PHESGO Maintenance After T-DXd Short Induction for HER2+ Unresectable Locally Recurrent or Metastatic Breast Cancer

Inclusion Criteria: To be eligible to participate in this trial, an individual must meet ALL the following criteria: 1. Patient must be capable to understand the purpose of the study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures. 2. Male or female patients ≥ 18 years of age at the time of signing ICF. 3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 4. Life expectancy of ≥ 12 weeks at screening. 5. Evidence of HER2-overexpressing tumor status confirmed by any MEDSIR's designated central lab or patient has a pathology report confirming HER2-overexpression by local testing, preferably on the most recent available metastatic sample. In the latest case, tumor tissue or blood must be sent to any MEDSIR's designated central lab for confirmation of HER2 status. Analysis of the primary tumor sample will be accepted if the metastatic tissue is inaccessible. 6. Must have known estrogen receptor (ER) and progesterone receptor (PgR) status locally determined prior to study entry. 7. Unresectable locally recurrent or MBC documented by computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to resection with curative intent. 8. Evaluable disease as per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v.1.1) criteria. 9. Willingness and ability to provide the most recently available formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks at the time of the inclusion (mandatory). If archival tissue is not available, a newly obtained baseline biopsy of an accessible tumor lesion is required prior to start of study treatment. 10. No prior chemotherapy and/or HER2-targeted therapy for advanced disease (one prior line of endocrine therapy is allowed for MBC). 11. May have received adjuvant or neoadjuvant chemotherapy and/or HER2-targeted therapy before study treatment initiation, with a disease-free interval (DFI) from completion of the systemic treatment (excluding hormonal therapy) to metastatic diagnosis of at least 12 months. 12. Adequate hematologic and organ function, defined by the following: 1. Hematological (without platelet, red blood cell transfusion, and/or granulocyte colony-stimulating factor support within seven days before first study treatment dose): White blood cell (WBC) count \> 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x 109/L, and hemoglobin (Hb) ≥ 9.0 g/dL. 2. Hepatic: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times the upper limit of normal (x ULN) (≤ 3 x ULN in patients with known history of Gilbert's disease); alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5 × ULN in patients with liver and/or bone metastases); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 x ULN (≤ 3 x ULN in patients with liver metastases). 3. Renal: Creatinine clearance ≥ 50 mL/min as determined by Cockcroft Gault (using actual body weight). 4. Coagulation: International normalized ratio or prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN. 13. Resolution of all acute toxic effects of prior anticancer therapy to grade ≤ 1 as determined by the NCI-CTCAE v.5.0 criteria (except for alopecia or other toxicities not considered a safety risk for the patient at Investigator's discretion). 14. For women of childbearing potential who are sexually active with a non-sterilized male partner: must have a negative serum pregnancy test within 14 days before study treatment initiation. In addition, agreement to remain abstinent (refrain from heterosexual intercourse) or use one highly effective method of birth control or two effective contraceptive methods, as defined in the protocol from the time of screening until 7 months after the last dose of study treatments. Female patients must agree to refrain from egg cell donation and breastfeeding during this same period. 15. Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or use highly effective contraceptive methods, or two effective contraceptive methods, as defined in the protocol from the time of screening until 4 months after the last dose of T-DXd or 7 months after the last dose of PHESGO to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same period. Not engaging in heterosexual activity (sexual abstinence) for the duration of the study and drug washout period is an acceptable practice if this is the preferred usual lifestyle of the participant the last dose of study treatments. 16. Patient must be accessible for treatment and follow-up. Exclusion Criteria: An individual who meets ANY of the following criteria will be excluded from participation in this trial: 1. Current participation in another therapeutic clinical trial, except other translational studies. 2. Treatment with approved or investigational cancer therapy within 14 days prior to initiation of study drugs. 3. Has previously been treated with T-DXd in the adjuvant or neoadjuvant setting. 4. Known active uncontrolled or symptomatic central nervous system (CNS) metastases and/or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Note: Patients with a history of CNS metastases are eligible if they have been previously treated with local therapy, are clinically stable, and off anticonvulsants and steroids for at least 14 days before the first dose of study treatment. 5. Concurrent malignancy or malignancy within 5 years of study enrollment with the exception of carcinoma in situ of the cervix, non-melanoma skin carcinoma, or stage I uterine cancer. For other cancers considered to have a low risk of recurrence, discussion with the Sponsor's Medical Monitor is required. 6. Known allergy or hypersensitivity reaction to any investigational medicinal products (IMPs) or their incorporated substances. 7. Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow within 4 weeks prior to start of study treatment. 8. Major surgical procedure or significant traumatic injury within 14 days before the first dose of study treatment or anticipation of need for major surgery within the course of the study treatment. 9. Has an active cardiac disease or a history of cardiac dysfunction or severe conduction abnormalities including, but not confined, to any of the following: 1. Unstable angina pectoris, documented myocardial infarction, or symptomatic cardiac heart failure (CHF) (New York Heart Association \[NYHA\] Class II-IV) within six months prior to study entry. 2. Poorly controlled hypertension (i.e., systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 100 mmHg). 3. Symptomatic pericarditis. 4. Left ventricular ejection fraction (LVEF) \< 55 % as determined by multigated acquisition (MUGA) scan or echocardiogram (ECHO). 5. History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, or ventricular tachycardia), which is symptomatic or requires treatment (NCI-CTCAE grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, asymptomatic sustained ventricular tachycardia, or higher-grade atrioventricular \[AV\]-block, such as second-degree AV-block Type 2 \[Mobitz 2\] or third-degree AV-block). Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers will be permitted to enroll. 6. QT Interval Corrected by Fridericia's formula (QTcF) prolongation to \> 470 ms (females) or \> 450 ms (males) based on average of the screening triplicate 12-lead ECG. 7. History of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause Torsades de Pointes. 8. Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives. 10. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within three months of the study enrolment, severe asthma, severe chronic obstructive pulmonary disease \[COPD\], restrictive lung disease, pleural effusion, post COVID-19 pulmonary fibrosis, etc.), and any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (e.g., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy. 11. Has a history of non-infectious interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. 12. Pregnant or lactating women or patients not willing to apply highly effective contraception as defined in the protocol. 13. Current known infection with hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antibody \[HBsAg\] test and a positive hepatitis B core antibody \[HBcAb\] test, accompanied by a negative HBV DNA test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 14. Has active primary immunodeficiency, known human immunodeficiency virus (HIV) infection. 15. Other active uncontrolled infection at the time of enrollment. 16. Receipt of live or attenuated vaccine within 30 days prior to the first dose of study treatment. 17. A history of uncontrolled seizures, CNS disorders or serious and/or unstable pre-existing psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to study drugs or interfering with subject safety. 18. Has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator's judgment contraindicate patient participation in the clinical study. 19. Known substance abuse or any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, contraindicate patient participation. 20. Inability or unwillingness to comply with study and follow-up procedures in the opinion of the Investigator.