Trial Outcomes & Findings for A Study of Pertuzumab in Combination With Trastuzumab Plus an Aromatase Inhibitor in Participants With Metastatic Human Epidermal Growth Factor Receptor 2 (HER2)-Positive and Hormone Receptor-Positive Advanced Breast Cancer (NCT NCT01491737)

Last Updated: 2020-10-28

Results Overview

Progression-free survival (PFS) was defined as the time from randomization until the first radiographically documented progression of disease or death from any cause, whichever occurred first (either during study treatment or during follow-up). Progression of disease was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 and is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum of target lesion diameters must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progression). Participants with no PFS events were censored at the time of the last evaluable tumor assessment. The primary analysis of PFS was planned to be performed when a total of 165 PFS events had occurred, and the final analysis after at least 60 months follow-up.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

258 participants

Primary outcome timeframe

Median [full range] of follow-up time on study for: Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B; Final Analysis: 73.20 [0.03-88.34] months vs. 71.06 [0.03-88.97] months in Arm A vs. Arm B

Results posted on

2020-10-28

Participant Flow

A total of 258 participants were enrolled in the study.

Participant milestones

Participant milestones
Measure	Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.	Arm B: Trastuzumab + AI +/- Chemotherapy Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.
Overall Study STARTED	129	129
Overall Study Received at Least One Dose of Study Drug	127	124
Overall Study Entered Follow-Up (Post-Treatment)	120	116
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	129	129

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.	Arm B: Trastuzumab + AI +/- Chemotherapy Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.
Overall Study Withdrawal by Subject	20	17
Overall Study Lost to Follow-up	2	10
Overall Study Death	63	57
Overall Study Study Termination by Sponsor	36	36
Overall Study Reason Not Specified	8	9

Baseline Characteristics

All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy n=129 Participants Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.	Arm B: Trastuzumab + AI +/- Chemotherapy n=129 Participants Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.	Total n=258 Participants Total of all reporting groups
Age, Continuous	60.9 Years STANDARD_DEVIATION 10.85 • n=129 Participants	62.3 Years STANDARD_DEVIATION 11.54 • n=129 Participants	61.6 Years STANDARD_DEVIATION 11.20 • n=258 Participants
Sex: Female, Male Female	129 Participants n=129 Participants	129 Participants n=129 Participants	258 Participants n=258 Participants
Sex: Female, Male Male	0 Participants n=129 Participants	0 Participants n=129 Participants	0 Participants n=258 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=129 Participants	1 Participants n=129 Participants	1 Participants n=258 Participants
Race (NIH/OMB) Asian	10 Participants n=129 Participants	18 Participants n=129 Participants	28 Participants n=258 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=129 Participants	0 Participants n=129 Participants	0 Participants n=258 Participants
Race (NIH/OMB) Black or African American	4 Participants n=129 Participants	5 Participants n=129 Participants	9 Participants n=258 Participants
Race (NIH/OMB) White	104 Participants n=129 Participants	93 Participants n=129 Participants	197 Participants n=258 Participants
Race (NIH/OMB) More than one race	0 Participants n=129 Participants	0 Participants n=129 Participants	0 Participants n=258 Participants
Race (NIH/OMB) Unknown or Not Reported	11 Participants n=129 Participants	12 Participants n=129 Participants	23 Participants n=258 Participants
Race/Ethnicity, Customized Hispanic/Latino	45 Participants n=129 Participants	40 Participants n=129 Participants	85 Participants n=258 Participants
Race/Ethnicity, Customized Chinese	0 Participants n=129 Participants	0 Participants n=129 Participants	0 Participants n=258 Participants
Race/Ethnicity, Customized Indian (Indian subcontinent)	10 Participants n=129 Participants	16 Participants n=129 Participants	26 Participants n=258 Participants
Race/Ethnicity, Customized Japanese	0 Participants n=129 Participants	1 Participants n=129 Participants	1 Participants n=258 Participants
Race/Ethnicity, Customized Mixed Ethnicity	0 Participants n=129 Participants	0 Participants n=129 Participants	0 Participants n=258 Participants
Race/Ethnicity, Customized Other	63 Participants n=129 Participants	60 Participants n=129 Participants	123 Participants n=258 Participants
Race/Ethnicity, Customized Missing	11 Participants n=129 Participants	12 Participants n=129 Participants	23 Participants n=258 Participants
Number of Participants by Induction Chemotherapy and Prior Adjuvant Hormone Therapy Induction Chemotherapy - Yes · <12 Months Since Hormone Therapy	12 Participants n=75 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).	12 Participants n=73 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).	24 Participants n=148 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).
Number of Participants by Induction Chemotherapy and Prior Adjuvant Hormone Therapy Induction Chemotherapy - Yes · ≥12 Months Since Hormone Therapy	24 Participants n=75 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).	23 Participants n=73 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).	47 Participants n=148 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).
Number of Participants by Induction Chemotherapy and Prior Adjuvant Hormone Therapy Induction Chemotherapy - Yes · No Prior Hormone Therapy	39 Participants n=75 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).	38 Participants n=73 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).	77 Participants n=148 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).
Number of Participants by Induction Chemotherapy and Prior Adjuvant Hormone Therapy Induction Chemotherapy - No · <12 Months Since Hormone Therapy	12 Participants n=54 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).	12 Participants n=56 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).	24 Participants n=110 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).
Number of Participants by Induction Chemotherapy and Prior Adjuvant Hormone Therapy Induction Chemotherapy - No · ≥12 Months Since Hormone Therapy	18 Participants n=54 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).	19 Participants n=56 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).	37 Participants n=110 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).
Number of Participants by Induction Chemotherapy and Prior Adjuvant Hormone Therapy Induction Chemotherapy - No · No Prior Hormone Therapy	24 Participants n=54 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).	25 Participants n=56 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).	49 Participants n=110 Participants • All 258 participants who were enrolled on this study are accounted for between the induction chemotherapy categories (yes vs. no).

PRIMARY outcome

Timeframe: Median [full range] of follow-up time on study for: Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B; Final Analysis: 73.20 [0.03-88.34] months vs. 71.06 [0.03-88.97] months in Arm A vs. Arm B

Population: Intent-to-Treat (ITT) population included all randomized participants.

Outcome measures

Outcome measures
Measure	Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy n=129 Participants Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.	Arm B: Trastuzumab + AI +/- Chemotherapy n=129 Participants Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.
Progression-Free Survival (PFS) Primary Analysis	18.89 months Interval 14.09 to 27.66	15.80 months Interval 11.04 to 18.56
Progression-Free Survival (PFS) Final Analysis	20.63 months Interval 14.39 to 28.35	15.80 months Interval 11.04 to 18.66

SECONDARY outcome

Population: ITT population included all randomized participants.

Overall survival (OS) was defined as the time from the date of randomization to the date of death, regardless of the cause of death. Participants who were alive at the time of the analysis were censored at the date of the last follow-up assessment. Participants without follow-up assessment were censored at the day of last study medication (pertuzumab, trastuzumab, AI or induction chemotherapy), and participants with no post-baseline information were censored at the date of randomization. The primary analysis of OS was planned to be performed at the same time as for PFS (when a total of 165 PFS events had occurred), and the final analysis was planned after at least 60 months follow-up for all participants.

Outcome measures

Outcome measures
Measure	Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy n=129 Participants Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.	Arm B: Trastuzumab + AI +/- Chemotherapy n=129 Participants Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.
Overall Survival (OS) Primary Analysis	NA Months Median and lower and upper limits of the 95% confidence interval were not reached because not enough events had occurred at the time of analysis.	NA Months Interval 41.4 to Median and upper limit of the 95% confidence interval were not reached because not enough events had occurred at the time of analysis.
Overall Survival (OS) Final Analysis	60.16 Months Interval 47.21 to 79.01	57.17 Months Interval 45.44 to Upper limit of 95% confidence interval was not reached because not enough events had occurred the time of analysis.

SECONDARY outcome

Timeframe: Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B

Population: ITT population included all randomized participants. Only participants with measurable disease at baseline were included in the analysis.

The overall response rate (ORR) was defined as the percentage of participants with best (confirmed) overall response (BOR) of either complete response (CR) or partial response (PR) from start of study treatment until progressive disease (PD)/recurrence or death, as assessed by the investigator according to RECIST version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference baseline sum diameters; stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Participants needed to have two consecutive assessments of PR or CR at least 4 weeks apart to be a responder. Analysis of this outcome measure was only planned to occur at the time of primary analysis.

Outcome measures

Outcome measures
Measure	Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy n=109 Participants Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.	Arm B: Trastuzumab + AI +/- Chemotherapy n=106 Participants Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.
Overall Response Rate (ORR) Partial Response (PR)	56.0 percentage of participants Interval 46.1 to 65.5	54.7 percentage of participants Interval 44.8 to 64.4
Overall Response Rate (ORR) ORR (CR + PR)	63.3 percentage of participants Interval 53.5 to 72.3	55.7 percentage of participants Interval 45.7 to 65.3
Overall Response Rate (ORR) Non-responders (SD + PD + NE)	36.7 percentage of participants Interval 27.7 to 46.5	44.3 percentage of participants Interval 34.7 to 54.3
Overall Response Rate (ORR) Complete Response (CR)	7.3 percentage of participants Interval 3.2 to 14.0	0.9 percentage of participants Interval 0.0 to 5.1
Overall Response Rate (ORR) Stable Disease (SD)	26.6 percentage of participants Interval 18.6 to 35.9	27.4 percentage of participants Interval 19.1 to 36.9
Overall Response Rate (ORR) Progressive Disease (PD)	5.5 percentage of participants Interval 2.0 to 11.6	12.3 percentage of participants Interval 6.7 to 20.1
Overall Response Rate (ORR) Not Evaluable (NE)	4.5 percentage of participants Interval 1.5 to 10.4	4.7 percentage of participants Interval 1.5 to 10.7

SECONDARY outcome

Timeframe: Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B

Population: ITT population included all randomized participants. Only participants with measurable disease at baseline were included in the analysis.

Clinical Benefit Rate (CBR) was defined as the percentage of participants with best (confirmed) partial response (PR) or complete response (CR) or stable disease (SD) for at least 6 months. According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Analysis of this outcome measure was only planned to occur at the time of primary analysis.

Outcome measures

Outcome measures
Measure	Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy n=109 Participants Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.	Arm B: Trastuzumab + AI +/- Chemotherapy n=106 Participants Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.
Clinical Benefit Rate (CBR) CBR (CR + PR + SD for ≥6 Months)	68.8 percentage of participants Interval 59.2 to 77.3	67.0 percentage of participants Interval 57.2 to 75.8
Clinical Benefit Rate (CBR) Complete Response (CR)	7.3 percentage of participants Interval 3.2 to 14.0	0.9 percentage of participants Interval 0.0 to 5.1
Clinical Benefit Rate (CBR) Partial Response (PR)	56.0 percentage of participants Interval 46.1 to 65.5	54.7 percentage of participants Interval 44.8 to 64.4
Clinical Benefit Rate (CBR) Stable Disease (SD) for ≥6 Months	5.5 percentage of participants Interval 2.0 to 11.6	11.3 percentage of participants Interval 6.0 to 18.9

SECONDARY outcome

Population: ITT population included all randomized participants. Only participants who had measurable disease at baseline and were responders (CR or PR) were included in this analysis.

Duration of response (DOR) was defined as the period from the date of initial confirmed partial response (PR) or complete response (CR) until the date of progressive disease or death from any cause. According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants with no documented progression after CR or PR were censored at the last date at which they were known to have had the CR or PR, respectively. The primary analysis of DOR was planned to be performed at the same time as for PFS (when a total of 165 PFS events had occurred), and the final analysis was planned after at least 60 months follow-up for all participants.

Outcome measures

Outcome measures
Measure	Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy n=69 Participants Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.	Arm B: Trastuzumab + AI +/- Chemotherapy n=61 Participants Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.
Duration of Response (DOR) Final Analysis	27.40 months Interval 15.24 to 44.35	16.36 months Interval 12.09 to 20.96
Duration of Response (DOR) Primary Analysis	27.10 months Interval 14.13 to Upper limit of the 95% confidence interval was not reached because not enough events had occurred at the time of analysis.	15.11 months Interval 12.09 to 20.96

SECONDARY outcome

Timeframe: Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B

Population: ITT population included all randomized participants. Only participants with measurable disease at baseline were included in this analysis.

Time to Response (TTR) was defined as the time from the date of randomization to the date of first complete response (CR) or partial response (PR). According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For participants who did not have a confirmed response, a censored TTR was calculated at the date of the last adequate tumor assessment. If no tumor assessment is performed for the participant (or all post-baseline assessments are not evaluable or PD) the censoring day would be set to day 1 (date of randomization). Analysis of this outcome measure was only planned to occur at the time of primary analysis.

Outcome measures

Outcome measures
Measure	Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy n=109 Participants Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.	Arm B: Trastuzumab + AI +/- Chemotherapy n=106 Participants Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.
Time to Response (TTR)	2.53 months Interval 2.1 to 4.37	3.91 months Interval 2.1 to 4.17

SECONDARY outcome

Timeframe: Baseline and every 3 cycles until treatment discontinuation (up to Cycle 120; 1 cycle is 21 days)

Population: ITT population included all randomized participants. The number analyzed only included those who had a non-missing assessment for a specified time point.

The EQ-5D VAS is a participant-rated questionnaire to assess health-related quality of life (QoL) in terms of a single index value. The VAS component rates current health state on a scale from 0 mm (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state.

Outcome measures

Outcome measures
Measure	Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy n=129 Participants Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.	Arm B: Trastuzumab + AI +/- Chemotherapy n=129 Participants Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 111	3.3 unit on a scale Standard Deviation 21.50	—
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Baseline (BL) - Value at Visit	73.0 unit on a scale Standard Deviation 19.34	72.8 unit on a scale Standard Deviation 18.83
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 3	3.3 unit on a scale Standard Deviation 14.90	1.9 unit on a scale Standard Deviation 15.67
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 6	3.5 unit on a scale Standard Deviation 18.91	0.5 unit on a scale Standard Deviation 13.63
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 9	5.3 unit on a scale Standard Deviation 18.80	2.1 unit on a scale Standard Deviation 15.20
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 12	10.7 unit on a scale Standard Deviation 17.91	4.0 unit on a scale Standard Deviation 15.34
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 15	9.1 unit on a scale Standard Deviation 17.25	1.4 unit on a scale Standard Deviation 22.16
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 18	7.5 unit on a scale Standard Deviation 12.85	3.5 unit on a scale Standard Deviation 15.76
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 21	5.8 unit on a scale Standard Deviation 13.68	3.5 unit on a scale Standard Deviation 19.70
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 24	6.2 unit on a scale Standard Deviation 14.30	3.2 unit on a scale Standard Deviation 16.66
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 27	7.5 unit on a scale Standard Deviation 14.01	3.9 unit on a scale Standard Deviation 22.00
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 30	8.3 unit on a scale Standard Deviation 14.25	4.9 unit on a scale Standard Deviation 16.98
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 33	5.1 unit on a scale Standard Deviation 14.70	4.3 unit on a scale Standard Deviation 15.59
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 36	7.3 unit on a scale Standard Deviation 15.19	5.9 unit on a scale Standard Deviation 15.13
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 39	8.1 unit on a scale Standard Deviation 16.33	2.4 unit on a scale Standard Deviation 29.68
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 42	6.4 unit on a scale Standard Deviation 19.18	9.0 unit on a scale Standard Deviation 17.55
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 45	9.7 unit on a scale Standard Deviation 15.01	9.9 unit on a scale Standard Deviation 19.52
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 48	8.8 unit on a scale Standard Deviation 12.50	6.8 unit on a scale Standard Deviation 17.22
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 51	7.2 unit on a scale Standard Deviation 14.81	9.1 unit on a scale Standard Deviation 19.11
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 54	4.7 unit on a scale Standard Deviation 23.48	7.6 unit on a scale Standard Deviation 17.85
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 57	6.8 unit on a scale Standard Deviation 18.08	10.5 unit on a scale Standard Deviation 16.81
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 60	8.2 unit on a scale Standard Deviation 15.88	10.9 unit on a scale Standard Deviation 18.27
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 63	4.0 unit on a scale Standard Deviation 20.88	8.8 unit on a scale Standard Deviation 14.64
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 66	10.4 unit on a scale Standard Deviation 16.92	4.1 unit on a scale Standard Deviation 15.69
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 69	7.5 unit on a scale Standard Deviation 17.35	5.0 unit on a scale Standard Deviation 16.77
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 72	6.2 unit on a scale Standard Deviation 16.10	5.8 unit on a scale Standard Deviation 16.10
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 75	8.6 unit on a scale Standard Deviation 19.12	5.1 unit on a scale Standard Deviation 15.50
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 78	12.8 unit on a scale Standard Deviation 17.45	6.9 unit on a scale Standard Deviation 14.58
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 81	11.5 unit on a scale Standard Deviation 18.39	8.0 unit on a scale Standard Deviation 14.76
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 84	11.2 unit on a scale Standard Deviation 19.71	1.3 unit on a scale Standard Deviation 18.13
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 87	11.2 unit on a scale Standard Deviation 18.17	-3.0 unit on a scale Standard Deviation 11.22
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 90	10.9 unit on a scale Standard Deviation 18.28	-3.0 unit on a scale Standard Deviation 12.36
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 93	7.1 unit on a scale Standard Deviation 15.43	6.6 unit on a scale Standard Deviation 13.89
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 96	7.5 unit on a scale Standard Deviation 16.04	8.6 unit on a scale Standard Deviation 12.64
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 99	4.4 unit on a scale Standard Deviation 17.22	5.6 unit on a scale Standard Deviation 16.71
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 102	5.6 unit on a scale Standard Deviation 16.35	10.0 unit on a scale Standard Deviation 17.32
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 105	4.4 unit on a scale Standard Deviation 16.35	0.0 unit on a scale Standard Deviation NA Standard deviation could not be calculated using data from a single participant.
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 108	4.0 unit on a scale Standard Deviation 14.39	0.0 unit on a scale Standard Deviation NA Standard deviation could not be calculated using data from a single participant.
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 114	-1.3 unit on a scale Standard Deviation 17.97	—
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 117	-5.0 unit on a scale Standard Deviation NA Standard deviation could not be calculated using data from a single participant.	—
Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores Change from BL at Cycle 120	-5.0 unit on a scale Standard Deviation NA Standard deviation could not be calculated using data from a single participant.	—

SECONDARY outcome

Timeframe: From Baseline until the end of post-treatment follow-up (up to 89 months)

Population: Safety population: included all participants who had received at least 1 dose of any study medication assigned to treatment arms as treated.

All adverse events (AEs) occurring during the study and until the post-treatment safety follow-up visit approximately 28 days after last study medication were recorded; thereafter, only study drug-related serious adverse events (SAEs) continued to be collected. The investigator graded all AEs for severity per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. AEs suggestive of congestive heart failure (CHF) were identified by the SMQ (wide) "Cardiac Failure" with a status of "serious", which included the preferred terms cardiac failure, left ventricular dysfunction, and pulmonary oedema.

Outcome measures

Outcome measures
Measure	Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy n=127 Participants Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.	Arm B: Trastuzumab + AI +/- Chemotherapy n=124 Participants Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 Any Adverse Event (AE)	122 Participants	122 Participants
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 Any AE, Grade ≥3	72 Participants	51 Participants
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 Any Serious Adverse Event (SAE), Grade ≥3	35 Participants	22 Participants
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 Any AE, Grade 5	1 Participants	1 Participants
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 Any SAE	46 Participants	28 Participants
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 SAE Related to Pertuzumab	10 Participants	NA Participants None of the participants in Arm B were treated with pertuzumab.
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 SAE Related to Trastuzumab	9 Participants	2 Participants
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 SAE Related to Docetaxel	6 Participants	4 Participants
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 SAE Related to Paclitaxel	3 Participants	0 Participants
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 Any AE Leading to Discontinuation of Any Treatment	20 Participants	10 Participants
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 Any AE Leading to Pertuzumab Discontinuation	16 Participants	NA Participants None of the participants in Arm B were treated with pertuzumab.
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 Any AE Leading to Trastuzumab Discontinuation	16 Participants	6 Participants
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 Any AE Leading to Interruption of Any Treatment	59 Participants	26 Participants
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 Any AE Leading to Pertuzumab Interruption	44 Participants	NA Participants None of the participants in Arm B were treated with pertuzumab.
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 Any AE Leading to Trastuzumab Interruption	48 Participants	16 Participants
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 Any AE Related to Pertuzumab	82 Participants	NA Participants None of the participants in Arm B were treated with pertuzumab.
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 Any AE Related to Trastuzumab	81 Participants	62 Participants
Overview of the Number of Participants With Adverse Events, Severity Determined According to NCI-CTCAE Version 4.03 AE Suggestive of Congestive Heart Failure	5 Participants	1 Participants

SECONDARY outcome

Timeframe: From Baseline until the end of post-treatment follow-up (up to 89 months)

Population: Safety Population: included all participants who had received at least 1 dose of any study medication assigned to treatment arms as treated.

The causes of death over the course of the study, regardless of whether the death was related to study treatment, are listed by preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA), version 22.1.

Outcome measures

Outcome measures
Measure	Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy n=127 Participants Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.	Arm B: Trastuzumab + AI +/- Chemotherapy n=124 Participants Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.
Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment Total Number of Deaths	62 Participants	57 Participants
Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment Deaths Related to Any Study Treatment	0 Participants	0 Participants
Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment Cause of Death: Cardiac Arrest	1 Participants	0 Participants
Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment Cause of Death: Craniocerebral Injury	1 Participants	0 Participants
Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment Cause of Death: Dyspnoea	1 Participants	0 Participants
Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment Cause of Death: High-grade B-cell Lymphoma	1 Participants	0 Participants
Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment Cause of Death: Sudden Death	0 Participants	1 Participants
Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment Cause of Death: Unevaluable Event	2 Participants	1 Participants
Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment Cause of Death: Progressive Disease	56 Participants	55 Participants
Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment Total Deaths Within 30 Days After First Dose	0 Participants	0 Participants
Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment Total Deaths Within 28 Days After Last Dose	1 Participants	2 Participants
Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment Total Deaths Within 60 Days After Last Dose	2 Participants	4 Participants

SECONDARY outcome

Timeframe: Baseline and every 3 cycles until treatment discontinuation (up to Cycle 120; 1 cycle is 21 days)

Population: Safety Population: included all participants who had received at least 1 dose of any study medication assigned to treatment arms as treated.

Left ventricular ejection fraction (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. A normal LVEF ranges from 55% to 70%, as measured by echocardiogram or multiple-gated acquisition (MUGA) scan. All participants must have had a baseline LVEF of at least (≥)50% to enroll in the study; patients with clinically significant cardiovascular disease or baseline LVEF below 50% were not eligible for this study.

Outcome measures

Adverse Events

Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy

Serious events: 46 serious events

Other events: 120 other events

Deaths: 63 deaths

Arm B: Trastuzumab + AI +/- Chemotherapy

Serious events: 28 serious events

Other events: 116 other events

Deaths: 57 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

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

Measure	Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy n=127 Participants Participants received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.	Arm B: Trastuzumab + AI +/- Chemotherapy n=124 Participants Participants received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurred first. Participants also received an aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Participants receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 81	-2.9 Percentage points of LVEF Standard Deviation 6.83	-2.6 Percentage points of LVEF Standard Deviation 6.00
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Baseline (BL) - Absolute LVEF at Visit	63.8 Percentage points of LVEF Standard Deviation 6.23	63.9 Percentage points of LVEF Standard Deviation 6.12
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 3	-1.0 Percentage points of LVEF Standard Deviation 6.25	-1.4 Percentage points of LVEF Standard Deviation 6.23
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 6	-2.3 Percentage points of LVEF Standard Deviation 6.66	-1.3 Percentage points of LVEF Standard Deviation 6.03
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 9	-2.5 Percentage points of LVEF Standard Deviation 6.80	-2.2 Percentage points of LVEF Standard Deviation 6.52
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 12	-2.4 Percentage points of LVEF Standard Deviation 8.05	-2.8 Percentage points of LVEF Standard Deviation 6.99
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 15	-2.9 Percentage points of LVEF Standard Deviation 8.67	-2.5 Percentage points of LVEF Standard Deviation 6.94
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 18	-1.9 Percentage points of LVEF Standard Deviation 6.42	-1.3 Percentage points of LVEF Standard Deviation 6.19
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 21	-1.1 Percentage points of LVEF Standard Deviation 6.01	-1.1 Percentage points of LVEF Standard Deviation 6.64
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 24	-2.1 Percentage points of LVEF Standard Deviation 6.82	-0.6 Percentage points of LVEF Standard Deviation 6.19
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 27	-1.6 Percentage points of LVEF Standard Deviation 5.05	-1.3 Percentage points of LVEF Standard Deviation 5.87
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 30	-1.4 Percentage points of LVEF Standard Deviation 5.20	-0.3 Percentage points of LVEF Standard Deviation 6.03
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 33	-2.8 Percentage points of LVEF Standard Deviation 5.60	1.2 Percentage points of LVEF Standard Deviation 6.71
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 36	-2.5 Percentage points of LVEF Standard Deviation 5.50	-0.2 Percentage points of LVEF Standard Deviation 5.41
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 39	-2.6 Percentage points of LVEF Standard Deviation 5.72	1.4 Percentage points of LVEF Standard Deviation 4.87
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 42	-2.1 Percentage points of LVEF Standard Deviation 5.91	1.9 Percentage points of LVEF Standard Deviation 6.12
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 45	-1.0 Percentage points of LVEF Standard Deviation 5.54	3.0 Percentage points of LVEF Standard Deviation 5.27
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 48	-3.3 Percentage points of LVEF Standard Deviation 6.56	-0.2 Percentage points of LVEF Standard Deviation 7.50
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 51	-1.4 Percentage points of LVEF Standard Deviation 5.82	1.0 Percentage points of LVEF Standard Deviation 4.19
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 54	-1.3 Percentage points of LVEF Standard Deviation 6.17	-1.0 Percentage points of LVEF Standard Deviation 6.23
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 57	-1.7 Percentage points of LVEF Standard Deviation 6.43	0.8 Percentage points of LVEF Standard Deviation 5.68
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 60	-2.5 Percentage points of LVEF Standard Deviation 5.54	-0.9 Percentage points of LVEF Standard Deviation 3.91
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 63	-2.1 Percentage points of LVEF Standard Deviation 6.10	0.8 Percentage points of LVEF Standard Deviation 5.99
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 66	-2.9 Percentage points of LVEF Standard Deviation 7.80	-0.4 Percentage points of LVEF Standard Deviation 5.17
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 69	-2.1 Percentage points of LVEF Standard Deviation 7.23	-1.5 Percentage points of LVEF Standard Deviation 7.68
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 72	-3.0 Percentage points of LVEF Standard Deviation 4.97	-1.0 Percentage points of LVEF Standard Deviation 5.75
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 75	-3.3 Percentage points of LVEF Standard Deviation 6.59	-1.1 Percentage points of LVEF Standard Deviation 6.97
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 78	-3.3 Percentage points of LVEF Standard Deviation 5.58	-1.1 Percentage points of LVEF Standard Deviation 7.82
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 84	-2.5 Percentage points of LVEF Standard Deviation 7.66	-4.5 Percentage points of LVEF Standard Deviation 3.59
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 87	-3.8 Percentage points of LVEF Standard Deviation 5.76	-1.4 Percentage points of LVEF Standard Deviation 5.12
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 90	-2.4 Percentage points of LVEF Standard Deviation 7.69	0.4 Percentage points of LVEF Standard Deviation 6.77
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 93	-1.8 Percentage points of LVEF Standard Deviation 6.57	-3.9 Percentage points of LVEF Standard Deviation 6.00
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 96	-0.7 Percentage points of LVEF Standard Deviation 7.45	-3.2 Percentage points of LVEF Standard Deviation 5.50
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 99	-3.4 Percentage points of LVEF Standard Deviation 5.78	-2.8 Percentage points of LVEF Standard Deviation 8.41
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 102	-1.3 Percentage points of LVEF Standard Deviation 6.12	-1.6 Percentage points of LVEF Standard Deviation 9.68
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 105	-0.4 Percentage points of LVEF Standard Deviation 7.05	-2.0 Percentage points of LVEF Standard Deviation 12.17
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 108	-3.4 Percentage points of LVEF Standard Deviation 5.32	-3.3 Percentage points of LVEF Standard Deviation 8.33
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 111	-6.3 Percentage points of LVEF Standard Deviation 5.91	-5.5 Percentage points of LVEF Standard Deviation NA Standard deviation could not be calculated with data from a single participant.
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 114	-4.0 Percentage points of LVEF Standard Deviation 5.35	-1.4 Percentage points of LVEF Standard Deviation NA Standard deviation could not be calculated with data from a single participant.
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 117	-11.0 Percentage points of LVEF Standard Deviation NA Standard deviation could not be calculated with data from a single participant.	—
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study Change from BL at Cycle 120	-11.0 Percentage points of LVEF Standard Deviation NA Standard deviation could not be calculated with data from a single participant.	—