Adj. Marker-adjusted Personalized Therapy Comparing ET+Ribociclib vs Chemotherapy in Intermediate Risk, HR+/HER2- EBC

Inclusion Criteria:

Patients eligible for inclusion in this study have to meet all of the following criteria:

A. Prior to REGISTRATION in the study:

1. Written informed consent prior to any screening procedures. 2. Female. 3. ≥ 18 yearsof age. 4a. EITHER: (Post)menopausal status at the time of initiation of (neo)adjuvant study medication

• patient underwent bilateral oophorectomy, or

• age ≥ 60, or

• age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy,tamoxifen, toremifene, or ovarian suppression) and/or FSH and estradiol in thepostmenopausal range per local normal range.

4b. OR: Pre-menopausal patients:

• confirmed negative serum pregnancy test (β-hCG) before starting study treatment, or

• patient has had a hysterectomy. 5. Histologically confirmed diagnosis of primaryestrogen-receptor positive and/or progesterone-receptor positive (> 1%) early breastcancer by local laboratory.

6. Patient has HER2-negative breast cancer defined as

• a negative in-situ hybridization test or an IHC status of 0, 1+, or 2+,

• if IHC is 2+, a negative in-situ hybridization (FISH, CISH, or SISH) test isrequired (based on the most recently analyzed tissue sample and all tested by alocal laboratory).

7. Local therapy of breast cancer (if adjuvant treatment or planned if neoadjuvanttreatment) according to current guidelines.

Note: This may include radiotherapy of breast cancer.

B. Prior to RANDOMIZATION in the study 8. No evidence of distant metastasis (confirmed prior to randomization by, preferentially, CT thorax / abdomen, X-ray chest, ultrasound liver, bone scan, or PET-CT).

9. Patient has available tumor tissue from diagnostic biopsy. 10. Patient is classifiedas intermediate risk according to the ADAPT intermediate-risk definition (i) (asfollows), or (only in case of missing Oncotype DX or Ki-67 response data), accordingto the clinical intermediate-risk definition (ii) (as follows).

(i). ADAPT intermediate-risk definition: Patient meets one of the following criteria:

• c/pN0, RS ≤ 25 with luminal-B-like (Ki-67 ≥20% or G3) or c/pT2-4 without endocrineresponse (post-endocrine Ki-67 > 10 %)

• c/pN1, RS ≤ 25 without endocrine response (post-endocrine Ki-67 > 10 %)

• c/pN0, RS > 25 with luminal-B-like (Ki-67 ≥20% or G3) or c/pT2-4 with endocrineresponse (Ki-67 ≤ 10 %)

• c/pN1, RS > 25 with endocrine response (Ki-67 ≤ 10 %)

• c/pN2-3, RS ≤ 25 with endocrine response (Ki-67 ≤ 10 %). Note: Postmenopausalpatients with pT1-2/pN0 disease and RS < 25, as well as premenopausal patients withpT1-2/pN0 disease and RS<16, are recommended to be treated by endocrine therapyalone and not to be randomized (at investigator´s discretion).

(ii). Clinical intermediate-risk definition (ascertained by investigator): Clinical intermediate risk may be ascertained by the investigator prior to randomization if at maximum two of the following three risk factors are present (according to primary diagnosis / 1st sample):

1. cT2-4

2. c/pN positive

3. G3 and / or Ki-67 ≥ 20% Note: Inclusion of a patient according to "clinicalintermediate risk" is permitted only in case of missing baseline Oncotype DX® orKi-67 decrease. In this case, investigators will follow a risk-based, step-wiseassessment process.

4. No contraindication for (neo)-adjuvant ET. 12. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 13. Patient has adequate bone marrow and organfunction as defined by the following laboratory values:

• absolute neutrophil count ≥ 1.5 × 109/L,

• platelets ≥ 100 × 109/L,

• hemoglobin ≥ 9.0 g/dL,

• estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by a Cockcroft-Gaultformula,

• INR ≤ 1.5,

• serum creatinine < 1.5 mg/dL,

• total bilirubin < ULN, except for patients with Gilbert's Syndrome who may only beincluded if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN,

• aspartate transaminase (AST) < 2.5 × ULN,

• alanine transaminase (ALT) < 2.5 × ULN. 14. 2-lead-ECG (CANKADO) with:

• QTcF interval at screening < 450 msec (using Fridericia's correction),

• mean resting heart rate 50-90 bpm (determined from the ECG). 15. Ability to swallowribociclib tablets or to administer other study medication, respectively.

16. Ability to communicate with the investigator and comply with study procedures.

17. Willing to remain during therapy at the clinical site, as required by theprotocol.

Exclusion Criteria:

Patients eligible for inclusion in this study must not meet any of the following criteria:

1. Patient with distant metastases of breast cancer beyond regional lymph nodes.

2. Patient has received prior (neo)-adjuvant treatment with chemotherapy, ET, or anyCDK4/6 inhibitor for breast cancer.

3. Patient has received tamoxifen, raloxifene, or aromatase inhibitors (AIs) forreduction in risk ("chemoprevention") of breast cancer and/or treatment forosteoporosis within last 2 years prior to screening.

4. Patient has received prior neoadjuvant/adjuvant treatment with anthracyclines atcumulative doses of 450 mg/m² or more for doxorubicin or 900 mg/m² or more forepirubicin.

5. Patient with a known hypersensitivity to any of the excipients of ribociclib, ET, orstandard-of-care chemotherapy.

6. Patient with inflammatory breast cancer at screening.

7. Patient is concurrently using other anti-cancer therapy.

8. Patient has had major surgery within 14 days prior to starting study drug or has notrecovered from major side effects.

9. Patient is currently receiving warfarin or other coumarin-derived anti-coagulant fortreatment, prophylaxis, or otherwise.

10. Patient has not recovered from clinical and laboratory acute toxicities related toprior anticancer therapies to NCI CTCAE version 5.0 Grade ≤ 1.

11. Patient has a concurrent malignancy, or malignancy within 5 years of randomization,or known history of invasive breast cancer.

12. Patient has impairment of gastrointestinal (GI) function or GI disease that maysignificantly alter the absorption of the study drugs (e.g., uncontrolled ulcerativediseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, orsmall-bowel resection).

13. Patient has a known history of HIV infection.

14. Patient has known active hepatitis-B-virus (HBV) or hepatitis-C-virus (HCV)infection.

15. Patient has any other concurrent severe and/or uncontrolled medical condition thatwould, in the investigator´s judgment, cause unacceptable safety risks,contraindicate patient participation in the clinical study, or compromise compliancewith the protocol (e.g., chronic pancreatitis, chronic active hepatitis, activeuntreated or uncontrolled fungal, bacterial, or viral infections, etc.).

16. Clinically significant, uncontrolled heart disease and/or cardiac repolarizationabnormality, including any of the following:

• history of myocardial infarction (MI), angina pectoris, symptomaticpericarditis, or coronary artery bypass graft (CABG) within 6 months prior tostudy entry,

• documented cardiomyopathy,

• left ventricular ejection fraction (LVEF) < 50 % as determined by multiplegated acquisition (MUGA) scan or echocardiogram (ECHO),

• long QT syndrome, family history of idiopathic sudden death, congenital long QTsyndrome, or any of the following:

• risk factors for Torsades de Pointe (TdP) including uncorrectedhypokalemia or hypomagnesemia, history of cardiac failure, or history ofclinically significant/ symptomatic bradycardia,

• concomitant medications with a known risk to prolong the QT intervaland/or known to cause Torsades de Pointe that cannot be discontinued orreplaced by safe alternative medication (e.g., within 5 half-lives or 7days prior to starting study drug),

• inability to determine the QTcF interval,

• clinically significant cardiac arrhythmias (e.g., ventriculartachycardia), complete left-bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II, and 3rd-degree AV block),

• systolic blood pressure (SBP) > 160 or < 90 mmHg.

17. Patient is currently receiving any of the following substances, which cannot bediscontinued 7 days prior to Cycle 1 Day 1:

• concomitant medications, herbal supplements, fruits (e.g. grapefruit,pomegranates, pomelos, star fruit, Seville oranges) and their juices that arestrong inducers or inhibitors of CYP3A4/5,

• medications that have a narrow therapeutic window and are predominantlymetabolized through CYP3A4/5.

18. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeksprior to starting study drug, or who have not fully recovered from side effects ofsuch treatment.

19. Participation in a prior investigational study within 30 days prior to enrollment orwithin five half-lives of the investigational product, whichever is longer.

20. Not able to understand and to comply with study instructions and requirements.

21. Pregnant or nursing (lactating) woman.

22. Woman of child-bearing potential defined as woman physiologically capable ofbecoming pregnant, unless she is using highly effective methods of contraceptionduring the study treatment and for 21 days after stopping the treatment:

• total abstinence (when this is in line with the preferred and usual lifestyleof the patient).

• female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy), total hysterectomy, or tubal ligation at least 6 weeks beforetaking study treatment.

• male partner sterilization (at least 6 months prior to study screening). Forfemale patients on the study, the vasectomized male partner should be the solepartner for that patient.

• placement of an intrauterine device (IUD).

23. Use of oral (estrogen and progesterone), transdermal, injected, or implantedhormonal methods of contraception as well as hormonal replacement therapy.