziness † 1	53/396 (13.38%)	73	67/408 (16.42%)	133	4/50 (8.00%)	4
Paraesthesia † 1	41/396 (10.35%)	60	43/408 (10.54%)	52	0/50 (0.00%)	0
Hypoaesthesia † 1	11/396 (2.78%)	15	21/408 (5.15%)	28	1/50 (2.00%)	1
Psychiatric disorders
Insomnia † 1	55/396 (13.89%)	72	67/408 (16.42%)	95	2/50 (4.00%)	3
Depression † 1	20/396 (5.05%)	22	26/408 (6.37%)	33	2/50 (4.00%)	2
Anxiety † 1	20/396 (5.05%)	28	20/408 (4.90%)	25	1/50 (2.00%)	1
Renal and urinary disorders
Dysuria † 1	11/396 (2.78%)	12	23/408 (5.64%)	27	0/50 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough † 1	79/396 (19.95%)	118	101/408 (24.75%)	146	6/50 (12.00%)	10
Dyspnoea † 1	62/396 (15.66%)	87	67/408 (16.42%)	99	1/50 (2.00%)	2
Epistaxis † 1	35/396 (8.84%)	47	41/408 (10.05%)	56	2/50 (4.00%)	4
Oropharyngeal pain † 1	27/396 (6.82%)	32	32/408 (7.84%)	55	1/50 (2.00%)	1
Rhinorrhoea † 1	23/396 (5.81%)	29	33/408 (8.09%)	43	3/50 (6.00%)	4
Skin and subcutaneous tissue disorders
Alopecia † 1	240/396 (60.61%)	256	248/408 (60.78%)	264	4/50 (8.00%)	5
Rash † 1	96/396 (24.24%)	185	156/408 (38.24%)	288	11/50 (22.00%)	19
Nail disorder † 1	92/396 (23.23%)	105	96/408 (23.53%)	106	2/50 (4.00%)	2
Pruritus † 1	40/396 (10.10%)	67	75/408 (18.38%)	117	6/50 (12.00%)	6
Dry skin † 1	25/396 (6.31%)	26	47/408 (11.52%)	53	4/50 (8.00%)	6
Palmar-plantar erythrodysaesthesia syndrome † 1	22/396 (5.56%)	25	28/408 (6.86%)	38	1/50 (2.00%)	1
Erythema † 1	20/396 (5.05%)	27	23/408 (5.64%)	28	1/50 (2.00%)	1
Eczema † 1	5/396 (1.26%)	6	5/408 (1.23%)	5	3/50 (6.00%)	3
Vascular disorders
Hypertension † 1	31/396 (7.83%)	93	53/408 (12.99%)	83	4/50 (8.00%)	4
Hot flush † 1	21/396 (5.30%)	39	23/408 (5.64%)	26	0/50 (0.00%)	0
Lymphoedema † 1	16/396 (4.04%)	18	24/408 (5.88%)	25	0/50 (0.00%)	0
1 Term from vocabulary, MedDRA 21.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact

• Name/Title: Medical Communications
• Organization: Genentech, Inc.
• Phone: 800 821-8590
• EMail: genentech@druginfo.com

Publications of Results:

Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. doi: 10.1056/NEJMoa1113216. Epub 2011 Dec 7.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, Ciruelos E, Schneeweiss A, Loi S, Monturus E, Clark E, Knott A, Restuccia E, Benyunes MC, Cortes J; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Apr;21(4):519-530. doi: 10.1016/S1470-2045(19)30863-0. Epub 2020 Mar 12.

Miles D, Im YH, Fung A, Yoo B, Knott A, Heeson S, Beattie MS, Swain SM. Effect of docetaxel duration on clinical outcomes: exploratory analysis of CLEOPATRA, a phase III randomized controlled trial. Ann Oncol. 2017 Nov 1;28(11):2761-2767. doi: 10.1093/annonc/mdx406.

Swain SM, Schneeweiss A, Gianni L, Gao JJ, Stein A, Waldron-Lynch M, Heeson S, Beattie MS, Yoo B, Cortes J, Baselga J. Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab. Ann Oncol. 2017 Apr 1;28(4):761-768. doi: 10.1093/annonc/mdw695. Erratum In: Ann Oncol. 2018 Apr 1;29(4):1075. Ann Oncol. 2018 Jul 1;29(7):1607. Ann Oncol. 2019 Aug 1;30(8):1404.

Luen SJ, Salgado R, Fox S, Savas P, Eng-Wong J, Clark E, Kiermaier A, Swain SM, Baselga J, Michiels S, Loi S. Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study. Lancet Oncol. 2017 Jan;18(1):52-62. doi: 10.1016/S1470-2045(16)30631-3. Epub 2016 Dec 7. Erratum In: Lancet Oncol. 2018 Dec;19(12):e667.

Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortes J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. doi: 10.1056/NEJMoa1413513.

Baselga J, Cortes J, Im SA, Clark E, Ross G, Kiermaier A, Swain SM. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J Clin Oncol. 2014 Nov 20;32(33):3753-61. doi: 10.1200/JCO.2013.54.5384. Epub 2014 Oct 20.

Swain SM, Baselga J, Miles D, Im YH, Quah C, Lee LF, Cortes J. Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA. Ann Oncol. 2014 Jun;25(6):1116-21. doi: 10.1093/annonc/mdu133. Epub 2014 Mar 31.

Miles D, Baselga J, Amadori D, Sunpaweravong P, Semiglazov V, Knott A, Clark E, Ross G, Swain SM. Treatment of older patients with HER2-positive metastatic breast cancer with pertuzumab, trastuzumab, and docetaxel: subgroup analyses from a randomized, double-blind, placebo-controlled phase III trial (CLEOPATRA). Breast Cancer Res Treat. 2013 Nov;142(1):89-99. doi: 10.1007/s10549-013-2710-z. Epub 2013 Oct 16.

Cortes J, Baselga J, Im YH, Im SA, Pivot X, Ross G, Clark E, Knott A, Swain SM. Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer. Ann Oncol. 2013 Oct;24(10):2630-2635. doi: 10.1093/annonc/mdt274. Epub 2013 Jul 17.

Swain SM, Kim SB, Cortes J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. doi: 10.1016/S1470-2045(13)70130-X. Epub 2013 Apr 18.

Baselga J, Swain SM. CLEOPATRA: a phase III evaluation of pertuzumab and trastuzumab for HER2-positive metastatic breast cancer. Clin Breast Cancer. 2010 Dec 1;10(6):489-91. doi: 10.3816/CBC.2010.n.065.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT00567190
• Other Study ID Numbers: TOC4129g; WO20698 ( Other Identifier: Hoffmann-La Roche ); 2007-002997-72 ( EudraCT Number )
• First Submitted: December 3, 2007
• First Posted: December 4, 2007
• Results First Submitted: August 14, 2012
• Results First Posted: September 13, 2012
• Last Update Posted: December 13, 2019