Study Evaluating Abemaciclib + Aromatase Inhibitors in HR+, HER2- Advanced Breast Cancer Patients (HERMIONE-7)

Inclusion Criteria:

1. Female ≥ 18 years of age regardless of menopausal status, who have relapsed while on prior first-line therapy with HD-FUL
2. Patients with advanced (loco-regionally recurrent, or metastatic) breast cancer not amenable to curative therapy.
3. Patient has a histological and/or cytological confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory.
4. 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 is required by local laboratory testing.
5. WHO performance status of 0-2
6. Measurable disease (according to Response Evaluation Criteria in Solid Tumors \[RECIST\], version 1.1) or at least one lytic bone lesion
7. The patient is able to swallow oral medications.
8. The patient has adequate organ function
9. Patient has signed ICF (ICF) obtained before any trial-related activities Patients must be able to communicate with the investigator and comply with the requirements of the study procedures.

Exclusion Criteria:

1. Patient has a known hypersensitivity to any of the excipients of Abemaciclib or letrozole/anastrozole
2. Patient who received any CDK4/6 inhibitor
3. Patient who received \> 1 prior systemic hormonal therapy for advanced breast cancer; the only admitted previous therapy as 1st-line treatment is HD FUL. Note: Patients who received ≤ 28 days of letrozole or anastrozole for advanced disease prior to inclusion in this trial are eligible.
4. Patient who has not had resolution of all acute toxic effects of prior anti-cancer therapy to NCI CTCAE version 4.03 Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion)
5. Patient who has received extended-field radiotherapy ≤ 4 weeks or limited field radiotherapy for palliation ≤ 2 weeks prior to start of treatment, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the patient at the investigator's discretion).
6. Patients from whom ≥ 25% (Ellis RE 1961) of the bone marrow has been previously irradiated are also excluded.
7. Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of treated, basal or squamous cell carcinoma, non melanomatous skin cancer or curatively resected cervical cancer.
8. Patient with central nervous system (CNS) metastases unless they meet ALL of the following criteria:

   1. At least 4 weeks from prior therapy for CNS disease completion (including radiation and/or surgery) to starting the study treatment
   2. Clinically stable CNS lesions at the time of study treatment initiation and not receiving steroids and/or enzyme-inducing anti-epileptic medications for the management of brain metastases for at least 2 weeks
9. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection, or preexisting Crohn's disease or ulcerative colitis, or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea)
10. Patient has a known history of HIV infection (testing not mandatory)
11. The patient has serious preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (such as severe renal impairment, \[for example, estimated creatinine clearance \<30 mL/min\], interstitial lung disease, sever dyspnea at rest or requiring oxygen therapy
12. The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. Exception: patients with controlled atrial fibrillation for \>30 days prior to randomization are eligible. Any patient with a history of VTE (for example, DVT of the leg or arm and/or PE) will be excluded.