Trastuzumab Deruxtecan Alone, in Combination with Anastrozole, or Followed by Chemotherapy for the Treatment of Early Stage HER2 Low, Hormone Receptor Positive Breast Cancer

Inclusion Criteria

• Previously untreated operable invasive carcinoma of the breast that meets the following criteria: * Tumor grade >= 2 (BRS >= 6/9) by local assessment * Disease that is determined by treating investigator to be appropriate for chemotherapy * Documentation of either clinical node positivity (> N1) or tumor size > 5.0 cm (based on examination and/or imaging). Size eligibility must be met by measuring breast primary tumor, not by lymph node size. OR * Patients with clinical anatomic stage IIA or IIB disease (by American Joint Committee on Cancer [AJCC] 8th Edition), must also fulfill one of the following criteria: ** Ki67 > 30% by local assessment ** Grade 3 by local assessment ** Standard of care Oncotype DX RS > 25 ** Standard of care MammaPrint high risk
• Bilateral invasive concurrent breast cancer (multifocal or multicentric) breast cancer is allowed provided that all biopsied lesions are HER2 1+ or 2+ by IHC (if 2+, not fluorescence in situ hybridization [FISH] amplified) and are HR positive per American Society of Clinical Oncology (ASCO) guidelines
• Participants with clinically involved lymph nodes should not have radiological evidence of distant metastatic disease per standard of care staging
• Women or men aged 18 and older, in the United States
• Tumor is HER2-low by IHC, defined as 1+ or 2+, confirmed by central testing (tissue must be sent to central lab for testing. Central lab results not required for enrollment, unless no local results available). If HER2 is 2+ by IHC, FISH must be performed (per standard of care) and the FISH result must be HER2 non-amplified per 2018 ASCO College of American Pathologists (CAP) guidelines
• Tumor is HR positive (HR+) per ASCO CAP guidelines with known estrogen and progesterone receptor status, locally tested * Estrogen receptor (ER) and/or progesterone receptor (PR) positive is considered HR+
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Normal cardiac function (left ventricular ejection fraction [LVEF] >= 50%) based on echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before enrollment
• Platelet count >= 100 000/mm^3 (Platelet transfusion is not allowed within 14 days prior to screening assessment) (within 14 days before enrollment)
• Hemoglobin >= 9.0 g/dL (red blood cell transfusion is not allowed within 14 days prior to screening assessment) (within 14 days before enrollment)
• Absolute neutrophil count (ANC) >=1500/mm^3 (G-CSF administration is not allowed within 1 week prior to screening assessment) (within 14 days before enrollment)
• Creatinine clearance >= 30 mL/min as calculated using the Cockcroft-Gault equation or serum creatinine =< 1.5 x upper limit of normal (ULN) (within 14 days before enrollment)
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) =< 3 x ULN (within 14 days before enrollment)
• Total bilirubin =< 1.5 x ULN (within 14 days of enrollment). Participants with Gilbert’s syndrome with a total bilirubin =< 2.0 times ULN and direct bilirubin within normal limits are permitted
• Serum albumin >= 2.5 g/dL (within 14 days before enrollment)
• International normalized ratio (INR)/prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (within 14 days before enrollment)
• Has adequate treatment washout period before initiation of study treatment, defined as: * Major surgery >= 4 weeks * Chloroquine/hydroxychloroquine > 14 days
• Negative pregnancy test (serum) for women of child bearing potential (CBP): * Women are considered of CBP unless: they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks prior to randomization. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment she is considered not of CBP
• Male and female participants of reproductive/childbearing potential 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 for females and 4 months for males after the last dose of study drug. Highly effective contraception methods include: * Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Double barrier method of contraception. The following are considered adequate barrier methods of contraception, must use 2: diaphragm, condom (by the partner), sponge, or spermicide/spermicidal jelly * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking trial treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Male partner sterilization (at least 6 months prior to randomization). For female patients on the trial the vasectomized male partner should be the sole partner for that patient. If vasectomy of the male partner is the highly effective method of contraception chosen, the success of the vasectomy should be medically confirmed according to local practice * Placement of an intrauterine device (IUD)
• Male participants must not freeze or donate sperm starting at screening and throughout the study period, and at least 4 months after the final study drug administration. Preservation of sperm should be considered prior to enrollment in this study
• Female participants 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

Exclusion Criteria

• Recurrent or metastatic breast cancer (stage IV disease)
• Prior excisional biopsy or sentinel lymph node biopsy for current breast cancer
• Inflammatory breast cancer
• Prior systemic therapy for currently diagnosed invasive cancer
• Prior ipsilateral chest wall radiation
• Major surgery < 4 weeks prior to enrollment
• Medical history of myocardial infarction (MI) within 6 months before enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV). Patients with troponin levels above ULN at screening (as defined by manufacturer), and without any MI related symptoms should have a cardiologic consultation before enrollment to rule out MI
• Unable to swallow oral medications
• Is pregnant or lactating, or planning to become pregnant during the course of this trial and up to 7 months (mos) after end of study
• Has a corrected QT (QTc) interval prolongation to > 470 ms (females) or > 450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram (ECG)
• Known hypercoagulable disorder requiring use of anticoagulant
• Significant gastrointestinal disorders limiting absorption or tolerance of oral medications
• History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
• History of another cancer confirmed by biopsy–diagnosed within 3 years of date of biopsy confirming current diagnosis, except: * Adequately resected non-melanoma skin cancer * Curatively treated non-breast in-situ disease * Prior history of ductal carcinoma in situ (DCIS) within 3 years is allowed as long as patient has not received an aromatase inhibitor and has not received ipsilateral breast/chest radiation. * Prior history of contralateral invasive breast cancer within 3 years is allowed as long as 1.) It was diagnosed by biopsy > 2 years prior to current diagnosis, 2.) Patient has not received prior systemic therapy (including aromatase inhibitor, CDK4/6 inhibitor (CDK4/6i), HER2-targeted therapy or chemotherapy), 3.) Patient has not experienced any recurrence and 4.) Patient has no evidence of recurrence (based on standard clinical evaluation). Note: Prior history of contralateral breast cancer more than 3 years ago is allowed as long as patient has not received any systemic therapy (chemotherapy, endocrine therapy, other targeted therapy) within 3 years of date of biopsy confirming current diagnosis. Prior history of ipsilateral breast cancer is not allowed. Note: Solid non-breast tumors curatively treated are allowed if > 3 years from diagnosis and no evidence of recurrence in that time. Prior chemotherapy for other malignancy > 3 years previous will need prior approval by medical monitor
• Other concurrent anti-cancer therapy. Note: ovarian function suppression drugs (goserelin, leuprolide, or triptorelin) and/or bone modifying agents (bisphosphonates, denosumab) do not count as anti-cancer therapy for this criteria. If taking bisphosphonates or denosumab, must have been on these agents prior to signing consent
• Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results
• Has known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA). Patients should be tested for HIV prior to enrollment if required by local regulations or institutional review board (IRB)/ethics committee (EC). * Patients with past or resolved hepatitis B virus (HBV) infection are eligible only if they meet all of the following criteria: ** Hepatitis B surface antigen HBsAg(-) (for > 6 months off anti-viral treatment) ** Anti-HBc(+) (IgG or total Ig) ** HBV deoxyribonucleic acid (DNA) undetectable ** Absence of cirrhosis or fibrosis on prior imaging or biopsy ** Absence of HCV co-infection or history of HCV co-infection ** Access to a local Hepatitis B expert during and after the study ** Such participants should be closely monitored for HBV reactivation
• Have personal history within the last 12 months of any of the following conditions: syncope of cardiovascular etiology, ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest
• Have received an autologous or allogeneic stem-cell transplant
• Has an uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals
• Concurrent treatment with ovarian hormonal replacement or hormonally-based contraceptive therapy (i.e. birth control pills). Prior treatment must be stopped at least 21 days prior to cycle 1 day 1
• Has history of severe hypersensitivity reactions to other monoclonal antibodies and/or to either the drug substances or inactive ingredients in the drug product
• Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study randomization, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion)
• Any autoimmune, connective tissue or inflammatory disorders (e.g., Rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the electronic case report form (eCRF) for patients who are included in the study
• Prior pneumonectomy
• Life expectancy < 3 months