Trial Outcomes & Findings for A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer (NCT NCT00567190)

Last Updated: 2019-12-13

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

808 participants

Primary outcome timeframe

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)

Results posted on

2019-12-13

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Pertuzumab + Trastuzumab + Docetaxel 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.	Placebo + Trastuzumab + Docetaxel 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 Study STARTED	402	406
Overall Study Did Not Receive Any Study Treatment	2	2
Overall Study Received at Least One Dose of Pertuzumab	399	9
Overall Study Received at Least One Dose of Placebo	1	395
Overall Study Crossover From Placebo to Pertuzumab	0	50
Overall Study COMPLETED	119	73
Overall Study NOT COMPLETED	283	333

Reasons for withdrawal

Reasons for withdrawal
Measure	Pertuzumab + Trastuzumab + Docetaxel 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.	Placebo + Trastuzumab + Docetaxel 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 Study Death	235	280
Overall Study Withdrew Consent or Lost to Follow-up	48	53

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pertuzumab + Trastuzumab + Docetaxel n=402 Participants 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.	Placebo + Trastuzumab + Docetaxel n=406 Participants 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 n=808 Participants Total of all reporting groups
Age, Continuous	53.4 years STANDARD_DEVIATION 10.94 • n=5 Participants	53.5 years STANDARD_DEVIATION 11.35 • n=7 Participants	53.5 years STANDARD_DEVIATION 11.14 • n=5 Participants
Sex: Female, Male Female	402 Participants n=5 Participants	404 Participants n=7 Participants	806 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	39 Participants n=5 Participants	44 Participants n=7 Participants	83 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	362 Participants n=5 Participants	362 Participants n=7 Participants	724 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Race (NIH/OMB) Asian	128 Participants n=5 Participants	133 Participants n=7 Participants	261 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	10 Participants n=5 Participants	20 Participants n=7 Participants	30 Participants n=5 Participants
Race (NIH/OMB) White	245 Participants n=5 Participants	235 Participants n=7 Participants	480 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	16 Participants n=5 Participants	14 Participants n=7 Participants	30 Participants n=5 Participants
Region Asia	125 Participants n=5 Participants	128 Participants n=7 Participants	253 Participants n=5 Participants
Region Europe	154 Participants n=5 Participants	152 Participants n=7 Participants	306 Participants n=5 Participants
Region North America	67 Participants n=5 Participants	68 Participants n=7 Participants	135 Participants n=5 Participants
Region South America	56 Participants n=5 Participants	58 Participants n=7 Participants	114 Participants n=5 Participants
Prior Treatment Status Adjuvant or Neo-Adjuvant Therapy	184 Participants n=5 Participants	192 Participants n=7 Participants	376 Participants n=5 Participants
Prior Treatment Status De Novo	218 Participants n=5 Participants	214 Participants n=7 Participants	432 Participants n=5 Participants
Independent-Review Facility (IRF)-Determined Disease Status at Screening Measurable Disease	343 Participants n=5 Participants	336 Participants n=7 Participants	679 Participants n=5 Participants
Independent-Review Facility (IRF)-Determined Disease Status at Screening Non-Measurable Disease	44 Participants n=5 Participants	43 Participants n=7 Participants	87 Participants n=5 Participants
Independent-Review Facility (IRF)-Determined Disease Status at Screening Not Evaluated	15 Participants n=5 Participants	27 Participants n=7 Participants	42 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=402 Participants 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.	Placebo + Trastuzumab + Docetaxel n=406 Participants 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.	Crossover From Placebo to Pertuzumab 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.
Progression-Free Survival (PFS) Determined by an Independent Review Facility	18.5 Months Interval 15.0 to 23.0	12.4 Months Interval 10.0 to 13.0	—

SECONDARY outcome

Timeframe: 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)

Population: ITT Population: All randomized participants

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 \[0.4-514.7\].

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=402 Participants 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.	Placebo + Trastuzumab + Docetaxel n=406 Participants 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.	Crossover From Placebo to Pertuzumab 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 Survival End-of-Study OS Analysis	57.1 Months Interval 50.0 to 72.0	40.8 Months Interval 36.0 to 48.0	—
Overall Survival Event-Driven Final OS Analysis	56.5 Months Interval 49.0 to 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.	40.8 Months Interval 36.0 to 48.0	—
Overall Survival Second Interim OS Analysis	NA Months Interval 42.0 to 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.	37.6 Months Interval 34.0 to 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.	—
Overall Survival First Interim OS Analysis	NA Months 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.	NA Months Interval 30.0 to 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.	—

SECONDARY outcome

Timeframe: 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)

Population: Intent-to-treat population: All randomized patients.

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.

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=402 Participants 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.	Placebo + Trastuzumab + Docetaxel n=406 Participants 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.	Crossover From Placebo to Pertuzumab 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.
Progression-Free Survival (PFS) Determined by the Investigator	18.7 Months Interval 17.0 to 22.0	12.4 Months Interval 10.0 to 14.0	—

SECONDARY outcome

Timeframe: 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)

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

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.

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=343 Participants 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.	Placebo + Trastuzumab + Docetaxel n=336 Participants 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.	Crossover From Placebo to Pertuzumab 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.
Objective Response Determined by an Independent Review Facility Complete Response (CR)	5.5 Percentage of patients Interval 3.4 to 8.5	4.2 Percentage of patients Interval 2.3 to 6.9	—
Objective Response Determined by an Independent Review Facility Objective Response (CR + PR)	80.2 Percentage of patients Interval 75.6 to 84.3	69.3 Percentage of patients Interval 64.1 to 74.2	—
Objective Response Determined by an Independent Review Facility Partial Response (PR)	74.6 Percentage of patients Interval 69.7 to 79.2	65.2 Percentage of patients Interval 59.8 to 70.3	—
Objective Response Determined by an Independent Review Facility Stable Disease (SD)	14.6 Percentage of patients Interval 11.0 to 18.8	20.8 Percentage of patients Interval 16.6 to 25.6	—
Objective Response Determined by an Independent Review Facility Progressive Disease (PD)	3.8 Percentage of patients Interval 2.0 to 6.4	8.3 Percentage of patients Interval 5.6 to 11.8	—
Objective Response Determined by an Independent Review Facility Unable to Assess (UA)	0.6 Percentage of patients Interval 0.1 to 2.1	0.6 Percentage of patients Interval 0.1 to 2.1	—
Objective Response Determined by an Independent Review Facility Missing (No Assessment)	0.9 Percentage of patients 95% confidence intervals were calculated only for clinical responses.	0.9 Percentage of patients 95% confidence intervals were calculated only for clinical responses.	—

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=275 Participants 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.	Placebo + Trastuzumab + Docetaxel n=233 Participants 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.	Crossover From Placebo to Pertuzumab 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.
Duration of Objective Response Determined by an Independent Review Facility	87.6 Weeks Interval 71.0 to 106.0	54.1 Weeks Interval 46.0 to 64.0	—

SECONDARY outcome

Timeframe: Every 9 weeks from Baseline until investigator-determined progressive disease, up to the primary completion date (up to 3 years, 3 months)

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

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.

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=402 Participants 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.	Placebo + Trastuzumab + Docetaxel n=404 Participants 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.	Crossover From Placebo to Pertuzumab 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.
Time to Symptom Progression	18.4 Weeks Interval 18.0 to 27.0	18.3 Weeks Interval 18.0 to 27.0	—

SECONDARY outcome

Timeframe: 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)

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

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.

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=396 Participants 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.	Placebo + Trastuzumab + Docetaxel n=408 Participants 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.	Crossover From Placebo to Pertuzumab n=50 Participants 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 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 At Least One Serious AE - All Grades	116 Participants	160 Participants	10 Participants
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 At Least One Non-Serious AE - All Grades	386 Participants	400 Participants	45 Participants
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 At Least One AE - All Grades	391 Participants	408 Participants	47 Participants
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 At Least One AE - Grade 1	368 Participants	386 Participants	44 Participants
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 At Least One AE - Grade 2	350 Participants	383 Participants	34 Participants
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 At Least One AE - Grade 3	229 Participants	264 Participants	11 Participants
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 At Least One AE - Grade 4	158 Participants	167 Participants	1 Participants
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 At Least One AE - Grade 5	12 Participants	8 Participants	1 Participants

SECONDARY outcome

Timeframe: 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)

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

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.

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=9062 Adverse Events 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.	Placebo + Trastuzumab + Docetaxel n=11908 Adverse Events 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.	Crossover From Placebo to Pertuzumab 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 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 All Grades	1720.2 Events per 100 patient-years Interval 1690.6 to 1750.2	1203.0 Events per 100 patient-years Interval 1184.9 to 1221.3	—
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 Grades 3 to 5	225.3 Events per 100 patient-years Interval 214.7 to 236.4	131.7 Events per 100 patient-years Interval 125.8 to 137.9	—

SECONDARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=396 Participants 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.	Placebo + Trastuzumab + Docetaxel n=408 Participants 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.	Crossover From Placebo to Pertuzumab n=50 Participants 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.
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 Symptomatic LVD(Investigator)-All NYHA Classes	7 Participants	6 Participants	1 Participants
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 Symptomatic LVD(Investigator)-NYHA Classes III/IV	4 Participants	4 Participants	1 Participants
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 Any LVD - All NCI-CTCAE Grades	34 Participants	32 Participants	3 Participants
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 Any LVD - NCI-CTCAE Grade ≥3	13 Participants	6 Participants	2 Participants
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 SAE Suggestive of CHF - All NCI-CTCAE Grades	8 Participants	8 Participants	1 Participants
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 SAE Suggestive of CHF - NCI-CTCAE Grade ≥3	7 Participants	7 Participants	1 Participants

SECONDARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=396 Participants 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.	Placebo + Trastuzumab + Docetaxel n=408 Participants 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.	Crossover From Placebo to Pertuzumab n=50 Participants 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.
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period QT Prolongation (SMQ-wide) - All Grades	5 Participants	16 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period QT Prolongation (SMQ-wide) - Grade ≥3	1 Participants	7 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Mucositis (AEGT) - All Grades	154 Participants	208 Participants	12 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Mucositis (AEGT) - Grade ≥3	8 Participants	14 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Drug-Related Hepatic Disorder(SMQ-wide)-All Grades	43 Participants	47 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Drug-Related Hepatic Disorder (SMQ-wide)-Grade ≥3	5 Participants	8 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Diarrhoea (HLT+PT) - All Grades	191 Participants	280 Participants	25 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Diarrhoea (HLT+PT) - Grade ≥3	20 Participants	40 Participants	1 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Rash (AEGT) - All Grades	155 Participants	213 Participants	18 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Rash (AEGT) - Grade ≥3	6 Participants	15 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Leukopenia (SMQ-narrow) - All Grades	231 Participants	257 Participants	1 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Leukopenia (SMQ-narrow) - Grade ≥3	211 Participants	238 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Leukopenic Infection (PTs) - All Grades	38 Participants	53 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Leukopenic Infection (PTs) - Grade ≥3	9 Participants	18 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Febrile Neutropenic Infection (PTs) - All Grades	3 Participants	14 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Febrile Neutropenic Infection (PTs) - Grade ≥3	1 Participants	6 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Anaphylaxis and Hypersensitivity (AEGT)-All Grades	37 Participants	48 Participants	1 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Anaphylaxis and Hypersensitivity (AEGT)-Grade ≥3	10 Participants	9 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Interstitial Lung Disease (SMQ-narrow) -All Grades	6 Participants	10 Participants	1 Participants
Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period Interstitial Lung Disease (SMQ-narrow) -Grade ≥3	2 Participants	3 Participants	0 Participants

SECONDARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=396 Participants 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.	Placebo + Trastuzumab + Docetaxel n=408 Participants 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.	Crossover From Placebo to Pertuzumab n=50 Participants 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 Who Experienced at Least One Adverse Event Leading to Discontinuation of Any or All Study Medication AE Leading to Discontinuation-Any Study Medication	114 Participants	131 Participants	5 Participants
Overall Number of Participants Who Experienced at Least One Adverse Event Leading to Discontinuation of Any or All Study Medication AE Leading to Discontinuation-All Study Medication	24 Participants	39 Participants	4 Participants

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=396 Participants 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.	Placebo + Trastuzumab + Docetaxel n=408 Participants 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.	Crossover From Placebo to Pertuzumab n=50 Participants 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 Who Experienced at Least One Adverse Event That Resulted in Interruption or Modification of Any Study Medication	217 Participants	265 Participants	16 Participants

SECONDARY outcome

Timeframe: From Day 43 after discontinuation of all study medication to end of post-treatment follow-up period (up to 3 years)

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

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.

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=396 Participants 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.	Placebo + Trastuzumab + Docetaxel n=408 Participants 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.	Crossover From Placebo to Pertuzumab n=50 Participants 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.
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Cardiac Disorders (SOC)	8 Participants	9 Participants	1 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Left Ventricular Dysfunction (PT)	6 Participants	5 Participants	1 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Cardiac Failure (PT)	0 Participants	2 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Bundle Branch Block Left (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Cardiopulmonary Failure (PT)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Myocardial Ischaemia (PT)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Pericardial Effusion (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Prinzmetal Angina (PT)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period General Disorders & Admin. Site Conditions (SOC)	3 Participants	2 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Oedema Peripheral (PT)	2 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Asthenia (PT)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Influenza Like Illness (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Infections & Infestations (SOC)	0 Participants	0 Participants	2 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Influenza (PT)	0 Participants	0 Participants	1 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Viral Infection (PT)	0 Participants	0 Participants	1 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Abscess Limb (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Nasopharyngitis (PT)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Subcutaneous Abscess (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Musculoskeletal & Connective Tissue Disorders(SOC)	0 Participants	0 Participants	1 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Back Pain (PT)	0 Participants	0 Participants	1 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Pain in Extremity (PT)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Nervous System Disorders (SOC)	2 Participants	2 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Neuropathy Peripheral (PT)	1 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Cognitive Disorder (PT)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Dizziness (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Headache (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Respiratory, Thoracic & Mediastinal Disorders(SOC)	2 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Cough (PT)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Dyspnoea (PT)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Rhinitis Allergic (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Skin & Subcutaneous Tissue Disorders (SOC)	1 Participants	2 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Erythema (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Nail Disorder (PT)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Rash Macular (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Blood & Lymphatic System Disorders (SOC)	1 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Febrile Neutropenia (PT)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Leukopenia (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Gastrointestinal Disorders (SOC)	0 Participants	2 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Diarrhoea (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Stomatitis (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Endocrine Disorders (SOC)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Thyroid Mass (PT)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Eye Disorders (SOC)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Retinal Detachment (PT)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Immune System Disorders (SOC)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Iodine Allergy (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Investigations (SOC)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Aspartate Aminotransferase Increased (PT)	1 Participants	0 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Renal & Urinary Disorders (SOC)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Dysuria (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Reproductive System & Breast Disorders (SOC)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Breast Induration (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Vascular Disorders (SOC)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Venous Thrombosis (PT)	0 Participants	1 Participants	0 Participants
Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period Total with at Least One AE During Post-Treatment	18 Participants	17 Participants	3 Participants

SECONDARY outcome

Timeframe: Every 9 weeks from the date of randomization until Treatment Discontinuation Visit (see Description for time on study treatment per arm)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=396 Participants 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.	Placebo + Trastuzumab + Docetaxel n=408 Participants 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.	Crossover From Placebo to Pertuzumab n=50 Participants 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.
Number of Participants by Categories for the Maximum Absolute Decrease From Baseline in LVEF Value During the Treatment Period LVEF Increase/No Change/Decrease FromBL <10%Points	252 Participants	249 Participants	30 Participants
Number of Participants by Categories for the Maximum Absolute Decrease From Baseline in LVEF Value During the Treatment Period LVEF <50% and Decrease From BL ≥10% to <15% Points	9 Participants	7 Participants	0 Participants
Number of Participants by Categories for the Maximum Absolute Decrease From Baseline in LVEF Value During the Treatment Period LVEF <50% and Decrease From BL ≥15% Points	19 Participants	21 Participants	3 Participants
Number of Participants by Categories for the Maximum Absolute Decrease From Baseline in LVEF Value During the Treatment Period LVEF ≥50% and Decrease From BL ≥10% Points	95 Participants	115 Participants	15 Participants
Number of Participants by Categories for the Maximum Absolute Decrease From Baseline in LVEF Value During the Treatment Period No Baseline (BL) LVEF Value	3 Participants	2 Participants	1 Participants

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=396 Participants 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.	Placebo + Trastuzumab + Docetaxel n=408 Participants 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.	Crossover From Placebo to Pertuzumab 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.
Baseline LVEF Value and Change in LVEF From Baseline at Maximum Absolute Decrease Value During the Treatment Period Baseline (BL) LVEF Value	65.6 Percentage points of LVEF Standard Deviation 6.51	64.8 Percentage points of LVEF Standard Deviation 6.71	—
Baseline LVEF Value and Change in LVEF From Baseline at Maximum Absolute Decrease Value During the Treatment Period Change in LVEF From BL at Maximum Decrease Value	-7.3 Percentage points of LVEF Standard Deviation 7.15	-7.5 Percentage points of LVEF Standard Deviation 7.75	—

SECONDARY outcome

Timeframe: 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)

Population: 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.

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

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=396 Participants 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.	Placebo + Trastuzumab + Docetaxel n=408 Participants 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.	Crossover From Placebo to Pertuzumab n=50 Participants 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.
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Creatinine (umol/L) - High, Gr. 2	44 Participants	54 Participants	9 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Albumin (g/L) - Low, Any Grade (Gr.)	163 Participants	196 Participants	15 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Albumin (g/L) - Low, Gr. 1	113 Participants	132 Participants	10 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Albumin (g/L) - Low, Gr. 2	46 Participants	58 Participants	4 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Albumin (g/L) - Low, Gr. 3	4 Participants	6 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Albumin (g/L) - Low, Gr. 4	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period ALP (U/L) - High, Any Gr.	184 Participants	210 Participants	17 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period ALP (U/L) - High, Gr. 1	158 Participants	177 Participants	17 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period ALP (U/L) - High, Gr. 2	19 Participants	24 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period ALP (U/L) - High, Gr. 3	7 Participants	9 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period ALP (U/L) - High, Gr. 4	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Calcium (mmol/L) - Low, Any Gr.	156 Participants	203 Participants	14 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Calcium (mmol/L) - Low, Gr. 1	107 Participants	139 Participants	11 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Calcium (mmol/L) - Low, Gr. 2	45 Participants	49 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Calcium (mmol/L) - Low, Gr. 3	3 Participants	7 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Calcium (mmol/L) - Low, Gr. 4	1 Participants	8 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Calcium (mmol/L) - High, Any Gr.	54 Participants	79 Participants	12 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Calcium (mmol/L) - High, Gr. 1	50 Participants	65 Participants	7 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Calcium (mmol/L) - High, Gr. 2	0 Participants	2 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Calcium (mmol/L) - High, Gr. 3	3 Participants	2 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Calcium (mmol/L) - High, Gr. 4	1 Participants	10 Participants	4 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Creatinine (umol/L) - High, Any Gr.	317 Participants	346 Participants	38 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Creatinine (umol/L) - High, Gr. 1	271 Participants	279 Participants	27 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Creatinine (umol/L) - High, Gr. 3	2 Participants	6 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Creatinine (umol/L) - High, Gr. 4	0 Participants	7 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Fasting Glucose (mmol/L) - Low, Any Gr.	42 Participants	75 Participants	6 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Fasting Glucose (mmol/L) - Low, Gr. 1	32 Participants	61 Participants	4 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Fasting Glucose (mmol/L) - Low, Gr. 2	9 Participants	9 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Fasting Glucose (mmol/L) - Low, Gr. 3	1 Participants	2 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Fasting Glucose (mmol/L) - Low, Gr. 4	0 Participants	3 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Fasting Glucose (mmol/L) - High, Any Gr.	271 Participants	299 Participants	34 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Fasting Glucose (mmol/L) - High, Gr. 1	168 Participants	192 Participants	26 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Fasting Glucose (mmol/L) - High, Gr. 2	83 Participants	78 Participants	8 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Fasting Glucose (mmol/L) - High, Gr. 3	20 Participants	26 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Fasting Glucose (mmol/L) - High, Gr. 4	0 Participants	3 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period GGT (U/L) - High, Any Gr.	209 Participants	225 Participants	14 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period GGT (U/L) - High, Gr. 1	133 Participants	144 Participants	9 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period GGT (U/L) - High, Gr. 2	41 Participants	52 Participants	4 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period GGT (U/L) - High, Gr. 3	30 Participants	27 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period GGT (U/L) - High, Gr. 4	5 Participants	2 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Magnesium (mmol/L) - Low, Any Gr.	79 Participants	117 Participants	8 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Magnesium (mmol/L) - Low, Gr. 1	71 Participants	98 Participants	6 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Magnesium (mmol/L) - Low, Gr. 2	7 Participants	13 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Magnesium (mmol/L) - Low, Gr. 3	1 Participants	3 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Magnesium (mmol/L) - Low, Gr. 4	0 Participants	3 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Magnesium (mmol/L) - High, Any Gr.	76 Participants	105 Participants	16 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Magnesium (mmol/L) - High, Gr. 1	58 Participants	80 Participants	11 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Magnesium (mmol/L) - High, Gr. 2	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Magnesium (mmol/L) - High, Gr. 3	18 Participants	22 Participants	4 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Magnesium (mmol/L) - High, Gr. 4	0 Participants	3 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Potassium (mmol/L) - Low, Any Gr.	80 Participants	144 Participants	11 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Potassium (mmol/L) - Low, Gr. 1	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Potassium (mmol/L) - Low, Gr. 2	68 Participants	118 Participants	8 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Potassium (mmol/L) - Low, Gr. 3	10 Participants	18 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Potassium (mmol/L) - Low, Gr. 4	2 Participants	8 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Potassium (mmol/L) - High, Any Gr.	67 Participants	78 Participants	13 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Potassium (mmol/L) - High, Gr. 1	49 Participants	55 Participants	11 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Potassium (mmol/L) - High, Gr. 2	15 Participants	17 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Potassium (mmol/L) - High, Gr. 3	3 Participants	6 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Potassium (mmol/L) - High, Gr. 4	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period SGOT (U/L) - High, Any Gr.	184 Participants	193 Participants	17 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period SGOT (U/L) - High, Gr. 1	169 Participants	170 Participants	15 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period SGOT (U/L) - High, Gr. 2	11 Participants	12 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period SGOT (U/L) - High, Gr. 3	4 Participants	10 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period SGOT (U/L) - High, Gr. 4	0 Participants	1 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period SGPT (U/L) - High, Any Gr.	195 Participants	209 Participants	19 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period SGPT (U/L) - High, Gr. 1	172 Participants	175 Participants	17 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period SGPT (U/L) - High, Gr. 2	18 Participants	19 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period SGPT (U/L) - High, Gr. 3	5 Participants	14 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period SGPT (U/L) - High, Gr. 4	0 Participants	1 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Sodium (mmol/L) - Low, Any Gr.	109 Participants	135 Participants	25 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Sodium (mmol/L) - Low, Gr. 1	87 Participants	121 Participants	22 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Sodium (mmol/L) - Low, Gr. 2	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Sodium (mmol/L) - Low, Gr. 3	21 Participants	12 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Sodium (mmol/L) - Low, Gr. 4	1 Participants	2 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Sodium (mmol/L) - High, Any Gr.	76 Participants	103 Participants	9 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Sodium (mmol/L) - High, Gr. 1	71 Participants	91 Participants	7 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Sodium (mmol/L) - High, Gr. 2	4 Participants	9 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Sodium (mmol/L) - High, Gr. 3	1 Participants	2 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Sodium (mmol/L) - High, Gr. 4	0 Participants	1 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Total Bilirubin (umol/L) - High, Any Gr.	35 Participants	57 Participants	7 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Total Bilirubin (umol/L) - High, Gr. 1	26 Participants	44 Participants	6 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Total Bilirubin (umol/L) - High, Gr. 2	7 Participants	9 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Total Bilirubin (umol/L) - High, Gr. 3	2 Participants	2 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Total Bilirubin (umol/L) - High, Gr. 4	0 Participants	2 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Uric Acid (umol/L) - High, Any Gr.	118 Participants	113 Participants	15 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Uric Acid (umol/L) - High, Gr. 1	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Uric Acid (umol/L) - High, Gr. 2	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Uric Acid (umol/L) - High, Gr. 3	116 Participants	98 Participants	10 Participants
Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Uric Acid (umol/L) - High, Gr. 4	2 Participants	15 Participants	5 Participants

SECONDARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	Pertuzumab + Trastuzumab + Docetaxel n=396 Participants 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.	Placebo + Trastuzumab + Docetaxel n=408 Participants 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.	Crossover From Placebo to Pertuzumab n=50 Participants 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.
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Neutrophils (10^9/L)- Low, Gr. 4	236 Participants	234 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Hemoglobin (g/L) - Low, Any Grade (Gr.)	350 Participants	372 Participants	20 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Hemoglobin (g/L) - Low, Gr. 1	202 Participants	186 Participants	9 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Hemoglobin (g/L) - Low, Gr. 2	127 Participants	161 Participants	6 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Hemoglobin (g/L) - Low, Gr. 3	21 Participants	25 Participants	5 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Hemoglobin (g/L) - Low, Gr. 4	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Hemoglobin (g/L) - High, Any Gr.	10 Participants	23 Participants	4 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Hemoglobin (g/L) - High, Gr. 1	9 Participants	20 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Hemoglobin (g/L) - High, Gr. 2	1 Participants	2 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Hemoglobin (g/L) - High, Gr. 3	0 Participants	1 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Hemoglobin (g/L) - High, Gr. 4	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Lymphocytes (10^9/L) - Low, Any Gr.	259 Participants	276 Participants	8 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Lymphocytes (10^9/L) - Low, Gr. 1	36 Participants	39 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Lymphocytes (10^9/L) - Low, Gr. 2	128 Participants	136 Participants	4 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Lymphocytes (10^9/L) - Low, Gr. 3	64 Participants	69 Participants	3 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Lymphocytes (10^9/L) - Low, Gr. 4	31 Participants	32 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Lymphocytes (10^9/L)- High, Any Gr.	58 Participants	72 Participants	9 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Lymphocytes (10^9/L)- High, Gr. 1	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Lymphocytes (10^9/L)- High, Gr. 2	49 Participants	57 Participants	6 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Lymphocytes (10^9/L)- High, Gr. 3	9 Participants	15 Participants	3 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Lymphocytes (10^9/L)- High, Gr. 4	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Neutrophils (10^9/L)- Low, Any Gr.	349 Participants	371 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Neutrophils (10^9/L)- Low, Gr. 1	7 Participants	4 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Neutrophils (10^9/L)- Low, Gr. 2	25 Participants	34 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Neutrophils (10^9/L)- Low, Gr. 3	81 Participants	99 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period PTT (sec) - High, Any Gr.	6 Participants	9 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period PTT (sec) - High, Gr. 1	5 Participants	2 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period PTT (sec) - High, Gr. 2	0 Participants	4 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period PTT (sec) - High, Gr. 3	1 Participants	3 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period PTT (sec) - High, Gr. 4	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Platelets (10^9/L) - Low, Any Gr.	82 Participants	92 Participants	13 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Platelets (10^9/L) - Low, Gr. 1	75 Participants	78 Participants	11 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Platelets (10^9/L) - Low, Gr. 2	5 Participants	5 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Platelets (10^9/L) - Low, Gr. 3	2 Participants	3 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Platelets (10^9/L) - Low, Gr. 4	0 Participants	6 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Prothrombin Time (INR) - High, Any Gr.	135 Participants	157 Participants	11 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Prothrombin Time (INR) - High, Gr. 1	127 Participants	136 Participants	9 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Prothrombin Time (INR) - High, Gr. 2	3 Participants	6 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Prothrombin Time (INR) - High, Gr. 3	5 Participants	15 Participants	2 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period Prothrombin Time (INR) - High, Gr. 4	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period WBC (10^9/L) - Low, Any Gr.	366 Participants	387 Participants	5 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period WBC (10^9/L) - Low, Gr. 1	36 Participants	34 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period WBC (10^9/L) - Low, Gr. 2	92 Participants	92 Participants	3 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period WBC (10^9/L) - Low, Gr. 3	186 Participants	206 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period WBC (10^9/L) - Low, Gr. 4	52 Participants	55 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period WBC (10^9/L) - High, Any Gr.	0 Participants	3 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period WBC (10^9/L) - High, Gr. 1	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period WBC (10^9/L) - High, Gr. 2	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period WBC (10^9/L) - High, Gr. 3	0 Participants	3 Participants	1 Participants
Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period WBC (10^9/L) - High, Gr. 4	0 Participants	0 Participants	0 Participants

Adverse Events

Placebo + Trastuzumab + Docetaxel

Serious events: 116 serious events

Other events: 386 other events

Deaths: 261 deaths

Pertuzumab + Trastuzumab + Docetaxel

Serious events: 160 serious events

Other events: 400 other events

Deaths: 238 deaths

Crossover From Placebo to Pertuzumab

Serious events: 10 serious events

Other events: 45 other events

Deaths: 14 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Genentech, Inc.

Phone: 800 821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER