NEOadjuvant Abemaciclib and GIredestrant TriaL in Patients with ER-positive, HER2-negative Early Breast Cancer

Inclusion Criteria:

1. Female patients willing and able to give written informed consent;

2. Women≥18 years of age;

3. Postmenopausal women, as defined by at least one of the following criteria:

• ≥12 months of amenorrhea without an alternate medical cause plusfollicle-stimulating hormone (FSH) and plasma estradiol levels withinpostmenopausal range by local laboratory assessment, in the absence of oralcontraceptive pills, hormone replacement therapy, or gonadotropin-releasinghormone agonist or antagonist. However, in the absence of 12 months ofamenorrhea, a single FSH measurement is insufficient;

• Documented bilateral oophorectomy (≥ 14 days prior to first treatment on Day 1of Cycle 1 and recovery from surgery to baseline);

4. Patients with cT1c (≥1.0 cm)-cT4a-c BC at presentation; a-c primary tumor must be ≥ 1.0 cm in longest diameter by ultrasound;

5. Confirmed ER+ disease by local testing on primary disease specimen: tumor must be ER ≥ 10% defined by immunohistochemistry (IHC) according to American Society ofClinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines forhormone receptor testing;

6. Confirmed HER2- disease by local testing on primary disease specimen: tumor must beHER2- according to ASCO/CAP 2023 guidelines for HER2 testing;

7. Patients with multifocal or multicentric breast cancer with at least one tumorlesion ≥1.0 cm in the longest diameter by ultrasound (reference lesion) are alsoeligible if the two largest tumor lesions have been histologically confirmed in theclinical evaluation and meet pathologic criteria for ER positivity and HER2negativity.

8. No previous treatment of the disease by chemotherapy, hormone therapy, surgery orradiotherapy;

9. Patients considered appropriate for endocrine therapy according to physicianjudgment;

10. Ki67 score ≥10% analyzed locally and centrally confirmed. Ki67 will be analyzedlocally at the time of inclusion. Patients with basal Ki67≥20% will be assessedlocally and centrally confirmed retrospectively and patients with 10-19% will beassessed centrally before inclusion.

11. Patients with breast cancer eligible for primary surgery;

12. Eastern Cooperative Oncology Group (ECOG) performance status≤1;

13. Adequate bone marrow and coagulation and adequate organ function defined as follows:

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L;

• Platelets count ≥100x 109/L;

• Haemoglobin ≥9 g/dL (90 g/L);

• Serum creatinine≤1.5 x upper limit of normal (ULN) or estimated creatinineclearance≥60 ml/min as calculated using the standard method for theinstitution;

• Total serum bilirubin ≤1.5 x ULN (Patients with Gilbert's syndrome with a totalbilirubin ≤2.0 times ULN and direct bilirubin within normal limits could beincluded);

• AST and/or ALT ≤3 x ULN;

• Alkaline phosphatase ≤2.5 x ULN;

14. Patients able to swallow oral medications.

Exclusion Criteria:

1. Patients with bilateral invasive BC;

2. Patients with metastatic BC (local spread to axillary lymph nodes is permitted (cN1_cN2a);

3. Patients with inflammatory BC;

4. Non post-menopausal patients;

5. Patients having received previous systemic or local treatment for BC, in particularhistory of any prior treatment with aromatase inhibitors (AIs), tamoxifen, selectiveestrogen receptor down regulator, or cyclin-dependent kinase 4 and 6 inhibitors;

6. Participants who have active cardiac disease or history of cardiac dysfunction,including any of the following:

• History (within 2 years of screening) or presence of idiopathic bradycardia orresting heart rate < 50 beats per minute at screening

• History of angina pectoris or symptomatic coronary heart disease within 12months prior to randomization

• History of documented congestive heart failure (New York Heart AssociationClass III or IV) or cardiomyopathy

• QT interval corrected through use of Fridericia's formula >470 ms for women > 450 ms for men based on mean value of triplicate ECGs, history of long or shortQT syndrome, Brugada syndrome or known history of corrected QT intervalprolongation, or torsades de pointes

• Presence of an abnormal ECG that is clinically significant in theinvestigator's opinion, including complete left bundle branch block, second- orthird-degree heart block, or sick sinus syndrome o Participants withfirst-degree heart block may be considered for inclusion following consultationwith a cardiologist and determination that no additional cardiac risks arepresent.

• Participants with pacemakers to treat more severe heart blocks and otherarrhythmias are permitted.

• Patients with history of well-controlled atrial fibrillation are eligible.

• History (within 12 months) or presence of ventricular dysrhythmias or riskfactors for ventricular dysrhythmias, such as significant structural heartdisease (e.g., severe left ventricular systolic dysfunction, restrictivecardiomyopathy, hypertrophic cardiomyopathy, infiltrative cardiomyopathy,moderate-to-severe valve disease), or family history of long QT syndrome) oClinically significant electrolyte abnormalities (e.g., hypokalemia,hypomagnesemia, hypocalcemia) should be corrected prior to enrollment.

7. Patients with known clinically significant history of liver disease consistent withChild-Pugh Class B or C, including hepatitis;

8. Patients with history of invasive BC, ductal carcinoma in situ or lobular carcinomain situ and other malignancy within 5 years prior to screening;

9. Patients with documented history of haemorrhagic diathesis, coagulopathy, orthromboembolism;

10. Patients on concurrent treatment with exogenous reproductive hormone therapy (forexample, birth control pills, hormone replacement therapy, or megestrol acetate);

11. Patients with active systemic bacterial infection (requiring intravenous antibioticsat time of initiating study treatment), fungal infection, or detectable viralinfection (such as known human immunodeficiency virus positivity or with knownactive hepatitis B or C [for example, hepatitis B surface antigen positive];

12. Patients with serious and/or uncontrolled pre-existing medical condition(s) that, inthe judgment of the investigator, would preclude participation in this study, e.g.interstitial lung disease (ILD), severe dyspnoea at rest requiring oxygen therapy,severe renal impairment (i.e. estimated creatinine clearance <30 ml/min), history ofmajor surgical resection involving the stomach or small bowel, or preexistingCrohn's disease or ulcerative colitis or a preexisting chronic condition resultingin baseline Grade 2 or higher diarrhea);

13. Patients with known allergy or hypersensitivity to any of the study drugs or any oftheir excipients;

14. Patients with history of non-compliance to medical regimens;

15. Patients refusing to perform liquid and tissue biopsy;

16. Patients unwilling to or unable to comply with the protocol;

17. Patients having had major surgery within 14 days prior to screening;

18. Pregnant or lactating females prior to treatment;

19. Patients having received an experimental treatment in a clinical trial within thelast 30 days or 5 half-lives, whichever is longer, prior to initiation of studytreatment, or is currently enrolled in any other type of medical research (forexample: medical device) judged by the sponsor not to be scientifically or medicallycompatible with this study;

20. Patients should be excluded if they have a known history of testing positive forhuman immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).