T-DXd–based therapy followed by targeted HER2 blockade and endocrine therapy in first-line HER2+ / HR+ 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. ECOG PS of 0 or 1 assessed no more than 3 days prior to initiation of trial intervention.
6. 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.
7. 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.