Trial Outcomes & Findings for Study of Trastuzumab Deruxtecan (T-DXd) vs Investigator's Choice Chemotherapy in HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer (NCT NCT04494425)

Last Updated: 2025-06-18

Results Overview

PFS per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) assessed by BICR was defined as the time from the date of randomization until the date of PD, as defined or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anticancer therapy prior to progression. PD was defined as at least a 20% increase in the sum of diameters of target lesions (TLs), taking as reference the smallest previous sum of diameters (nadir), this included the baseline sum if that was the smallest on study. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 millimeter (mm) from nadir. Median PFS was calculated using Kaplan-Meier method and its confidence interval (CI) using Brookmeyer-Crowley method.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

866 participants

Primary outcome timeframe

Response evaluations performed at screening, every 6 weeks (q6w) ± 1 week from randomization for 48 weeks, and then every 9 weeks (q9w) ± 1 week, starting at Week 48 until PD, up to PCD of 18 March 2024 (maximum of approximately 43.85 months)

Results posted on

2025-06-18

Participant Flow

This Phase III, multi-center, open-label study was conducted in participants with human epidermal growth factor receptor 2 (HER2)-low, hormone receptor-positive (HR+) breast cancer at 273 sites in 28 countries. Results are presented based on primary completion date (PCD) of up to 18 March 2024.

866 participants were randomized in a 1:1 ratio to receive trastuzumab deruxtecan (T-DXd) or standard of care: Investigator's choice single agent chemotherapy (capecitabine, paclitaxel or nab-paclitaxel). As pre-specified in the protocol and statistical analysis plan (SAP), results are presented by treatment group.

Participant milestones

Participant milestones
Measure	T-DXd Participants received T-DXd 5.4 milligram per kilogram (mg/kg) via intravenous (IV) infusion every 3 weeks until disease progression (PD), unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg per meter square \[m\^2\] orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion every week \[qw\] in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Overall Study STARTED	436	430
Overall Study Randomized and Received Treatment	434	417
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	436	430

Reasons for withdrawal

Reasons for withdrawal
Measure	T-DXd Participants received T-DXd 5.4 milligram per kilogram (mg/kg) via intravenous (IV) infusion every 3 weeks until disease progression (PD), unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg per meter square \[m\^2\] orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion every week \[qw\] in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Overall Study Death	160	166
Overall Study Withdrawal by Subject	10	40
Overall Study Other	1	1
Overall Study Ongoing at the time of PCD	265	223

Baseline Characteristics

Study of Trastuzumab Deruxtecan (T-DXd) vs Investigator's Choice Chemotherapy in HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	T-DXd n=436 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=430 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Total n=866 Participants Total of all reporting groups
Age, Continuous	58.2 years STANDARD_DEVIATION 11.46 • n=5 Participants	58.2 years STANDARD_DEVIATION 10.92 • n=7 Participants	58.2 years STANDARD_DEVIATION 11.19 • n=5 Participants
Sex: Female, Male Female	436 Participants n=5 Participants	429 Participants n=7 Participants	865 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian	154 Participants n=5 Participants	151 Participants n=7 Participants	305 Participants n=5 Participants
Race/Ethnicity, Customized White	231 Participants n=5 Participants	230 Participants n=7 Participants	461 Participants n=5 Participants
Race/Ethnicity, Customized Other	7 Participants n=5 Participants	12 Participants n=7 Participants	19 Participants n=5 Participants
Race/Ethnicity, Customized Not reported	39 Participants n=5 Participants	34 Participants n=7 Participants	73 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	28 Participants n=5 Participants	32 Participants n=7 Participants	60 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	397 Participants n=5 Participants	387 Participants n=7 Participants	784 Participants n=5 Participants
Race/Ethnicity, Customized Missing	11 Participants n=5 Participants	11 Participants n=7 Participants	22 Participants n=5 Participants

PRIMARY outcome

Timeframe: Response evaluations performed at screening, every 6 weeks (q6w) ± 1 week from randomization for 48 weeks, and then every 9 weeks (q9w) ± 1 week, starting at Week 48 until PD, up to PCD of 18 March 2024 (maximum of approximately 43.85 months)

Population: The HER2-low population included the subset of participants in the ITT population with HER2 immunohistochemistry (IHC) 2+/ in situ hybridization (ISH)- and IHC 1+ as determined per the interactive response technology (IRT) data for HER2 IHC expression.

Outcome measures

Outcome measures
Measure	T-DXd n=359 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=354 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Progression-Free Survival (PFS) Assessed by Blinded Independent Central Review (BICR) in the Hormone Receptor-Positive (HR+), Human Epidermal Growth Factor Receptor 2 (HER2)-Low Population	13.2 months Interval 11.4 to 15.2	8.1 months Interval 7.0 to 9.0

SECONDARY outcome

Timeframe: From date of randomization until death due to any cause, up to PCD of 18 March 2024 (maximum of approximately 43.85 months)

Population: The HER2-low population included the subset of participants in the ITT population with HER2 IHC 2+/ISH- and IHC 1+ as determined per the IRT data for HER2 IHC expression.

OS was defined as the time from the date of randomization until death due to any cause regardless of whether the participant withdrew from randomized therapy or received another anticancer therapy. Median OS was calculated using Kaplan-Meier method and its CI using Brookmeyer-Crowley method.

Outcome measures

Outcome measures
Measure	T-DXd n=359 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=354 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Overall Survival (OS) in the Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-low Population	28.9 months Interval 25.7 to 33.7	27.1 months Interval 23.5 to 29.9

SECONDARY outcome

Timeframe: Response evaluations performed at screening, q6w ± 1 week from randomization for 48 weeks, and then q9w ± 1 week, starting at Week 48 until PD, up to PCD of 18 March 2024 (maximum of approximately 43.85 months)

Population: ITT population: all randomized participants. HER2 IHC \>0 \<1+ population: subset of participants included in ITT population with HER2 IHC \>0 \<1+ as determined by central laboratory testing and who have had at least 24 weeks of follow-up at time of interim futility PCD. HER2-low population: subset of participants in ITT population with HER2 IHC 2+/ISH- and IHC 1+ as determined per IRT data for HER2 IHC expression. Only participants with data collected in specified categories are reported.

PFS per RECIST 1.1 assessed by BICR was defined as the time from the date of randomization until the date of PD, as defined or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anticancer therapy prior to progression. PD was defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir), this included the baseline sum if that was the smallest on study. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm from nadir. Median PFS was calculated using Kaplan-Meier method and its CI using Brookmeyer-Crowley method.

Outcome measures

Outcome measures
Measure	T-DXd n=436 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=430 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Progression-Free Survival Assessed by Blinded Independent Central Review in the Intent-to-Treat, Human Epidermal Growth Factor Receptor 2 Immunohistochemistry (IHC) >0 <1+ and Human Epidermal Growth Factor Receptor 2-low Population ITT Population	13.2 months Interval 12.0 to 15.2	8.1 months Interval 7.0 to 9.0
Progression-Free Survival Assessed by Blinded Independent Central Review in the Intent-to-Treat, Human Epidermal Growth Factor Receptor 2 Immunohistochemistry (IHC) >0 <1+ and Human Epidermal Growth Factor Receptor 2-low Population HER2-low Population	12.8 months Interval 11.1 to 13.2	7.0 months Interval 6.4 to 7.5
Progression-Free Survival Assessed by Blinded Independent Central Review in the Intent-to-Treat, Human Epidermal Growth Factor Receptor 2 Immunohistochemistry (IHC) >0 <1+ and Human Epidermal Growth Factor Receptor 2-low Population HER2 IHC >0 <1+ Population	13.2 months Interval 9.8 to 17.3	8.3 months Interval 5.8 to 15.2

SECONDARY outcome

Timeframe: From date of randomization until death due to any cause, up to PCD of 18 March 2024 (maximum of approximately 43.85 months)

Population: The ITT population included all randomized participants.

Outcome measures

Outcome measures
Measure	T-DXd n=436 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=430 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Overall Survival (OS) in the Intent-to-Treat Population	28.9 months Interval 26.4 to 32.7	27.4 months Interval 23.9 to 29.9

SECONDARY outcome

Population: The HER2-low population included the subset of participants in the ITT population with HER2 IHC 2+/ISH- and IHC 1+ as determined per the IRT data for HER2 IHC expression.

PFS per RECIST 1.1 assessed by Investigator was defined as the time from the date of randomization until the date of PD, as defined or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anticancer therapy prior to progression. PD was defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir), this included the baseline sum if that was the smallest on study. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm from nadir. Median PFS was calculated using Kaplan-Meier method and its CI using Brookmeyer-Crowley method.

Outcome measures

Outcome measures
Measure	T-DXd n=359 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=354 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Progression-Free Survival Assessed by Investigator in the Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-low Population	12.8 months Interval 11.1 to 13.2	7.0 months Interval 6.4 to 7.5

SECONDARY outcome

Population: The HER2-low population included the subset of participants in the ITT population with HER2 IHC 2+/ISH- and IHC 1+ as determined per the IRT data for HER2 IHC expression.

ORR per RECIST 1.1 assessed by BICR and Investigator was defined as the percentage of participants with at least 1 visit response of complete response (CR) or partial response (PR). CR was defined as disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to \<10 mm. PR was defined as at least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of diameters.

Outcome measures

Outcome measures
Measure	T-DXd n=359 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=354 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Objective Response Rate (ORR) Assessed by Blinded Independent Central Review and Investigator in the Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-low Population BICR Assessment	60.4 percentage of participants	37.9 percentage of participants
Objective Response Rate (ORR) Assessed by Blinded Independent Central Review and Investigator in the Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-low Population Investigator Assessment	60.4 percentage of participants	40.4 percentage of participants

SECONDARY outcome

Population: The HER2-low population included the subset of participants in the ITT population with HER2 IHC 2+/ISH- and IHC 1+ as determined per the IRT data for HER2 IHC expression. Only participants with response in each specified category are reported.

DOR per RECIST v1.1 was defined as the time from the date of first documented response until date of documented progression or death in the absence of PD. PD was defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest previous sum of diameters (nadir), this included the baseline sum if that was the smallest on study. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm from nadir. Median DOR was calculated using Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	T-DXd n=217 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=143 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Duration of Response (DOR) Assessed by Blinded Independent Central Review and Investigator in the Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-low Population BICR Assessment	13.6 months Interval 6.2 to 24.9	7.3 months Interval 4.2 to 15.2
Duration of Response (DOR) Assessed by Blinded Independent Central Review and Investigator in the Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-low Population Investigator Assessment	12.0 months Interval 6.6 to 20.0	6.9 months Interval 3.1 to 11.1

SECONDARY outcome

Population: The ITT population included all randomized participants. The HER2 IHC \>0 \<1+ population included subset of participants included in ITT population with HER2 IHC \>0 \<1+ as determined by central laboratory testing and who have had at least 24 weeks of follow-up at time of interim futility PCD. Only participants with data collected in specified categories are reported.

ORR per RECIST 1.1 assessed by BICR and Investigator was defined as the percentage of participants with at least 1 visit response of CR or PR. CR was defined as disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis diameter to \<10 mm. PR was defined as at least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of diameters.

Outcome measures

Outcome measures
Measure	T-DXd n=436 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=430 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Objective Response Rate Assessed by Blinded Independent Central Review and Investigator in the Intent-to-Treat and Human Epidermal Growth Factor Receptor 2 Immunohistochemistry >0 <1+ Population BICR Assessment: ITT Population	61.5 percentage of participants	36.7 percentage of participants
Objective Response Rate Assessed by Blinded Independent Central Review and Investigator in the Intent-to-Treat and Human Epidermal Growth Factor Receptor 2 Immunohistochemistry >0 <1+ Population BICR Assessment: HER2 IHC >0 <1+ Population	67.1 percentage of participants	31.6 percentage of participants
Objective Response Rate Assessed by Blinded Independent Central Review and Investigator in the Intent-to-Treat and Human Epidermal Growth Factor Receptor 2 Immunohistochemistry >0 <1+ Population Investigator Assessment: HER2 IHC >0 <1+ Population	65.8 percentage of participants	31.6 percentage of participants
Objective Response Rate Assessed by Blinded Independent Central Review and Investigator in the Intent-to-Treat and Human Epidermal Growth Factor Receptor 2 Immunohistochemistry >0 <1+ Population Investigator Assessment: ITT Population	61.5 percentage of participants	38.8 percentage of participants

SECONDARY outcome

Population: The ITT population included all randomized participants. Only participants with response in each specified category are reported.

Outcome measures

Outcome measures
Measure	T-DXd n=268 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=167 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Duration of Response Assessed by Blinded Independent Central Review and Investigator in the Intent-to-Treat Population BICR Assessment	13.7 months Interval 6.5 to 24.9	7.3 months Interval 4.2 to 15.9
Duration of Response Assessed by Blinded Independent Central Review and Investigator in the Intent-to-Treat Population Investigator Assessment	12.1 months Interval 6.8 to 20.0	6.9 months Interval 3.0 to 12.5

SECONDARY outcome

Population: The HER2-low population included subset of participants in ITT population with HER2 IHC 2+/ISH- and IHC 1+ as determined per IRT data for HER2 IHC expression. The ITT population included all randomized participants. Only participants with data collected in specified categories are reported.

PFS2 was defined as time from randomization to second progression (the earliest of the progression event subsequent to first subsequent therapy) or death; second progression was defined according to local standard clinical practice and might involve any of the following: objective radiological imaging, symptomatic progression, or death. Median PFS2 was calculated using Kaplan-Meier method and its CI using Brookmeyer-Crowley method.

Outcome measures

Outcome measures
Measure	T-DXd n=436 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=430 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Time From Randomization to Second Progression or Death (PFS2) in the Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-low and Intent-to-Treat Population ITT Population	20.3 months Interval 18.9 to 23.8	14.7 months Interval 13.5 to 15.9
Time From Randomization to Second Progression or Death (PFS2) in the Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-low and Intent-to-Treat Population HER2-low Population	20.0 months Interval 18.9 to 23.8	14.5 months Interval 12.9 to 15.5

SECONDARY outcome

Timeframe: From first dose of study drug (Day 1) up to PCD of 18 March 2024 (maximum of approximately 43.85 months)

Population: The Safety population included all participants who received at least 1 dose of study drug.

An adverse event (AE) was any untoward medical occurrence in a participant or clinical study participant administered a medicinal product and which did not necessarily had a causal relationship with this treatment. A serious adverse event (SAE) was an AE occurring during any study phase, that fulfilled 1 or more of following criteria: resulted in death, was immediately life-threatening, required in-participant hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was congenital abnormality or birth defect, and was an important medical event that jeopardized participant or required medical treatment to prevent 1 of outcomes listed above. TEAE was any AE that occurred, having been absent before the first dose of study drug, or had worsened in severity or seriousness after initiation of the study drug until the 40-day (+7 days) safety follow-up visit.

Outcome measures

Outcome measures
Measure	T-DXd n=434 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=417 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) TEAEs	429 Participants	397 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) TESAEs	88 Participants	67 Participants

SECONDARY outcome

Timeframe: Pre-dose on Day 1 of Cycles 1, 2, 4, 6 and 8; 15 minutes post-dose on Day 1 of Cycles 1, 2 and 4; and 5 hours post-dose on Day 1 of Cycle 1 (each cycle is 21 days)

Population: The Pharmacokinetic population included all participants who received at least 1 dose of T-DXd per the protocol for whom any post-dose data were available. Only participants with data collected in specified timepoints are reported.

Blood samples were collected at indicated time points to determine the concentration of T-DXd, total anti-HER2 antibody and MAAA-1181a in serum.

Outcome measures

Outcome measures
Measure	T-DXd n=407 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a T-DXd: Day 1: 15 minutes post-dose, Cycle 1	135.90160 micrograms per milliliter (mcg/mL) Standard Deviation 102.989325	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a T-DXd: Day 1: 15 minutes post-dose, Cycle 2	136.74872 micrograms per milliliter (mcg/mL) Standard Deviation 108.860006	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a MAAA-1181a: Day 1: pre-dose, Cycle 6	0.446237 micrograms per milliliter (mcg/mL) Standard Deviation 0.2957478	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a T-DXd: Day 1: pre-dose, Cycle 1	NA micrograms per milliliter (mcg/mL) Standard Deviation NA NA indicated that mean and standard deviation (SD) were not estimable as the values were below the lower limit of quantification (LLOQ). LLOQ was 0.4 mcg/mL.	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a T-DXd: Day 1: pre-dose, Cycle 2	4.35225 micrograms per milliliter (mcg/mL) Standard Deviation 8.958729	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a T-DXd: Day 1: pre-dose, Cycle 4	8.21037 micrograms per milliliter (mcg/mL) Standard Deviation 9.464435	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a T-DXd: Day 1: pre-dose, Cycle 6	8.65950 micrograms per milliliter (mcg/mL) Standard Deviation 4.753592	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a T-DXd: Day 1: pre-dose, Cycle 8	11.31496 micrograms per milliliter (mcg/mL) Standard Deviation 22.894112	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a T-DXd: Day 1: 15 minutes post-dose, Cycle 4	124.60481 micrograms per milliliter (mcg/mL) Standard Deviation 39.812165	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a T-DXd: Day 1: 5 hours post-dose, Cycle 1	123.82288 micrograms per milliliter (mcg/mL) Standard Deviation 30.513998	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a Total anti-HER2 antibody: Day 1: pre-dose, Cycle 1	NA micrograms per milliliter (mcg/mL) Standard Deviation NA NA indicated that mean and SD were not estimable as the values were below the LLOQ. LLOQ was 0.4 mcg/mL.	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a Total anti-HER2 antibody: Day 1: pre-dose, Cycle 2	5.75841 micrograms per milliliter (mcg/mL) Standard Deviation 11.351915	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a Total anti-HER2 antibody: Day 1: pre-dose, Cycle 4	12.00513 micrograms per milliliter (mcg/mL) Standard Deviation 11.087226	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a Total anti-HER2 antibody: Day 1: pre-dose, Cycle 6	13.97891 micrograms per milliliter (mcg/mL) Standard Deviation 8.720790	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a Total anti-HER2 antibody: Day 1: pre-dose, Cycle 8	17.47641 micrograms per milliliter (mcg/mL) Standard Deviation 27.144299	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a Total anti-HER2 antibody: Day 1: 15 minutes post-dose, Cycle 1	141.27586 micrograms per milliliter (mcg/mL) Standard Deviation 114.137606	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a Total anti-HER2 antibody: Day 1: 15 minutes post-dose, Cycle 2	146.17993 micrograms per milliliter (mcg/mL) Standard Deviation 134.780719	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a Total anti-HER2 antibody: Day 1: 15 minutes post-dose, Cycle 4	131.06830 micrograms per milliliter (mcg/mL) Standard Deviation 44.228380	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a Total anti-HER2 antibody: Day 1: 5 hours post-dose, Cycle 1	119.64619 micrograms per milliliter (mcg/mL) Standard Deviation 26.591288	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a MAAA-1181a: Day 1: pre-dose, Cycle 1	NA micrograms per milliliter (mcg/mL) Standard Deviation NA NA indicated that mean and SD were not estimable as the values were below the LLOQ. LLOQ was 0.00001 mcg/mL.	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a MAAA-1181a: Day 1: pre-dose, Cycle 2	0.261850 micrograms per milliliter (mcg/mL) Standard Deviation 0.2096642	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a MAAA-1181a: Day 1: pre-dose, Cycle 4	0.401004 micrograms per milliliter (mcg/mL) Standard Deviation 0.2825761	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a MAAA-1181a: Day 1: pre-dose, Cycle 8	0.432894 micrograms per milliliter (mcg/mL) Standard Deviation 0.2819292	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a MAAA-1181a: Day 1: 15 minutes post-dose, Cycle 1	6.014366 micrograms per milliliter (mcg/mL) Standard Deviation 3.1859583	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a MAAA-1181a: Day 1: 15 minutes post-dose, Cycle 2	2.985606 micrograms per milliliter (mcg/mL) Standard Deviation 1.9276120	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a MAAA-1181a: Day 1: 15 minutes post-dose, Cycle 4	2.411409 micrograms per milliliter (mcg/mL) Standard Deviation 1.5862547	—
Serum Concentration of Trastuzumab Deruxtecan (T-DXd), Total Anti-Human Epidermal Growth Factor Receptor 2 Antibody and MAAA-1181a MAAA-1181a: Day 1: 5 hours post-dose, Cycle 1	13.917874 micrograms per milliliter (mcg/mL) Standard Deviation 6.5178612	—

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 91

Population: The ITT population included all randomized participants. Only participants with data collected in specified categories are reported.

EORTC QLQ-C30 is a 30-item self-administered questionnaire grouped into 5 multi-item functional scales(physical,role,emotional,cognitive and social),3 multiitem symptom scales(fatigue,pain and nausea/vomiting),2-item global QoL scale,5 single items assessing additional symptoms reported by cancer participants(dyspnea,loss of appetite,insomnia,constipation and diarrhea). All but 2 questions have 4-point scales:1:not at all,2:a little,3:quite a bit,4:very much.2 questions concerning global health status and QoL have 7-point scales with responses ranging from 1:very poor to 7:excellent;higher score:better level of functioning/greater degree of symptoms.For each of 15 scales,final scores were averaged from scores of component items,transformed,range: 0 to 100;higher scores:better functioning,better health related (HR)QoL,or greater level of symptoms(higher scores:opposite interpretations for functioning/QoL and symptoms/problems).Baseline:last observed measurement prior to randomization.

Outcome measures

Outcome measures
Measure	T-DXd n=44 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=22 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Score at Week 91 Global Health Status/QoL	-7.77 score on a scale Standard Deviation 23.529	-10.61 score on a scale Standard Deviation 22.150
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Score at Week 91 Physical Functioning	-7.88 score on a scale Standard Deviation 17.389	-4.85 score on a scale Standard Deviation 13.520
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Score at Week 91 Role Functioning	-14.77 score on a scale Standard Deviation 21.631	-12.12 score on a scale Standard Deviation 26.318
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Score at Week 91 Emotional Functioning	-6.06 score on a scale Standard Deviation 25.440	1.52 score on a scale Standard Deviation 22.218
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Score at Week 91 Cognitive Functioning	-8.71 score on a scale Standard Deviation 22.872	-6.82 score on a scale Standard Deviation 19.009
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Score at Week 91 Social Functioning	-10.98 score on a scale Standard Deviation 23.000	-7.58 score on a scale Standard Deviation 21.656
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Score at Week 91 Fatigue	11.87 score on a scale Standard Deviation 24.367	8.59 score on a scale Standard Deviation 18.444
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Score at Week 91 Pain	-1.89 score on a scale Standard Deviation 21.025	-0.76 score on a scale Standard Deviation 24.922
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Score at Week 91 Nausea/Vomiting	9.85 score on a scale Standard Deviation 19.128	-0.76 score on a scale Standard Deviation 12.037
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Score at Week 91 Dyspnea	6.06 score on a scale Standard Deviation 23.041	1.52 score on a scale Standard Deviation 21.767
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Score at Week 91 Loss of Appetite	12.88 score on a scale Standard Deviation 30.682	6.06 score on a scale Standard Deviation 19.616
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Score at Week 91 Insomnia	6.06 score on a scale Standard Deviation 26.190	-15.15 score on a scale Standard Deviation 24.618
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Score at Week 91 Constipation	11.36 score on a scale Standard Deviation 30.452	1.52 score on a scale Standard Deviation 12.503
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scale Score at Week 91 Diarrhea	6.82 score on a scale Standard Deviation 19.792	13.64 score on a scale Standard Deviation 28.469

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 58

Population: The ITT population included all randomized participants. Only participants with data collected in specified categories are reported.

EORTC QLQ-BR45 is an updated version of the BR23. Self-administered instrument includes original 23-items yielding 5 multi-item scores (body image, sexual functioning, arm symptoms, breast symptoms, and systemic therapy side effects). Additional 22 items yield 4 additional multi-item scales (breast satisfaction, endocrine therapy symptoms, skin mucosis symptoms, and endocrine sexual symptoms). Single items assess sexual enjoyment, future perspective and being upset by hair loss. Items are scored on a 4-point verbal rating scale: 1: not at all, 2: a little, 3: quite a bit, and 4: very much; higher score: better level of functioning or greater degree of symptoms. Scores of these scales were averaged from scores of component items, transformed, and ranged from 0 to 100; higher scores for functioning scales or items indicate better functioning, whereas higher scores for symptom scales or items represent a higher level of symptoms. Baseline:last observed measurement prior to randomization.

Outcome measures

Outcome measures
Measure	T-DXd n=107 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=80 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Breast Module 45 (BR45) Scale Score at Week 58 Body Image	-3.12 score on a scale Standard Deviation 23.585	-5.42 score on a scale Standard Deviation 22.349
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Breast Module 45 (BR45) Scale Score at Week 58 Sexual Functioning	-2.96 score on a scale Standard Deviation 12.708	1.46 score on a scale Standard Deviation 14.081
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Breast Module 45 (BR45) Scale Score at Week 58 Arm Symptoms	-5.30 score on a scale Standard Deviation 20.496	-3.06 score on a scale Standard Deviation 18.540
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Breast Module 45 (BR45) Scale Score at Week 58 Breast Symptoms	-2.41 score on a scale Standard Deviation 17.132	-2.19 score on a scale Standard Deviation 12.631
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Breast Module 45 (BR45) Scale Score at Week 58 Systemic Therapy Side Effects	5.65 score on a scale Standard Deviation 15.536	3.99 score on a scale Standard Deviation 15.536
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Breast Module 45 (BR45) Scale Score at Week 58 Breast Satisfaction	2.65 score on a scale Standard Deviation 30.982	0.85 score on a scale Standard Deviation 31.428
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Breast Module 45 (BR45) Scale Score at Week 58 Endocrine Therapy Symptoms	-0.14 score on a scale Standard Deviation 11.316	0.17 score on a scale Standard Deviation 12.458
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Breast Module 45 (BR45) Scale Score at Week 58 Skin Mucosis Symptoms	4.67 score on a scale Standard Deviation 14.721	12.22 score on a scale Standard Deviation 18.232
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Breast Module 45 (BR45) Scale Score at Week 58 Endocrine Sexual Symptoms	3.66 score on a scale Standard Deviation 20.831	2.00 score on a scale Standard Deviation 15.969
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Breast Module 45 (BR45) Scale Score at Week 58 Sexual Enjoyment	-3.03 score on a scale Standard Deviation 17.979	0.00 score on a scale Standard Deviation 20.101
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Breast Module 45 (BR45) Scale Score at Week 58 Future Perspective	8.72 score on a scale Standard Deviation 32.161	11.25 score on a scale Standard Deviation 29.022
Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Breast Module 45 (BR45) Scale Score at Week 58 Being Upset By Hair Loss	2.47 score on a scale Standard Deviation 34.500	0.00 score on a scale Standard Deviation 40.825

SECONDARY outcome

Timeframe: From randomization until date of first symptom deterioration that is confirmed, up to PCD of 18 March 2024 (maximum of approximately 43.85 months)

Population: The ITT population included all randomized participants.

Time to deterioration was defined as the time from randomization until the date of the first clinically meaningful deterioration that was confirmed at next available assessment, at least 14 days apart, regardless of whether the participant withdrew from study treatment or receives another anti-cancer therapy prior to deterioration.

Outcome measures

Outcome measures
Measure	T-DXd n=436 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy n=430 Participants Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Time to Deterioration in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale Score Constipation	9.2 months Interval 5.5 to 12.5	22.0 months Interval 15.9 to NA indicated that the upper limit of 95% CI was not estimable due to insufficient number of participants with events.
Time to Deterioration in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale Score Diarrhea	29.0 months Interval 17.2 to NA indicated that the upper limit of 95% CI was not estimable due to insufficient number of participants with events.	16.5 months Interval 13.9 to 23.4
Time to Deterioration in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale Score Physical Functioning	18.0 months Interval 15.9 to NA indicated that the upper limit of 95% CI was not estimable due to insufficient number of participants with events.	9.9 months Interval 6.9 to 15.2
Time to Deterioration in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale Score Role Functioning	10.3 months Interval 6.9 to 14.6	5.5 months Interval 4.1 to 6.9
Time to Deterioration in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale Score Emotional Functioning	28.2 months Interval 18.6 to NA indicated that the upper limit of 95% CI was not estimable due to insufficient number of participants with events.	17.3 months Interval 12.4 to NA indicated that the upper limit of 95% CI was not estimable due to insufficient number of participants with events.
Time to Deterioration in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale Score Cognitive Functioning	11.8 months Interval 8.3 to 16.6	9.9 months Interval 7.8 to 13.8
Time to Deterioration in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale Score Social Functioning	11.7 months Interval 7.6 to 16.3	7.7 months Interval 6.2 to 10.4
Time to Deterioration in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale Score Fatigue	4.3 months Interval 3.4 to 7.7	2.9 months Interval 2.2 to 4.2
Time to Deterioration in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale Score Pain	22.0 months Interval 17.2 to NA indicated that the upper limit of 95% CI was not estimable due to insufficient number of participants with events.	6.3 months Interval 4.8 to 9.6
Time to Deterioration in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale Score Nausea/Vomiting	3.5 months Interval 2.8 to 5.6	13.8 months Interval 7.7 to 21.5
Time to Deterioration in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale Score Global Health Status/QoL	11.3 months Interval 8.3 to 14.7	10.5 months Interval 7.7 to 13.3
Time to Deterioration in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale Score Dyspnea	20.0 months Interval 19.3 to NA indicated that the upper limit of 95% CI was not estimable due to insufficient number of participants with events.	20.8 months Interval 13.1 to NA indicated that the upper limit of 95% CI was not estimable due to insufficient number of participants with events.
Time to Deterioration in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale Score Loss of Appetite	8.3 months Interval 5.0 to 11.7	13.8 months Interval 9.6 to 16.1
Time to Deterioration in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale Score Insomnia	NA months Interval 17.3 to NA indicated that the median and upper limit of 95% CI was not estimable due to insufficient number of participants with events.	15.2 months Interval 12.4 to NA indicated that the upper limit of 95% CI was not estimable due to insufficient number of participants with events.

SECONDARY outcome

Timeframe: From Day 1 up to PCD of 18 March 2024 (maximum of approximately 43.85 months)

Population: The ADA population included all participants who received at least 1 dose of T-DXd and who had a non-missing ADA result at any time.

Blood samples were collected at indicated timepoints to determine ADA. Treatment-induced ADA was defined as ADA positive post-baseline and not detected at baseline (negative or missing). Treatment-boosted ADA was defined as a baseline positive ADA titer that was boosted to a 4-fold or higher-level following drug administration.

Outcome measures

Outcome measures
Measure	T-DXd n=433 Participants Participants received T-DXd 5.4 mg/kg via IV infusion every 3 weeks until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.	Chemotherapy Participants received Investigator's choice single-agent chemotherapy (capecitabine 1000 or 1250 mg/m\^2 orally twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles, paclitaxel 80 mg/m\^2 via IV infusion qw in 3-week cycles or nab-paclitaxel 100 mg/m\^2 via IV infusion qw for 3 weeks followed by 1-week rest period in 4-week cycles) until PD, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation was met.
Number of Participants With Anti-Drug Antibodies (ADAs) Against Trastuzumab Deruxtecan Treatment-induced ADA	22 Participants	—
Number of Participants With Anti-Drug Antibodies (ADAs) Against Trastuzumab Deruxtecan Treatment-boosted ADA	0 Participants	—

SECONDARY outcome

Timeframe: From Day 1 up to 64 months

TFST was defined as time from randomization to the start date of the first subsequent anti-cancer therapy after discontinuation of randomized treatment or death due to any cause.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Day 1 up to 64 months

TSST was defined as time from randomization to the start date of the second subsequent anti-cancer therapy after discontinuation of randomized treatment or death due to any cause.

Outcome measures

Outcome data not reported

Adverse Events

T-DXd

Serious events: 88 serious events

Other events: 427 other events

Deaths: 161 deaths

Chemotherapy

Serious events: 67 serious events

Other events: 383 other events

Deaths: 174 deaths

Serious adverse events

Other adverse events

Additional Information

Global Clinical Lead

AstraZeneca

Phone: 1-877-240-9479

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place