PUFFIN: A Study to Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel Versus Placebo + Trastuzumab + Docetaxel in Previously Untreated Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Breast Cancer

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02896855
• Collaborator: (none)
• Enrollment: 243
• Locations: 15
• Arms: 2
• Actual Duration (Months): 52.3
• Patients Per Site: 16.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This Phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial in China will evaluate the efficacy and safety of pertuzumab + trastuzumab + docetaxel compared with placebo + trastuzumab + docetaxel in participants with previously untreated HER2-positive metastatic breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Docetaxel; Drug: Pertuzumab; Drug: Placebo; Drug: Trastuzumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 243 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Efficacy and Safety of Pertuzumab+Herceptin+Docetaxel Versus Placebo+Herceptin+Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer
• Actual Study Start Date: Sep 13, 2016
• Actual Primary Completion Date: Jun 27, 2018
• Actual Study Completion Date: Jan 22, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A: Placebo + Trastuzumab + Docetaxel Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity.	Drug: Docetaxel; Docetaxel (75-mg/m^2) was administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.; Drug: Placebo; Placebo matched to pertuzumab was administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.; Drug: Trastuzumab; Trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles) was administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.; Other Names: Herceptin
Experimental: Arm B: Pertuzumab + Trastuzumab + Docetaxel Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Drug: Docetaxel; Docetaxel (75-mg/m^2) was administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.; Drug: Pertuzumab; Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles) was administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.; Other Names: Perjeta ; Drug: Trastuzumab; Trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles) was administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.; Other Names: Herceptin

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival, as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) [From date of randomization until date of PFS event (Median [range] time on study for Arm A vs. Arm B at Primary analysis: 57.14 [3.3-93.3] weeks vs. 59.64 [0.9-90.4] weeks; Final analysis: 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks)]

   Progression-free survival (PFS) was defined as the time from randomization to first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause within 18 weeks after the last tumor assessment, whichever occurred first. As per RECIST v1.1, PD is defined as a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeters (mm), and the appearance of new lesions. The Kaplan-Meier approach was used to estimate median PFS for each treatment arm. Data for participants who did not have a PFS event were censored at the time of the last tumor assessment (if no tumor assessments performed after baseline, at randomization plus 1 day).

2. Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Progression-Free Survival at 1 to 3 Years, as Determined by the Investigator Using RECIST v1.1 [At 1, 2, and 3 years]

   Progression-free survival (PFS) was defined as the time from randomization to first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause within 18 weeks after the last tumor assessment, whichever occurred first. As per RECIST v1.1, PD is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm, and the appearance of new lesions. The Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for PFS at 1, 2, and 3 years. Data for participants who did not have a PFS event were censored at the time of the last tumor assessment (if no tumor assessments performed after baseline visit, at randomization plus 1 day). At final analysis, the median [range] time on study for Arm A vs. Arm B was 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks.

Secondary Outcome Measures

1. Overall Survival [From date of randomization until the date of death from any cause (Median [range] time on study for Arm A vs. Arm B at Final analysis: 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks)]

   Overall survival (OS) was defined as the time from randomization to death from any cause. The Kaplan-Meier approach was used to estimate median OS for each treatment arm. Participants who were alive or lost to follow-up at the time of the analysis were censored at the date they were last known to be alive. Participants with no post-baseline information were censored at the time of randomization plus 1 day. The results reported here are from the final analysis. At the primary completion date, the median duration of OS had not been reached and OS data was not considered mature due to the few number of events reported.

2. Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival at 1 to 3 Years [At 1, 2, and 3 Years]

   Overall survival (OS) was defined as the time from randomization to death from any cause. The Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for OS (i.e., alive) at 1, 2, and 3 years. Participants who were alive or lost to follow-up at the time of the analysis were censored at the date they were last known to be alive. Participants with no post-baseline information were censored at the time of randomization plus 1 day. At final analysis, the median [range] time on study for Arm A vs. Arm B was 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks.

3. Percentage of Participants With Measurable Disease at Baseline Who Achieved an Objective Response (Complete or Partial Response), as Determined by the Investigator Using RECIST v1.1 [At Baseline and every 9 weeks from date of randomization until disease progression or death, whichever occurs first (Median [range] time on study for Arm A vs. Arm B at Primary analysis: 57.14 [3.3-93.3] weeks vs. 59.64 [0.9-90.4] weeks)]

   An objective response was defined as a complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1. As per RECIST v1.1, CR is defined as the disappearance of all target lesions, and PR is defined as at least a 30% decrease in the sum of diameters of target lesions. Also per RECIST v1.1, stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum on study; PD is defined as a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm, and the appearance of new lesions. The same assessment technique must be used throughout the study for evaluating a particular lesion, and the same investigator should assess all tumor responses for each participant. Participants without a post-baseline tumor assessment were considered non-responders.

4. Duration of Objective Response, as Determined by the Investigator Using RECIST v1.1 [From date of first occurrence of documented objective response to date of event (Median [range] time on study for Arm A vs. Arm B at Primary analysis: 57.14 [3.3-93.3] weeks vs. 59.64 [0.9-90.4] weeks)]

   Duration of objective response was defined as the time from the first occurrence of a documented objective response (complete response [CR] or partial response [PR]) to the time of disease progression, as determined by the investigator using RECIST v1.1, or death from any cause within 18 weeks after the last tumor assessment, whichever occurred first. As per RECIST v1.1, CR is defined as the disappearance of all target lesions, and PR is defined as at least a 30% decrease in the sum of diameters of target lesions. The Kaplan-Meier approach was used to estimate median duration of objective response. Data for participants who did not have an event were censored at the time of the last tumor assessment (if no tumor assessments were performed after baseline visit, at randomization plus 1 day).

5. Number of Participants With at Least One Adverse Event [From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)]

   The number of participants per treatment arm experiencing at least one adverse event, including all non-serious and serious adverse events, is reported here. Adverse events reported prior to first crossover treatment were included in the Placebo arm, and in the Crossover arm after that date, for participants in Arm A who crossed over from placebo to pertuzumab. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.

6. Number of Participants With at Least One Grade ≥3 Adverse Event [From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)]

   Adverse event (AE) severity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0); 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. AEs reported prior to first crossover treatment were included in the Placebo arm, and in the Crossover arm after that date, for participants in Arm A who crossed over from placebo to pertuzumab. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.

7. Number of Participants With at Least One Adverse Event Leading to Withdrawal From Any Treatment [From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)]

   Adverse events reported prior to first crossover treatment were included in the Placebo arm, and in the Crossover arm after that date, for participants in Arm A who crossed over from placebo to pertuzumab. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.

8. Number of Participants With Symptomatic Left Ventricular Systolic Dysfunction (LVSD), as Determined Using Echocardiography (ECHO) or Multiple-Gated Acquisition (MUGA) Scan [From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)]

   The number of participants with symptomatic left ventricular systolic dysfunction (LVSD) at any time during the study, as determined using echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan, were summarized by treatment arm. Symptomatic LVSD was evaluated according to NCI CTCAE v4.0 (for "heart failure") and the New York Heart Association (NYHA) classification. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.

9. Number of Participants With an Asymptomatic Decline in Left Ventricular Ejection Fraction (LVEF) Event, as Determined Using ECHO or MUGA Scan [From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)]

   An asymptomatic decline in LVEF event is reported as an adverse event of "ejection fraction decreased" and is defined as either of the following: an absolute decrease in LVEF of ≥10 percentage points from baseline to an LVEF of <50%; or an asymptomatic decrease in LVEF requiring treatment or leading to discontinuation of pertuzumab (or placebo) and trastuzumab. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.

10. Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans [Baseline, Weeks 9, 18, 27, 36, 45, 54, 63, 72, 81, 90, 99, 108, 117, 126, 135, 144, 153, 162, 171, 180, 189, 198, 207, 216, and 225, Study Drug Discontinuation Visit (up to 4 years, 4 months), and Treatment-Free Follow-Up at 6 months, and 1 and 2 years]

    Left ventricular ejection fraction (LVEF) is the measurement of how much blood is being pumped out of the left ventricle of the heart with each contraction. LVEF was calculated using the modified Simpson method and must have been ≥55% at baseline as determined by the local facility before a participant could be enrolled in the study. The investigator decided which method of LVEF assessment (ECHO [preferred] or MUGA scan) would be used for each participant at baseline, and the same method was to be used throughout the study, to the extent possible. The LVEF abnormality status categories, as a change relative to LVEF at baseline, included: Increase or no change in LVEF; Decrease of <10 LVEF points; Absolute LVEF value ≥50% and a decrease of ≥10 LVEF points; and Absolute LVEF value <50% and a decrease of ≥10 LVEF points. The overall worst LVEF value was defined as the lowest post-baseline value up to the end of the study, including unscheduled assessments and the post-treatment period.

11. Baseline LVEF and Change From Baseline to Maximum On-Treatment Decrease in LVEF at Any Point During the Study [Baseline and every 9 weeks from date of randomization until treatment discontinuation (up to 4 years, 4 months)]

    The baseline left ventricular ejection fraction (LVEF) and change from baseline to the maximum on-treatment decrease in LVEF at any point during the study are reported here. LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. LVEF was calculated using the modified Simpson method and must have been ≥55% at baseline as determined by the local facility before a participant could be enrolled in the study. The investigator decided which method of LVEF assessment (ECHO [preferred] or MUGA scan) would be used for each participant at baseline, and the same method should have been used throughout the study, to the extent possible. At final analysis, the median [range] time on study for Arm A vs. Arm B was 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease that is suitable for chemotherapy

• HER2-positive metastatic breast cancer (MBC)

• Left ventricular ejection fraction (LVEF) greater than or equal to (>=) 55 percent (%) at baseline (within 42 days of randomization)

• Eastern Cooperative Oncology Group Performance Status of 0 or 1

• Women of childbearing potential and men should agree to use an effective form of contraception and to continue its use for the duration of study treatment and for at least 7 months after the last dose of study treatment (trastuzumab and/or pertuzumab)

Exclusion Criteria:

• History of anti-cancer therapy for MBC (with the exception of one prior hormonal regimen for MBC)

• History of approved or investigative tyrosine kinase/HER inhibitors for breast cancer in any treatment setting, except trastuzumab used in the neoadjuvant or adjuvant setting

• History of systemic breast cancer treatment in the neo-adjuvant or adjuvant setting with a disease-free interval from completion of the systemic treatment (excluding hormonal therapy) to metastatic diagnosis of less than (<) 12 months

• History of persistent Grade >= 2 hematologic toxicity resulting from previous adjuvant therapy

• Grade >= 3 peripheral neuropathy at randomization

• History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or non-melanoma skin carcinoma that has been previously treated with curative intent

• Current clinical or radiographic evidence of central nervous system (CNS) metastases

• History of exposure to cumulative doses of anthracyclines

• Current uncontrolled hypertension or unstable angina

• History of congestive heart failure (CHF) of any New York Heart Association (NYHA) classification, or serious cardiac arrhythmia requiring treatment

• History of myocardial infarction within 6 months of randomization

• History of LVEF decrease to < 50% during or after prior trastuzumab neo-adjuvant or adjuvant therapy

• Current dyspnea at rest due to complications of advanced malignancy, or other diseases that require continuous oxygen therapy

• Inadequate organ function within 28 days prior to randomization

• Current severe, uncontrolled systemic disease

• Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start or anticipation of the need for major surgery during the course of study treatment

• Pregnant or lactating women

• History of receiving any investigational treatment within 28 days of randomization

• Current known infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or active hepatitis B virus (HBV)

• Receipt of intravenous (IV) antibiotics for infection within 14 days of randomization

• Current chronic daily treatment with corticosteroids (excluding inhaled steroids)

• Known hypersensitivity to any of the protocol-specified study treatments

• Concurrent participation in an interventional or noninterventional study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CHINESE ACADEMY OF MEDICAL SCIENCE; CANCER INST. & HOSPITAL; Medical ward	Beijing		China	100021
2	Beijing Cancer Hospital	Beijing		China	100142
3	Chinese PLA General Hospital	Beijing		China	100853
4	the First Hospital of Jilin University	Changchun		China	130021
5	Changzhou First People's Hospital	Changzhou		China	213003
6	West China Hospital, Sichuan University	Chengdu		China	610041
7	The 900th Hospital of PLA joint service support force	Fuzhou		China	110016
8	Guangdong General Hospital	Guangzhou		China	510080
9	Harbin Medical University Cancer Hospital	Harbin		China	150081
10	Jiangsu Cancer Hospital	Nanjing City		China	211100
11	Jiangsu province hospital; surgery on galactophore	Nanjing		China	210029
12	Fudan University Shanghai Cancer Center	Shanghai City		China	200120
13	First Hospital of China Medical University	Shenyang		China	110001
14	Liaoning cancer Hospital & Institute	Shenyang		China	110042
15	Zhejiang Cancer Hospital	Zhejiang		China	310022

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Mar 7, 2020
• Statistical Analysis Plan - Mar 28, 2018

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02896855
• Other Study ID Numbers: YO29296
• First Posted: Sep 12, 2016
• Last Update Posted: Dec 16, 2021
• Last Verified: Nov 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Breast Neoplasms; Docetaxel; Trastuzumab; Pertuzumab

Study Results

Participant Flow

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	121	122
Received Any Study Treatment	120	122
Crossed Over From Placebo to Receive Pertuzumab	12	0
COMPLETED	49	69
NOT COMPLETED	72	53

Baseline Characteristics

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel	Total
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	121	122	243
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.3 (11.2)	50.7 (10.6)	51.0 (10.9)
Sex: Female, Male (Count of Participants)
Female	121 100%	122 100%	243 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	121 100%	122 100%	243 100%
Disease Type: Visceral or Non-Visceral Disease (Count of Participants)
Visceral Disease	86 71.1%	88 72.1%	174 71.6%
Non-Visceral Disease	35 28.9%	34 27.9%	69 28.4%
Hormone Receptor Status (Count of Participants)
Estrogen and Progesterone Receptor Negative	48 39.7%	53 43.4%	101 41.6%
Estrogen and/or Progesterone Receptor Positive	73 60.3%	69 56.6%	142 58.4%
Measurable or Non-Measurable Disease, According to RECIST v1.1 (Count of Participants)
Measurable Disease	97 80.2%	105 86.1%	202 83.1%
Non-Measurable Disease	24 19.8%	17 13.9%	41 16.9%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival, as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Description	Progression-free survival (PFS) was defined as the time from randomization to first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause within 18 weeks after the last tumor assessment, whichever occurred first. As per RECIST v1.1, PD is defined as a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeters (mm), and the appearance of new lesions. The Kaplan-Meier approach was used to estimate median PFS for each treatment arm. Data for participants who did not have a PFS event were censored at the time of the last tumor assessment (if no tumor assessments performed after baseline, at randomization plus 1 day).
Time Frame	From date of randomization until date of PFS event (Median [range] time on study for Arm A vs. Arm B at Primary analysis: 57.14 [3.3-93.3] weeks vs. 59.64 [0.9-90.4] weeks; Final analysis: 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) population: consists of all randomized participants, regardless of whether they received any study treatment. Participants are grouped according to the treatment group to which they were randomized.

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Measure Participants	121	122
Primary Analysis	12.4	14.5
Final Analysis	12.5	16.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Placebo + Trastuzumab + Docetaxel, Arm B: Pertuzumab + Trastuzumab + Docetaxel
	Comments	This was for the primary analysis. Hypothesis testing is considered exploratory in this bridging study.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0418
	Comments
	Method	Log Rank
	Comments	A two-sided log-rank test was used, stratified by disease type and hormone-receptor status.
Method of Estimation	Estimation Parameter	Stratified Hazard Ratio
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	This stratified Hazard Ratio (HR) is calculated as Arm B: Pertuzumab versus Arm A: Placebo. Cox proportional hazards model, stratified by disease type and hormone-receptor status, was used to estimate HR and its 95% CI.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Placebo + Trastuzumab + Docetaxel, Arm B: Pertuzumab + Trastuzumab + Docetaxel
	Comments	This was for the primary analysis. Hypothesis testing is considered exploratory in this bridging study.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0556
	Comments
	Method	Log Rank
	Comments	This two-sided log-rank test was unstratified.
Method of Estimation	Estimation Parameter	Unstratified Hazard Ratio
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.50 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	This unstratified Hazard Ratio (HR) is calculated as Arm B: Pertuzumab versus Arm A: Placebo. Cox proportional hazards model was used to estimate HR and its 95% CI.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm A: Placebo + Trastuzumab + Docetaxel, Arm B: Pertuzumab + Trastuzumab + Docetaxel
	Comments	This was for the final analysis. Hypothesis testing is considered exploratory in this bridging study.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	Log Rank
	Comments	A two-sided log-rank test was used, stratified by disease type and hormone-receptor status.
Method of Estimation	Estimation Parameter	Stratified Hazard Ratio
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	This stratified Hazard Ratio (HR) is calculated as Arm B: Pertuzumab versus Arm A: Placebo. Cox proportional hazards model, stratified by disease type and hormone-receptor status, was used to estimate HR and its 95% CI.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm A: Placebo + Trastuzumab + Docetaxel, Arm B: Pertuzumab + Trastuzumab + Docetaxel
	Comments	This was for the final analysis. Hypothesis testing is considered exploratory in this bridging study.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	Log Rank
	Comments	This two-sided log-rank test was unstratified.
Method of Estimation	Estimation Parameter	Unstratified Hazard Ratio
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.47 to 0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	This unstratified Hazard Ratio (HR) is calculated as Arm B: Pertuzumab versus Arm A: Placebo. Cox proportional hazards model was used to estimate HR and its 95% CI.

2. Primary Outcome

Title	Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Progression-Free Survival at 1 to 3 Years, as Determined by the Investigator Using RECIST v1.1
Description	Progression-free survival (PFS) was defined as the time from randomization to first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause within 18 weeks after the last tumor assessment, whichever occurred first. As per RECIST v1.1, PD is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm, and the appearance of new lesions. The Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for PFS at 1, 2, and 3 years. Data for participants who did not have a PFS event were censored at the time of the last tumor assessment (if no tumor assessments performed after baseline visit, at randomization plus 1 day). At final analysis, the median [range] time on study for Arm A vs. Arm B was 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks.
Time Frame	At 1, 2, and 3 years

Outcome Measure Data

Analysis Population Description

ITT population: consists of all randomized participants, regardless of whether they received any study treatment. Participants are grouped according to the treatment group to which they were randomized. The number analyzed per timepoint represents the number of participants remaining at risk for a PFS event at that timepoint.

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Measure Participants	121	122
1 Year	52.90 43.7%	66.37 54.4%
2 Years	19.19 15.9%	37.85 31%
3 Years	12.73 10.5%	29.44 24.1%

3. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS) was defined as the time from randomization to death from any cause. The Kaplan-Meier approach was used to estimate median OS for each treatment arm. Participants who were alive or lost to follow-up at the time of the analysis were censored at the date they were last known to be alive. Participants with no post-baseline information were censored at the time of randomization plus 1 day. The results reported here are from the final analysis. At the primary completion date, the median duration of OS had not been reached and OS data was not considered mature due to the few number of events reported.
Time Frame	From date of randomization until the date of death from any cause (Median [range] time on study for Arm A vs. Arm B at Final analysis: 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks)

Outcome Measure Data

Analysis Population Description

ITT population: consists of all randomized participants, regardless of whether they received any study treatment. Participants are grouped according to the treatment group to which they were randomized.

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Measure Participants	121	122
Median (Inter-Quartile Range) [months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Placebo + Trastuzumab + Docetaxel, Arm B: Pertuzumab + Trastuzumab + Docetaxel
	Comments	Hypothesis testing is considered exploratory in this bridging study.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0658
	Comments
	Method	Log Rank
	Comments	A two-sided log-rank test was used, stratified by disease type and hormone-receptor status.
Method of Estimation	Estimation Parameter	Stratified Hazard Ratio
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.45 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	This stratified Hazard Ratio (HR) is calculated as Arm B: Pertuzumab versus Arm A: Placebo. Cox proportional hazards model, stratified by disease type and hormone-receptor status, was used to estimate HR and its 95% CI.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Placebo + Trastuzumab + Docetaxel, Arm B: Pertuzumab + Trastuzumab + Docetaxel
	Comments	Hypothesis testing is considered exploratory in this bridging study.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0864
	Comments
	Method	Log Rank
	Comments	This two-sided log-rank test was unstratified.
Method of Estimation	Estimation Parameter	Unstratified Hazard Ratio
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.46 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	This unstratified Hazard Ratio (HR) is calculated as Arm B: Pertuzumab versus Arm A: Placebo. Cox proportional hazards model was used to estimate HR and its 95% CI.

4. Secondary Outcome

Title	Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival at 1 to 3 Years
Description	Overall survival (OS) was defined as the time from randomization to death from any cause. The Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for OS (i.e., alive) at 1, 2, and 3 years. Participants who were alive or lost to follow-up at the time of the analysis were censored at the date they were last known to be alive. Participants with no post-baseline information were censored at the time of randomization plus 1 day. At final analysis, the median [range] time on study for Arm A vs. Arm B was 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks.
Time Frame	At 1, 2, and 3 Years

Outcome Measure Data

Analysis Population Description

ITT population: consists of all randomized participants, regardless of whether they received any study treatment. Participants are grouped according to the treatment group to which they were randomized. The number analyzed per timepoint represents the number of participants remaining at risk for an OS event at that timepoint.

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Measure Participants	121	122
1 Year	90.64 74.9%	93.44 76.6%
2 Years	73.85 61%	78.87 64.6%
3 Years	58.41 48.3%	70.79 58%

5. Secondary Outcome

Title	Percentage of Participants With Measurable Disease at Baseline Who Achieved an Objective Response (Complete or Partial Response), as Determined by the Investigator Using RECIST v1.1
Description	An objective response was defined as a complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1. As per RECIST v1.1, CR is defined as the disappearance of all target lesions, and PR is defined as at least a 30% decrease in the sum of diameters of target lesions. Also per RECIST v1.1, stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum on study; PD is defined as a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm, and the appearance of new lesions. The same assessment technique must be used throughout the study for evaluating a particular lesion, and the same investigator should assess all tumor responses for each participant. Participants without a post-baseline tumor assessment were considered non-responders.
Time Frame	At Baseline and every 9 weeks from date of randomization until disease progression or death, whichever occurs first (Median [range] time on study for Arm A vs. Arm B at Primary analysis: 57.14 [3.3-93.3] weeks vs. 59.64 [0.9-90.4] weeks)

Outcome Measure Data

Analysis Population Description

ITT population: consists of all randomized participants, regardless of whether they received any study treatment. Participants are grouped according to the treatment group to which they were randomized. Only participants with measurable disease at baseline were included in the analysis.

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Measure Participants	97	105
Objective Response (CR + PR)	69.1 57.1%	79.0 64.8%
Complete Response (CR)	8.2 6.8%	5.7 4.7%
Partial Response (PR)	60.8 50.2%	73.3 60.1%
Stable Disease (SD)	20.6 17%	15.2 12.5%
Progressive Disease (PD)	4.1 3.4%	3.8 3.1%
Missing or Unevaluable	6.2 5.1%	1.9 1.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Placebo + Trastuzumab + Docetaxel, Arm B: Pertuzumab + Trastuzumab + Docetaxel
	Comments	Hypothesis testing is considered exploratory in this bridging study.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1126
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Statistical test is stratified by disease type and hormone receptor status.
Method of Estimation	Estimation Parameter	Difference in Objective Response
	Estimated Value	9.98
	Confidence Interval	(2-Sided) 95%; -2.65 to 22.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in objective response is calculated as Arm B: Pertuzumab minus Arm A: Placebo. 95% CI was calculated using Hauck-Anderson method.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Placebo + Trastuzumab + Docetaxel, Arm B: Pertuzumab + Trastuzumab + Docetaxel
	Comments	Hypothesis testing is considered exploratory in this bridging study.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1108
	Comments
	Method	Fisher Exact
	Comments	Unadjusted
Method of Estimation	Estimation Parameter	Difference in Objective Response
	Estimated Value	9.98
	Confidence Interval	(2-Sided) 95%; -2.65 to 22.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in objective response is calculated as Arm B: Pertuzumab minus Arm A: Placebo. 95% CI was calculated using Hauck-Anderson method.

6. Secondary Outcome

Title	Duration of Objective Response, as Determined by the Investigator Using RECIST v1.1
Description	Duration of objective response was defined as the time from the first occurrence of a documented objective response (complete response [CR] or partial response [PR]) to the time of disease progression, as determined by the investigator using RECIST v1.1, or death from any cause within 18 weeks after the last tumor assessment, whichever occurred first. As per RECIST v1.1, CR is defined as the disappearance of all target lesions, and PR is defined as at least a 30% decrease in the sum of diameters of target lesions. The Kaplan-Meier approach was used to estimate median duration of objective response. Data for participants who did not have an event were censored at the time of the last tumor assessment (if no tumor assessments were performed after baseline visit, at randomization plus 1 day).
Time Frame	From date of first occurrence of documented objective response to date of event (Median [range] time on study for Arm A vs. Arm B at Primary analysis: 57.14 [3.3-93.3] weeks vs. 59.64 [0.9-90.4] weeks)

Outcome Measure Data

Analysis Population Description

ITT population: consists of all randomized participants, regardless of whether they received any study treatment. Participants are grouped according to the treatment group to which they were randomized. Only participants with measurable disease at baseline who achieved an objective response during the study were included in the analysis.

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Measure Participants	67	83
Median (95% Confidence Interval) [months]	10.4	12.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Placebo + Trastuzumab + Docetaxel, Arm B: Pertuzumab + Trastuzumab + Docetaxel
	Comments	Hypothesis testing is considered exploratory in this bridging study.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2867
	Comments
	Method	Log Rank
	Comments	Two-sided log-rank test was used, stratified by disease type and hormone-receptor status.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.49 to 1.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	This stratified Hazard Ratio (HR) is calculated as Arm B: Pertuzumab versus Arm A: Placebo. Cox proportional hazards model, stratified by disease type and hormone-receptor status, was used to estimate HR and its 95% CI.

7. Secondary Outcome

Title	Number of Participants With at Least One Adverse Event
Description	The number of participants per treatment arm experiencing at least one adverse event, including all non-serious and serious adverse events, is reported here. Adverse events reported prior to first crossover treatment were included in the Placebo arm, and in the Crossover arm after that date, for participants in Arm A who crossed over from placebo to pertuzumab. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Time Frame	From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)

Outcome Measure Data

Analysis Population Description

Safety population, which includes participants who received at least one dose of any study drug, with participants grouped according to the treatment received. Following approval of Protocol version 4 (07-March-2020), 12 Arm A participants who were receiving placebo crossed over to receive open-label treatment with pertuzumab.

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Measure Participants	120	122	12
Count of Participants [Participants]	115 95%	121 99.2%	5 2.1%

8. Secondary Outcome

Title	Number of Participants With at Least One Grade ≥3 Adverse Event
Description	Adverse event (AE) severity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0); 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. AEs reported prior to first crossover treatment were included in the Placebo arm, and in the Crossover arm after that date, for participants in Arm A who crossed over from placebo to pertuzumab. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Time Frame	From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)

Outcome Measure Data

Analysis Population Description

Safety population, which includes participants who received at least one dose of any study drug, with participants grouped according to the treatment received. Following approval of Protocol version 4 (07-March-2020), 12 Arm A participants who were receiving placebo crossed over to receive open-label treatment with pertuzumab.

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Measure Participants	120	122	12
Count of Participants [Participants]	83 68.6%	90 73.8%	1 0.4%

9. Secondary Outcome

Title	Number of Participants With at Least One Adverse Event Leading to Withdrawal From Any Treatment
Description	Adverse events reported prior to first crossover treatment were included in the Placebo arm, and in the Crossover arm after that date, for participants in Arm A who crossed over from placebo to pertuzumab. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Time Frame	From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)

Outcome Measure Data

Analysis Population Description

Safety population, which includes participants who received at least one dose of any study drug, with participants grouped according to the treatment received. Following approval of Protocol version 4 (07-March-2020), 12 Arm A participants who were receiving placebo crossed over to receive open-label treatment with pertuzumab.

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Measure Participants	120	122	12
Count of Participants [Participants]	10 8.3%	15 12.3%	0 0%

10. Secondary Outcome

Title	Number of Participants With Symptomatic Left Ventricular Systolic Dysfunction (LVSD), as Determined Using Echocardiography (ECHO) or Multiple-Gated Acquisition (MUGA) Scan
Description	The number of participants with symptomatic left ventricular systolic dysfunction (LVSD) at any time during the study, as determined using echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan, were summarized by treatment arm. Symptomatic LVSD was evaluated according to NCI CTCAE v4.0 (for "heart failure") and the New York Heart Association (NYHA) classification. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Time Frame	From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)

Outcome Measure Data

Analysis Population Description

Safety population, which includes participants who received at least one dose of any study drug, with participants grouped according to the treatment received. Following approval of Protocol version 4 (07-March-2020), 12 Arm A participants who were receiving placebo crossed over to receive open-label treatment with pertuzumab.

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Measure Participants	120	122	12
Count of Participants [Participants]	0 0%	0 0%	0 0%

11. Secondary Outcome

Title	Number of Participants With an Asymptomatic Decline in Left Ventricular Ejection Fraction (LVEF) Event, as Determined Using ECHO or MUGA Scan
Description	An asymptomatic decline in LVEF event is reported as an adverse event of "ejection fraction decreased" and is defined as either of the following: an absolute decrease in LVEF of ≥10 percentage points from baseline to an LVEF of <50%; or an asymptomatic decrease in LVEF requiring treatment or leading to discontinuation of pertuzumab (or placebo) and trastuzumab. At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Time Frame	From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months)

Outcome Measure Data

Analysis Population Description

Safety population, which includes participants who received at least one dose of any study drug, with participants grouped according to the treatment received. Following approval of Protocol version 4 (07-March-2020), 12 Arm A participants who were receiving placebo crossed over to receive open-label treatment with pertuzumab.

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel	Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.	Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Measure Participants	120	122	12
Count of Participants [Participants]	0 0%	2 1.6%	0 0%

12. Secondary Outcome

Title	Number of Participants by the LVEF Abnormality Status Categories Over Time, as Determined by the Change From Baseline in LVEF Using ECHO or MUGA Scans
Description	Left ventricular ejection fraction (LVEF) is the measurement of how much blood is being pumped out of the left ventricle of the heart with each contraction. LVEF was calculated using the modified Simpson method and must have been ≥55% at baseline as determined by the local facility before a participant could be enrolled in the study. The investigator decided which method of LVEF assessment (ECHO [preferred] or MUGA scan) would be used for each participant at baseline, and the same method was to be used throughout the study, to the extent possible. The LVEF abnormality status categories, as a change relative to LVEF at baseline, included: Increase or no change in LVEF; Decrease of <10 LVEF points; Absolute LVEF value ≥50% and a decrease of ≥10 LVEF points; and Absolute LVEF value <50% and a decrease of ≥10 LVEF points. The overall worst LVEF value was defined as the lowest post-baseline value up to the end of the study, including unscheduled assessments and the post-treatment period.
Time Frame	Baseline, Weeks 9, 18, 27, 36, 45, 54, 63, 72, 81, 90, 99, 108, 117, 126, 135, 144, 153, 162, 171, 180, 189, 198, 207, 216, and 225, Study Drug Discontinuation Visit (up to 4 years, 4 months), and Treatment-Free Follow-Up at 6 months, and 1 and 2 years

Outcome Measure Data

Analysis Population Description

Safety population, which includes participants who received at least one dose of any study drug, with participants grouped according to the treatment received. Number analyzed indicates the number of participants with a baseline LVEF measurement and a post-baseline LVEF measurement at each time point.

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Measure Participants	120	122
Increase or No Change in LVEF	57 47.1%	63 51.6%
Decrease <10 LVEF Points	51 42.1%	52 42.6%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	3 2.5%	4 3.3%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	61 50.4%	62 50.8%
Decrease <10 LVEF Points	33 27.3%	45 36.9%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	4 3.3%	3 2.5%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	1 0.8%
Increase or No Change in LVEF	54 44.6%	51 41.8%
Decrease <10 LVEF Points	35 28.9%	43 35.2%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	3 2.5%	5 4.1%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	45 37.2%	46 37.7%
Decrease <10 LVEF Points	28 23.1%	43 35.2%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	3 2.5%	4 3.3%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	1 0.8%
Increase or No Change in LVEF	34 28.1%	36 29.5%
Decrease <10 LVEF Points	29 24%	43 35.2%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	5 4.1%	3 2.5%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	26 21.5%	38 31.1%
Decrease <10 LVEF Points	27 22.3%	34 27.9%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	4 3.3%	3 2.5%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	21 17.4%	30 24.6%
Decrease <10 LVEF Points	17 14%	33 27%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	6 5%	3 2.5%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	17 14%	26 21.3%
Decrease <10 LVEF Points	15 12.4%	31 25.4%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	5 4.1%	4 3.3%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	19 15.7%	29 23.8%
Decrease <10 LVEF Points	12 9.9%	24 19.7%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	3 2.5%	2 1.6%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	17 14%	24 19.7%
Decrease <10 LVEF Points	11 9.1%	20 16.4%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	2 1.7%	3 2.5%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	14 11.6%	21 17.2%
Decrease <10 LVEF Points	10 8.3%	23 18.9%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	2 1.7%	2 1.6%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	13 10.7%	15 12.3%
Decrease <10 LVEF Points	7 5.8%	24 19.7%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 0.8%	3 2.5%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	14 11.6%	18 14.8%
Decrease <10 LVEF Points	3 2.5%	18 14.8%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 0.8%	3 2.5%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	7 5.8%	20 16.4%
Decrease <10 LVEF Points	9 7.4%	15 12.3%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 0.8%	2 1.6%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	6 5%	15 12.3%
Decrease <10 LVEF Points	8 6.6%	18 14.8%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 0.8%	2 1.6%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	10 8.3%	18 14.8%
Decrease <10 LVEF Points	3 2.5%	10 8.2%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 0.8%	3 2.5%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	7 5.8%	12 9.8%
Decrease <10 LVEF Points	7 5.8%	15 12.3%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	0 0%	3 2.5%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	7 5.8%	17 13.9%
Decrease <10 LVEF Points	6 5%	12 9.8%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	0 0%	1 0.8%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	7 5.8%	10 8.2%
Decrease <10 LVEF Points	4 3.3%	16 13.1%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 0.8%	2 1.6%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	9 7.4%	8 6.6%
Decrease <10 LVEF Points	3 2.5%	14 11.5%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	0 0%	1 0.8%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	5 4.1%	6 4.9%
Decrease <10 LVEF Points	3 2.5%	9 7.4%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 0.8%	0 0%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	4 3.3%	6 4.9%
Decrease <10 LVEF Points	2 1.7%	5 4.1%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	1 0.8%	0 0%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	2 1.7%	5 4.1%
Decrease <10 LVEF Points	1 0.8%	3 2.5%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	1 0.8%	3 2.5%
Decrease <10 LVEF Points	0 0%	1 0.8%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	1 0.8%
Decrease <10 LVEF Points	0 0%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	0 0%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%
Increase or No Change in LVEF	45 37.2%	45 36.9%
Decrease <10 LVEF Points	28 23.1%	39 32%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	8 6.6%	3 2.5%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	20 16.5%	18 14.8%
Decrease <10 LVEF Points	20 16.5%	18 14.8%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	3 2.5%	0 0%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	13 10.7%	4 3.3%
Decrease <10 LVEF Points	10 8.3%	14 11.5%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	0 0%	1 0.8%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	1 0.8%	2 1.6%
Decrease <10 LVEF Points	0 0%	1 0.8%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	2 1.7%	1 0.8%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	0 0%
Increase or No Change in LVEF	21 17.4%	20 16.4%
Decrease <10 LVEF Points	75 62%	75 61.5%
Absolute Value ≥50% & Decrease ≥10 LVEF Points	16 13.2%	22 18%
Absolute Value <50% & Decrease ≥10 LVEF Points	0 0%	2 1.6%

13. Secondary Outcome

Title	Baseline LVEF and Change From Baseline to Maximum On-Treatment Decrease in LVEF at Any Point During the Study
Description	The baseline left ventricular ejection fraction (LVEF) and change from baseline to the maximum on-treatment decrease in LVEF at any point during the study are reported here. LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. LVEF was calculated using the modified Simpson method and must have been ≥55% at baseline as determined by the local facility before a participant could be enrolled in the study. The investigator decided which method of LVEF assessment (ECHO [preferred] or MUGA scan) would be used for each participant at baseline, and the same method should have been used throughout the study, to the extent possible. At final analysis, the median [range] time on study for Arm A vs. Arm B was 145.29 [3.3-225.3] weeks vs. 174.79 [0.9-226.1] weeks.
Time Frame	Baseline and every 9 weeks from date of randomization until treatment discontinuation (up to 4 years, 4 months)

Outcome Measure Data

Analysis Population Description

Safety population, which includes participants who received at least one dose of any study drug, with participants grouped according to the treatment received. Number analyzed indicates participants with a baseline LVEF measurement and at least one post-baseline LVEF measurement, respectively.

Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel	Arm B: Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity. Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel.	Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
Measure Participants	120	122
Baseline LVEF (value at visit)	64.23 (4.90)	65.08 (4.43)
Change from Baseline to Max Decrease in LVEF	-4.88 (5.41)	-5.48 (5.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Placebo + Trastuzumab + Docetaxel, Arm B: Pertuzumab + Trastuzumab + Docetaxel
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.60
	Confidence Interval	(2-Sided) 95%; -1.96 to 0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments	The treatment difference for change from baseline to maximum on-treatment decrease in LVEF is defined as Arm B: Pertuzumab minus Arm A: Placebo.

Adverse Events

Time Frame	From first dose of study drug until 42 days after last dose of study drug (up to 4 years, 4 months). At final analysis, the median [range] time on study treatment with placebo or pertuzumab per arm was: Arm A - Placebo: 52.3 [3-207] weeks; Arm B - Pertuzumab: 66.1 [3-225] weeks; Arm A - Crossover to Pertuzumab: 18.1 [12-24] weeks.
Arm/Group Title	Arm A: Placebo + Trastuzumab + Docetaxel		Arm B: Pertuzumab + Trastuzumab + Docetaxel		Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel
Arm/Group Description	Placebo matched to pertuzumab, trastuzumab (8-milligrams per kilogram [mg/kg] loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-milligrams per square meter [mg/m^2]) were administered by intravenous (IV) infusion every 3 weeks until disease progression or unacceptable toxicity.		Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.		Following the primary analysis and upon approval of protocol version 4 (07-March-2020), the treatment assignment of participants in Arm A who were still on study treatment was unblinded, allowing the investigators to present those participants with the option to cross over and receive pertuzumab (in place of placebo) in addition to trastuzumab and docetaxel. Pertuzumab (840-mg loading dose for Cycle 1, followed by 420 mg for subsequent cycles), trastuzumab (8-mg/kg loading dose for Cycle 1, followed by 6 mg/kg for subsequent cycles), and docetaxel (75-mg/m^2) were administered by IV infusion every 3 weeks until disease progression or unacceptable toxicity.
All Cause Mortality
	Arm A: Placebo + Trastuzumab + Docetaxel		Arm B: Pertuzumab + Trastuzumab + Docetaxel		Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	50/120 (41.7%)		40/122 (32.8%)		0/12 (0%)
Serious Adverse Events
	Arm A: Placebo + Trastuzumab + Docetaxel		Arm B: Pertuzumab + Trastuzumab + Docetaxel		Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/120 (19.2%)		30/122 (24.6%)		1/12 (8.3%)
Blood and lymphatic system disorders
Febrile neutropenia	4/120 (3.3%)	4	3/122 (2.5%)	3	0/12 (0%)	0
Leukopenia	2/120 (1.7%)	3	3/122 (2.5%)	3	0/12 (0%)	0
Neutropenia	8/120 (6.7%)	16	9/122 (7.4%)	16	0/12 (0%)	0
Cardiac disorders
Cardiac tamponade	0/120 (0%)	0	2/122 (1.6%)	2	0/12 (0%)	0
Ventricular arrhythmia	1/120 (0.8%)	1	0/122 (0%)	0	0/12 (0%)	0
Gastrointestinal disorders
Ascites	0/120 (0%)	0	1/122 (0.8%)	1	0/12 (0%)	0
Oesophagitis	0/120 (0%)	0	1/122 (0.8%)	1	0/12 (0%)	0
Large intestine polyp	0/120 (0%)	0	0/122 (0%)	0	1/12 (8.3%)	1
General disorders
Death	1/120 (0.8%)	1	1/122 (0.8%)	1	0/12 (0%)	0
Hepatobiliary disorders
Liver injury	1/120 (0.8%)	1	0/122 (0%)	0	0/12 (0%)	0
Infections and infestations
Pneumonia	3/120 (2.5%)	3	5/122 (4.1%)	5	0/12 (0%)	0
Upper respiratory tract infection	0/120 (0%)	0	1/122 (0.8%)	1	0/12 (0%)	0
Osteomyelitis	0/120 (0%)	0	1/122 (0.8%)	1	0/12 (0%)	0
Soft tissue infection	0/120 (0%)	0	1/122 (0.8%)	1	0/12 (0%)	0
Injury, poisoning and procedural complications
Fracture	1/120 (0.8%)	1	1/122 (0.8%)	1	0/12 (0%)	0
Investigations
Alanine aminotransferase increased	2/120 (1.7%)	2	0/122 (0%)	0	0/12 (0%)	0
Aspartate aminotransferase increased	1/120 (0.8%)	1	0/122 (0%)	0	0/12 (0%)	0
Blood glucose increased	0/120 (0%)	0	1/122 (0.8%)	1	0/12 (0%)	0
Metabolism and nutrition disorders
Hyperuricaemia	1/120 (0.8%)	1	0/122 (0%)	0	0/12 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastrointestinal carcinoma in situ	0/120 (0%)	0	1/122 (0.8%)	1	0/12 (0%)	0
Nervous system disorders
Dizziness	0/120 (0%)	0	1/122 (0.8%)	1	0/12 (0%)	0
Reproductive system and breast disorders
Metrorrhagia	1/120 (0.8%)	1	0/122 (0%)	0	0/12 (0%)	0
Pelvic prolapse	0/120 (0%)	0	1/122 (0.8%)	1	0/12 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/120 (0.8%)	1	0/122 (0%)	0	0/12 (0%)	0
Vascular disorders
Peripheral arterial occlusive disease	0/120 (0%)	0	0/122 (0%)	0	1/12 (8.3%)	1
Other (Not Including Serious) Adverse Events
	Arm A: Placebo + Trastuzumab + Docetaxel		Arm B: Pertuzumab + Trastuzumab + Docetaxel		Arm A: Crossover to Pertuzumab + Trastuzumab + Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	114/120 (95%)		119/122 (97.5%)		5/12 (41.7%)
Blood and lymphatic system disorders
Anaemia	58/120 (48.3%)	112	67/122 (54.9%)	179	0/12 (0%)	0
Leukopenia	87/120 (72.5%)	319	91/122 (74.6%)	349	0/12 (0%)	0
Neutropenia	81/120 (67.5%)	305	87/122 (71.3%)	314	1/12 (8.3%)	1
Thrombocytopenia	12/120 (10%)	28	9/122 (7.4%)	25	0/12 (0%)	0
Cardiac disorders
Palpitations	8/120 (6.7%)	16	3/122 (2.5%)	3	0/12 (0%)	0
Gastrointestinal disorders
Abdominal distension	6/120 (5%)	6	7/122 (5.7%)	11	0/12 (0%)	0
Abdominal pain upper	8/120 (6.7%)	13	8/122 (6.6%)	9	0/12 (0%)	0
Constipation	11/120 (9.2%)	15	8/122 (6.6%)	10	0/12 (0%)	0
Diarrhoea	28/120 (23.3%)	57	56/122 (45.9%)	102	0/12 (0%)	0
Flatulence	4/120 (3.3%)	5	8/122 (6.6%)	8	0/12 (0%)	0
Mouth ulceration	6/120 (5%)	7	10/122 (8.2%)	16	0/12 (0%)	0
Nausea	15/120 (12.5%)	24	15/122 (12.3%)	28	0/12 (0%)	0
Stomatitis	4/120 (3.3%)	6	15/122 (12.3%)	20	0/12 (0%)	0
Vomiting	11/120 (9.2%)	13	13/122 (10.7%)	28	0/12 (0%)	0
General disorders
Asthenia	20/120 (16.7%)	45	25/122 (20.5%)	38	0/12 (0%)	0
Fatigue	7/120 (5.8%)	10	5/122 (4.1%)	5	0/12 (0%)	0
Influenza like illness	6/120 (5%)	7	9/122 (7.4%)	13	0/12 (0%)	0
Malaise	11/120 (9.2%)	14	9/122 (7.4%)	16	0/12 (0%)	0
Oedema peripheral	18/120 (15%)	31	12/122 (9.8%)	17	0/12 (0%)	0
Pain	22/120 (18.3%)	30	19/122 (15.6%)	39	0/12 (0%)	0
Pyrexia	21/120 (17.5%)	28	29/122 (23.8%)	46	0/12 (0%)	0
Hepatobiliary disorders
Hepatic function abnormal	6/120 (5%)	8	3/122 (2.5%)	3	0/12 (0%)	0
Infections and infestations
Nasopharyngitis	7/120 (5.8%)	8	9/122 (7.4%)	14	0/12 (0%)	0
Upper respiratory tract infection	16/120 (13.3%)	18	17/122 (13.9%)	20	0/12 (0%)	0
Urinary tract infection	6/120 (5%)	9	6/122 (4.9%)	8	0/12 (0%)	0
Investigations
Alanine aminotransferase increased	56/120 (46.7%)	101	45/122 (36.9%)	83	1/12 (8.3%)	1
Aspartate aminotransferase increased	49/120 (40.8%)	98	45/122 (36.9%)	95	2/12 (16.7%)	2
Blood alkaline phosphatase increased	9/120 (7.5%)	13	9/122 (7.4%)	14	1/12 (8.3%)	2
Blood bilirubin increased	14/120 (11.7%)	28	14/122 (11.5%)	20	0/12 (0%)	0
Blood creatinine increased	8/120 (6.7%)	10	11/122 (9%)	26	1/12 (8.3%)	1
Blood triglycerides increased	4/120 (3.3%)	13	7/122 (5.7%)	16	0/12 (0%)	0
Gamma-glutamyltransferase increased	10/120 (8.3%)	12	8/122 (6.6%)	11	0/12 (0%)	0
Weight decreased	6/120 (5%)	8	11/122 (9%)	12	0/12 (0%)	0
Weight increased	16/120 (13.3%)	20	4/122 (3.3%)	5	0/12 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	14/120 (11.7%)	19	15/122 (12.3%)	15	0/12 (0%)	0
Hyperglycaemia	8/120 (6.7%)	9	14/122 (11.5%)	25	1/12 (8.3%)	1
Hypoalbuminaemia	8/120 (6.7%)	10	11/122 (9%)	17	1/12 (8.3%)	1
Hypokalaemia	8/120 (6.7%)	24	18/122 (14.8%)	45	1/12 (8.3%)	1
Hypoproteinaemia	3/120 (2.5%)	3	7/122 (5.7%)	7	0/12 (0%)	0
Hyponatraemia	5/120 (4.2%)	5	8/122 (6.6%)	10	0/12 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	3/120 (2.5%)	4	7/122 (5.7%)	10	0/12 (0%)	0
Back pain	3/120 (2.5%)	5	7/122 (5.7%)	8	0/12 (0%)	0
Pain in extremity	9/120 (7.5%)	13	4/122 (3.3%)	4	0/12 (0%)	0
Nervous system disorders
Dizziness	11/120 (9.2%)	13	7/122 (5.7%)	8	0/12 (0%)	0
Headache	8/120 (6.7%)	11	9/122 (7.4%)	11	0/12 (0%)	0
Hypoaesthesia	8/120 (6.7%)	9	13/122 (10.7%)	13	0/12 (0%)	0
Neurotoxicity	7/120 (5.8%)	7	9/122 (7.4%)	10	0/12 (0%)	0
Psychiatric disorders
Insomnia	10/120 (8.3%)	12	10/122 (8.2%)	17	0/12 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	17/120 (14.2%)	21	26/122 (21.3%)	33	0/12 (0%)	0
Oropharyngeal pain	2/120 (1.7%)	2	7/122 (5.7%)	11	0/12 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	40/120 (33.3%)	40	50/122 (41%)	53	0/12 (0%)	0
Dermatitis acneiform	2/120 (1.7%)	4	7/122 (5.7%)	8	0/12 (0%)	0
Nail discolouration	15/120 (12.5%)	15	12/122 (9.8%)	12	0/12 (0%)	0
Pruritus	6/120 (5%)	7	8/122 (6.6%)	13	0/12 (0%)	0
Rash	11/120 (9.2%)	13	11/122 (9%)	22	0/12 (0%)	0
Vascular disorders
Hypertension	8/120 (6.7%)	10	12/122 (9.8%)	15	0/12 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.