This study will evaluate a structured sequential treatment strategy starting with T-DXd + pertuzumab upfront therapy, followed by an optimized maintenance therapy with dual HER2+blockade + CDK4/6i + ET and the opportunity to retreat with T-DXd once patients progress under maintenance aimed to maximizing disease control, optimizing tolerability, and preserving T-DXd as a future therapeutic option, while ensuring participant safety and regulatory compliance in participants with HER2+/HR+ advanced/metastatic breast cancer.

This global, interventional, open-label, phase 3b trial will evaluate the efficacy and safety of a sequential treatment approach for first-line HER2+/HR+ advanced/metastatic breast cancer, initiating with upfront T-DXd + pertuzumab administered for 18 to 24 cycles, followed by a transition to trastuzumab + pertuzumab + ET + palbociclib. Participants who experience disease progression while receiving trastuzumab + pertuzumab + ET + palbociclib will receive T-DXd as 2L therapy.

The study objectives will assess efficacy, safety, and quality-of-life in patients with advanced/metastatic breast cancer.

Key Inclusion Criteria for Upfront Treatment Phase

1. Sign and date the Main Trial informed consent form (ICF), prior to the start of any trial-specific procedures.

2. Participant must be ≥18 years of age at the time the ICF is signed.

3. Have pathologically documented breast cancer that:

   • Is locally advanced and unresectable or metastatic (participants who can be treated with curative intent are not eligible).
   • Participant must have histologically confirmed HER2+ and HR+ (ER+ and/or PR+), mBC. ER, PR, and HER2 measurements should be locally performed according to institutional guidelines.
   • Is documented by local testing as HR-positive (either ER and/or PgR positive [ER or PgR ≥1%]) per ASCO/CAP guidelines in the metastatic setting or from the primary tumor with the latest sample available.

4. Has not received prior chemotherapy or HER2-targeted therapy for mBC. Participant who has received chemotherapy or HER2-targeted therapy or radiotherapy or surgery in the neoadjuvant or adjuvant setting are eligible, with a DFI of >6 months (>183 days) from completion of systemic chemotherapy or any HER2-targeted therapy (antibody, TKI or T-DM1) to diagnosis of advanced or metastatic disease.

5. Participant who has received one prior line of endocrine therapy in the metastatic setting.

6. ECOG PS of 0 or 1 assessed no more than 3 days prior to initiation of trial intervention.

7. Has at least 1 lesion, not previously irradiated, that can be measured accurately at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have short axis ≥15 mm) with CT or MRI, which is suitable for accurate repeated measurements, or nonmeasurable, bone-only disease that can be assessed by CT, MRI, or X-ray.

8. Participant with brain metastases are allowed if participant is asymptomatic and does not require immediate local intervention.

Additional Key Criteria to Transition into the Maintenance Treatment Phase

1. Participant transitioning into the Maintenance Treatment Phase must meet the following inclusion criteria for Maintenance Treatment:

• Participant is without evidence of disease progression under T-DXd + pertuzumab treatment by local assessment according to RECIST v1.1 (ie, CR, PR, or SD), and
• Participant is willing to switch therapy, and
• Participant completed at least 8 cycles of T-DXd + pertuzumab and achieved cCR (confirmation of CR should be obtained during the next protocol defined scheduled tumor assessment.), or
• Participant completed 18 cycles (in total) of T-DXd and achieved a SD or PR, and the last 2 scans showed no further tumor shrinkage (defined as 2 subsequent scans at least 6 weeks apart) or has an unconfirmed CR.

Additional Key Criteria for T-DXd Retreatment Phase

1. Has received at least 1 dose of Maintenance Treatment.
2. Has documented disease progression per RECIST v1.1 per investigator assessment during Maintenance Treatment.
3. Participant who experienced ILD Grade 1 during the Maintenance Treatment Phase, must have fully resolved before starting T-DXd during the Retreatment Phase.

Key Exclusion Criteria for Upfront Treatment Phase

1. Has prior therapy with any CDK inhibitor.
2. Previous T-DXd therapy for early BC with an EFS or disease-free interval of < 12 months from completion of T-DXd therapy in the neoadjuvant or post-neoadjuvant setting.

Key Exclusion Criteria for Maintenance Treatment Phase

1. Is receiving concurrent therapy with other trial interventions (except pertuzumab which is part of Upfront Treatment and Maintenance Treatment).
2. Has prior therapy with any CDK inhibitor.
3. Has any unresolved SAE related to prior T-DXd + pertuzumab treatment from the Upfront Treatment Phase, defined as an event that has not resolved to baseline by the time of the eligibility assessment for the Maintenance Treatment Phase.
4. Has experienced Grade 3 or 4 ILD/pneumonitis during the Upfront Treatment Phase.
5. Has spinal cord compression or clinically active CNS metastases, defined as untreated or symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.

Key Exclusion Criteria for T-DXd Retreatment Phase

1. Participant who developed ILD/pneumonitis Grade ≥2 during the Upfront Treatment Phase or Maintenance Treatment Phase.
2. Participant has any unresolved SAE related to prior Maintenance Treatment Phase therapies defined as an event that has not resolved to baseline by the time of the eligibility assessment for the T-DXd Retreatment Phase.
3. Participant who developed non-ILD toxicities related to T-DXd in the Upfront Treatment Phase that required T-DXd discontinuation.

De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.

Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.