Adjuvant Therapy With Abemaciclib + SOC ET vs. SOC ET in Clinical or Genomic High Risk, HR+/HER2- EBC

Inclusion Criteria:

A. Prior to REGISTRATION

1. Written informed consent prior to any study procedures (outcomes of standard-of-careprocedures performed before signing of informed consent by the patient but withinallowed screening period can be used for screening of patient). 2. Female. 3. ≥ 18years of age. 4a. EITHER: (Post)menopausal status at the time of initiation ofadjuvant 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, or ovarian suppression) and/or FSH and estradiol in the postmenopausalrange per local normal range.

4b. OR: Pre-/perimenopausal patients:

• confirmed negative serum or urine pregnancy test (β-hCG) before starting studytreatment, or

• patient has had a hysterectomy. 5. Histologically confirmed diagnosis(by locallaboratory ) of estrogen-receptor positive and/or progesterone-receptor positive (>1% ) primary early breast cancer or local relapse. In case the receptor statusfrom local pathology is unclear a central pathology review is obligatory. Resultsmust be known prior to randomization.

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 analyzed tissue sample at initial diagnosis by a locallaboratory).

7. Patients are eligible

• with completed (i.e., 5 years according to SoC), planned or ongoing adjuvantendocrine therapy, without any signs of distant relapse or secondary malignancy AND

• if primary diagnosis was 6 years or less before enrollment 8a. Intermediate to highclinical or genomic risk, defined as either one of the following criteria:

• c or p or ypN 2-3 with/without (neo)adjuvant chemotherapy;

• in patients with c/ypN0-1:

• non-pCR in patients with G3 or c/ypN1

• high biological risk defined as G3 with Ki-67 ≥40%

• or high genomic risk (RS>25 (known or Oncotype Dx® in screening phase) or anothertest)

• high CTS5 score or UICC stage IIb (clinical if neoadjuvant chemotherapy orpathological)

OR, if patients do not fulfill above criteria:

• patients ≤50 years old or pre-/perimenopausal and c or (y)pN1 disease (in particularif ET-non-response or no chemotherapy)

• patients >50 years old and postmenopausal and c or (y)pN1 with intermediate genomicrisk (RS≥18) or non-low risk by another test

ET non-response definition:

Ki-67 post-treatment > 10% (central or local pathology value) OR 8b. Patients after isolated locoregional relapse with high-risk patterns (e.g., rpT2-3 or rpN1-3 or G3 or Ki-67 pre-treatment ≥20%), once surgery with free margins was completed Note: Inclusion is only possible for the first locoregional relapse removed by surgery (free margins) OR 8c. Patients with any high clinical risk at Investigator´s assessment but not fulfilling above criteria: consultation with sponsor required

B. Prior to RANDOMIZATION in the study 9. Completed primary therapy of breast cancer according to current guidelines, i.e., after (neo)adjuvant treatment, definite surgery and radiotherapy, if applicable.

10. No clinical evidence of distant metastasis (confirmation recommended prior torandomization by either combination of or either one of the following examinations:CT thorax / abdomen, chest X-ray, liver ultrasound, bone scan, PET-CT). 11. Patienthas available tumor tissue from primary diagnostic biopsy. 12. No contraindicationfor adjuvant ET. 13. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 14. Patient has adequate bone marrow and organ function as defined by thefollowing laboratory values:

• absolute neutrophil count ≥ 1.5 × 109/L,

• platelets ≥ 100 × 109/L,

• hemoglobin ≥ 8.0 g/dL,

• total bilirubin ≤ 1.5 ULN, except for patients with Gilbert's Syndrome who may onlybe included if the total bilirubin is ≤ 2.0 × ULN or direct bilirubin within normalranges,

• aspartate transaminase (AST) ≤ 3 × ULN,

• alanine transaminase (ALT) ≤ 3 × ULN,

• serum creatinine ≤ 1.5 x ULN. 15. Ability to swallow abemaciclib tablets or toadminister other study medication, respectively.

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

17. Willing to receive therapy by clinical site, as required by the protocol.

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. Previously received CDK 4/6 inhibitor.

3. Patient with a known hypersensitivity to any of the excipients of abemaciclib orstandard-of-care endocrine therapy.

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

5. Patient has not recovered from clinical and laboratory acute toxicities related toprior anticancer therapies to NCI CTCAE version 5.0 Grade ≤ 1 (polyneuropathy ≤ 2 isallowed).

6. Patient has a concurrent malignancy or non-breast malignancy within 5 years prior torandomization.

7. 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).

8. Patient has any active systemic bacterial infection (requiring intravenousantibiotics at time of initiating study treatment), fungal infection, or detectableviral infection (such as known human immunodeficiency virus positivity or with knownactive hepatitis B or C [for example, hepatitis B surface antigen positive].Screening is not required for enrollment.

9. 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., interstitial lung disease, severe dyspnea at rest orrequiring oxygen therapy, severe renal impairment [e.g. estimated creatinineclearance <30ml/min], history of major surgical resection involving the stomach orsmall bowel, or preexisting Crohn's disease or ulcerative colitis or a preexistingchronic condition resulting in baseline Grade 2 or higher diarrhea, etc.).

10. Patient has a personal history of any of the following conditions: syncope ofcardiovascular etiology, ventricular arrhythmia of pathological origin (including,but not limited to, ventricular tachycardia and ventricular fibrillation), or suddencardiac arrest.

11. Patient is currently receiving any of the following substances, which cannot bediscontinued 7 days prior to day 1 of study treatment: o concomitant medications and herbal supplements, that are strong inducers orinhibitors of CYP3A4.

12. Participation in a prior investigational study within 30 days prior to enrollment.

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

14. Pregnant or nursing (lactating) woman.

15. 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:

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

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

18. 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.

19. placement of an intrauterine device (IUD).

20. use of condom + spermicide.

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