Patritumab Deruxtecan (U3-1402) in Unresectable Locally Advanced or Metastatic Breast Cancer

Inclusion Criteria: * Adults with histologically-confirmed HER2 negative, unresectable locally advanced or metastatic breast cancer that is hormone receptor positive (HR+) at the time of the first breast cancer diagnosis * Participants with a documented radiologic unresectable or metastatic progression * Participants may have received anthracyclines and taxanes as (neo) adjuvant treatment and must have received one line of chemotherapy for Advanced breast cancer (ABC), but not more than one line. Participants must have a clinically or radiologically documented evidence of tumor progression on or after cyclin dependent kinase 4/6 (CDK 4/ 6) inhibitor combined with endocrine therapy. Previous treatments with PI3K inhibitors, mTOR inhibitors, AKT-inhibitors and poly ADP ribose polymerase (PARP)-inhibitors are allowed * Participants must have a tumor site easily accessible to biopsy (with exception of bone metastasis) * Participants must have at least one radiologically measurable lesion (different from the biopsy site) * Participants must have an ECOG PS equals to 0 or 1 * Participants must have a life expectancy of 12 weeks or more * Participants must have adequate bone marrow reserve and organ function, based on local laboratory data within 14 days prior to Cycle 1, Day 1 * Female patients of reproductive/childbearing potential must have a negative pregnancy test at screening (serum test within 14 days or urine test within 72 hours of enrollment). A positive urine pregnancy test result must be confirmed by a serum test. Patients must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 7 months after the last dose of study drug. The following contraception methods are considered highly effective: 1. Hormonal or nonhormonal intrauterine device (IUD) 2. Progestogen-only subdermal contraceptive implant 3. Bilateral tubal occlusion 4. Vasectomized partner 5. Complete sexual abstinence defined as refraining from heterosexual intercourse during and upon completion of the study and for at least 7 months for females after the last dose of study drug. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception. Penile/external condoms for male partners must be used in addition to the female patient's hormonal contraception for the duration treatment intervention and until 7 months following the last dose of trial intervention. Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration. * A male participant capable of producing sperm is eligible to participate if he agrees to the following during the intervention period and for at least the time needed to eliminate each trial intervention. The length of time required to continue contraception after last dose for each trial intervention is 4 months. Avoid donating sperm. Note: Preservation of sperm should be considered prior to enrollment/randomization in this trial. Use a penile/external condom when having penile-vaginal intercourse with a nonparticipant of childbearing potential, PLUS partner use of an additional contraceptive method (see below), as a condom may break or leak: 1. Progestogen-only contraceptive implant 2. Hormonal or nonhormonal IUD 3. Bilateral tubal occlusion (includes tubal ligation) 4. Combined (estrogen- and progestogen-containing) hormonal contraception (oral, intravaginal, transdermal, injectable) 5. Progestogen-only hormonal contraception (oral, injectable) 6. Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action 7. Cervical cap, diaphragm, or sponge with spermicide Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the trial interventions are more stringent than the requirements above, the local label requirements are to be followed. Note: If the participant is azoospermic (vasectomized or secondary to medical cause, documented from the site personnel's review of the participant's medical records, medical examination, or medical history interview), no contraception is required. Male participants must not freeze or donate sperm starting at screening and throughout the study period, and for at least 4 months after the final study drug administration * Participant must understand, sign, and date the written ICF prior to any protocol-specific procedures performed. Participant should be able and willing to comply with study visits and procedure as per protocol * Participant must be affiliated to a social security system or beneficiary of the same Exclusion Criteria: * Breast cancer amenable for resection or radiation therapy with curative intent * Any history of interstitial lung disease (ILD), actual ILD, or a suspicion of an ILD * Clinically severe pulmonary compromise (based on investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to: 1. Any underlying pulmonary disorder 2. Any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement 3. OR prior pneumonectomy * The use of chronic systemic corticosteroids at a dose superior to 10 mg daily of prednisone or equivalent or any form of immunosuppressive therapy prior to Cycle 1 Day 1. Participants who require use of bronchodilators, inhaled steroids, or local steroid injections may be included in the study * Evidence of any leptomeningeal disease * Evidence of corneal disease * Any evidence of severe or uncontrolled systemic diseases including active bleeding diatheses, active infection, psychiatric illness/social situations, geographical factors, substance abuse, or other factors which in the investigator's opinion makes it undesirable for the participant to participate in the study or which would jeopardize compliance with the protocol * Evidence of clinically active spinal cord compression or brain metastases defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms * Exposure to prior systemic anticancer therapy (including investigational agents) within 4 weeks or 5 half-lives (whichever is shorter) before enrollment. * Inadequate washout period prior to Cycle 1 Day 1, defined as: 1. Whole brain radiation therapy \<14 days or stereotactic brain radiation therapy \<7 days. 2. Immune checkpoint inhibitor therapy \<21 days 3. Hormonal therapy \<21 days 4. Major surgery (excluding placement of vascular access) \<28 days. 5. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation \<28 days or palliative radiation therapy \<14 days. 6. Chloroquine or hydroxychloroquine ≤ 14 days 7. Live virus vaccination \<28 days. * Prior treatment with an anti-HER3 antibody and/or ADC containing an exatecan derivative that is a topoisomerase I inhibitor * Participants with a grade equals or greater than 2 unresolved toxicities from previous anticancer therapy (other than alopecia) * A history of severe hypersensitivity reactions to either the drug substances or inactive ingredients of U3-1402, or to other monoclonal antibodies * Any evidence of primary malignancy other than locally advanced or metastatic lung cancer within three years prior to Cycle 1 Day 1, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated * Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day : 1. Corrected QT interval higher than 470 ms for females and 450 ms for males according to Fridericia's formula (QTcF) and assessed based on triplicate ECGs, approximately 1 minute apart 2. Left ventricular ejection fraction (LVEF) less than 50% by either ECHO or cardiac MRI or multigated acquisition scan (MUGA) 3. Resting systolic blood pressure higher than 140 mmHg or diastolic blood pressure higher than 90 mmHg 4. Myocardial infarction within six months 5. Symptomatic congestive heart failure (NYHA Classes 2 to 4 within 28 days before treatment) 6. Uncontrolled angina pectoris within six months. 7. Cardiac arrhythmia requiring antiarrhythmic treatment * Evidence of active or uncontrolled hepatitis B virus infection (HBV) Participants are eligible: 1. If HBsAg positive with chronic HBV infection (lasting 6 months or longer) and meet conditions below: * HBV DNA viral load \<2000 IU/mL * Start or maintain antiviral treatment if clinically indicated as per the investigator. 2. Have normal transaminase values, or, if liver metastases are present, abnormal transaminases with a result of AST/ALT \<3 × ULN, which are not attributable to HBV infection - Evidence of active or uncontrolled hepatitis C virus infection (HCV). Participants are eligible if: 1. History of hepatitis C infection eligible if the HCV viral load is below the level of detection in the absence of antiviral therapy during the previous 4 weeks 2. Have normal transaminase values, or, if liver metastases are present, abnormal transaminases with a result of AST/ALT \< 3 × ULN, which are not attributable to HCV infection - Evidence of active or uncontrolled human immunodeficiency virus (HIV infection. Subjects must be tested for HIV viral load during the Screening Period if acceptable by local regulations or IRBs/IECs. Participants are eligible if: 1. CD4+ T-cell count ≥350 cells/mm3 at the time of screening 16 2. Virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) at the time of screening and for at least 12 weeks before screening 3. No AIDS-defining opportunistic infections or conditions within the past 12 months 4. On stable ART regimen, without changes in drugs or dose modification, for at least 4 weeks before trial entry (Day 1) and agree to continue ART throughout the trial. * Prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator's judgment, could affect the safety of the subject; alter the absorption, distribution, metabolism or excretion of the study drug; or confound the assessment of study results. * Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection. Subjects with localized fungal infections of skin or nails are eligible. * Female patient who is pregnant or breastfeeding or intends to become pregnant during the study. * Patient with any psychological, familial, sociological or geographical condition potentially hindering compliance with the study protocol procedures and follow-up schedule. * Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent * Participation in another clinical trial evaluating an experimental drug (except non-interventional research