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

Inclusion Criteria:

• Previously untreated operable invasive carcinoma of the breast greater than 2.0 cm (cT2) in size based on physical exam or imaging. Patients with clinical nodenegative disease or clinical node (cN1/cN2) positive are allowed provided they aredeemed to have operable disease at study entry

• Participants with clinically involved lymph nodes should not have radiologicalevidence of distant disease per standard of care staging prior to patient informedconsent form (PICF) signature

• In the United States

• Tumor is HER2-low by immunohistochemistry (IHC), defined as 1+ or 2+, confirmed bycentral testing (central testing results not required for enrollment, unless nolocal results available). If HER2 is 2+ by IHC, fluorescence in situ hybridization (FISH) must be performed (per standard of care) and the FISH result must be HER2non-amplified per 2018 American Society of Clinical Oncology College of AmericanPathologists (ASCO CAP) guidelines

• Tumor is HR positive (HR+) per ASCO CAP guidelines with known estrogen andprogesterone receptor status, locally defined

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Normal cardiac function (left ventricular ejection fraction [LVEF] >= 50%) based onechocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days beforerandomization/enrollment

• Platelet count >= 100 000/mm^3 (Platelet transfusion is not allowed within 1 weekprior to screening assessment) (within 14 days before randomization/enrollment)

• Hemoglobin >= 9.0 g/dL (red blood cell transfusion is not allowed within 1 weekprior to screening assessment) (within 14 days before randomization/enrollment)

• Absolute neutrophil count (ANC) >=1500/mm^3 (Granulocyte colony-stimulating factor (G-CSF) administration is not allowed within 1 week prior to screening assessment) (within 14 days before randomization/enrollment)

• Creatinine clearance >= 30 mL/min as calculated using the Cockcroft-Gault equationor serum creatinine =< 1.5 x upper limit of normal (ULN) (within 14 days beforerandomization/enrollment)

• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) =< 3 x ULN (within 14 days before randomization/enrollment)

• Total bilirubin =< 1.5 x ULN (within 14 days of randomization/enrollment).Participants with Gilbert's syndrome with a total bilirubin =< 2.0 times ULN anddirect bilirubin within normal limits are permitted

• Serum albumin >= 2.5 g/dL (within 14 days before randomization/enrollment)

• International normalized ratio (INR)/prothrombin time (PT) and activated partialthromboplastin time (aPTT) =< 1.5 x ULN (within 14 days beforerandomization/enrollment)

• Has adequate treatment washout period before randomization/enrollment, 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. ageappropriate, history of vasomotor symptoms) or have had surgical bilateraloophorectomy (with or without hysterectomy), total hysterectomy, or tuballigation at least six weeks prior to randomization. In the case of oophorectomyalone, only when the reproductive status of the woman has been confirmed byfollow-up hormone level assessment she is considered not of CBP

• Male and female participants of reproductive/childbearing potential must agree touse a highly effective form of contraception or avoid intercourse during and uponcompletion of the study and for at least 7 months for females and 4 months for malesafter the last dose of study drug. Highly effective contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyleof the patient). Periodic abstinence (e.g. calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods ofcontraception

• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy), total hysterectomy or tubal ligation at least 6 weeks beforetaking trial treatment. In case of oophorectomy alone, only when thereproductive status of the woman has been confirmed by follow up hormone levelassessment

• Male partner sterilization (at least 6 months prior to randomization). Forfemale patients on the trial the vasectomized male partner should be the solepartner for that patient. If vasectomy of the male partner is the highlyeffective method of contraception chosen, the success of the vasectomy shouldbe medically confirmed according to local practice

• Placement of an intrauterine device (IUD)

• Male participants must not freeze or donate sperm starting at screening andthroughout the study period, and at least 4 months after the final study drugadministration. Preservation of sperm should be considered prior to enrollment inthis study

• Female participants must not donate, or retrieve for their own use, ova from thetime of screening and throughout the study treatment period, and for at least 7months after the final study drug administration

• Estradiol level must be in post-menopausal range per local lab interpretation priorto baseline biopsy

• Postmenopausal status is defined as:

• Patient underwent bilateral oophorectomy, or

• Age >= 60 years, or

• Age < 60 years and amenorrhea for 12 or more months (in the absence ofchemotherapy, tamoxifen, toremifene or ovarian suppression) andfollicle-stimulating hormone (FSH) and plasma estradiol are in thepostmenopausal ranges per local normal ranges

• Note: for women with therapy-induced amenorrhea, serial measurements of FSHand/or estradiol per local clinical guidelines are required for determinationof postmenopausal status. All women who do not meet the criteria forpostmenopausal status are considered premenopausal for the purpose of thistrial

• Pre- or peri-menopausal and amenable to being treated with ovarian functionsuppression drugs (goserelin, leuprolide, or triptorelin) per standard of care.Patients must have started treatment with ovarian function suppression at least 28days prior to first dose of study treatment

Exclusion Criteria:

• Recurrent or metastatic breast cancer

• Bilateral breast cancer (multifocal or multicentric breast cancer is allowedprovided that all biopsied lesions are HER2 1+ or 2+, not FISH amplified and are HRpositive per ASCO guidelines)

• Inflammatory breast cancer

• Prior systemic therapy for invasive cancer

• Prior tamoxifen for history of ductal breast carcinoma in situ (DCIS) allowed,but no prior aromatase inhibitor, no prior chemotherapy and no priorHER2-targeted therapy

• Prior ipsilateral chest wall radiation

• Major surgery < 4 weeks prior to enrollment

• Medical history of myocardial infarction within 6 months beforerandomization/enrollment, symptomatic congestive heart failure (CHF) (New York HeartAssociation Class II to IV), troponin levels consistent with myocardial infarctionas defined according to the manufacturer 28 days prior to randomization

• Unable to swallow oral medications

• Is pregnant or lactating, or planning to become pregnant

• Corrected QT interval prolongation to > 470 ms (females) or > 450 ms (males) basedon average of the screening triplicate 12-lead electrocardiogram

• Known hypercoaguable disorder requiring use of anticoagulant

• Significant gastrointestinal disorders limiting absorption or tolerance of oralmedications (for example, history of major surgical resection involving the stomachor small bowel, or preexisting Crohn's disease or ulcerative colitis or apreexisting chronic condition resulting in baseline grade 2 or higher diarrhea)

• History of (non-infectious) interstitial lung disease (ILD)/pneumonitis thatrequired steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitiscannot be ruled out by imaging at screening

• Has multiple primary malignancies within 3 years, except:

• Adequately resected non-melanoma skin cancer

• Curatively treated non breast in-situ disease, and other solid non-breasttumors curatively treated are allowed if > 3 years from diagnosis and noevidence of recurrence in that time

• Prior history of DCIS is allowed as long as patient has not received anaromatase inhibitor, has not received ipsilateral breast/chest radiation

• Prior history of contralateral invasive breast cancer (diagnosed by biopsy > 2years prior to current diagnosis) is allowed provided patient has not receivedprior aromatase inhibitor, CDK4/6 inhibitor (CDK4/6i), HER2-targeted therapy orchemotherapy and has not experienced any recurrence and has no evidence ofrecurrence (based on standard clinical evaluation)

• 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 tosigning consent

• Has substance abuse or any other medical conditions such as clinically significantcardiac or psychological conditions, that may, in the opinion of the investigator,interfere with the subject's participation in the clinical study or evaluation ofthe clinical study results

• Has known human immunodeficiency virus (HIV) infection, or active hepatitis B or Cinfection. Patients positive for hepatitis C (HCV) antibody are eligible only ifpolymerase chain reaction is negative for HCV ribonucleic acid (RNA). Subjectsshould be tested for HIV prior to randomization/enrollment if required by localregulations or Institutional Review Board (IRB)/ethics committee (EC)

• Have personal history within the last 12 months of any of the following conditions:syncope of cardiovascular etiology, ventricular tachycardia, ventricularfibrillation, or sudden cardiac arrest

• Have received an autologous or allogeneic stem-cell transplant

• Has active systemic bacterial infection (requiring intravenous [IV] antibiotics attime of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known activehepatitis B or C [for example, hepatitis B surface antigen positive]). Screening isnot required for enrollment

• Concurrent treatment with ovarian hormonal replacement therapy. Prior treatment mustbe stopped prior to first baseline biopsy

• Has history of severe hypersensitivity reactions to other monoclonal antibodiesand/or to either the drug substances or inactive ingredients in the drug product

• Clinically severe pulmonary compromise resulting from intercurrent pulmonaryillnesses including, but not limited to, any underlying pulmonary disorder (i.e.pulmonary emboli within three months of the study enrollment, severe asthma, severechronic obstructive pulmonary disease [COPD], restrictive lung disease, pleuraleffusion etc.), and any autoimmune, connective tissue or inflammatory disorders withpulmonary involvement (i.e. rheumatoid arthritis, Sjogren's, sarcoidosis etc.), orprior pneumonectomy

• Life expectancy < 3 months