• Patient has the signed informed consent form before any study-related activities according to local guidelines.

• Women or men aged ≥18 years, at the time of informed consent signature.

‣ Female patients may be either postmenopausal or pre/perimenopausal. Postmenopausal status is defined by:

⁃ Age ≥60 years

• Age \<60 years and amenorrhea for 12 or more months without an alternative cause) and follicle stimulating hormone and estradiol in postmenopausal ranges per local reference ranges

• Documentation of prior bilateral oophorectomy, at least 1 month before first dose of trial therapy).

• Patient must have ER-positive, HER-2 negative tumor status as confirmed by local laboratory testing in the following manner:

‣ Documentation of ER positive tumor with ≥ 1% staining by immunohistochemistry (IHC) as defined in the 2010 or 2020 American Society for Clinical Oncology (ASCO) recommendations for ER testing, with or without progesterone receptor (PGR) positivity

⁃ HER-2 negative tumor with an IHC result of 0 or 1+ for cellular membrane protein expression or an in situ hybridization negative result as defined in the 2013 or 2018 ASCO recommendations for HER-2 testing

• In Phase 2, patients must have at least one active and measurable brain metastasis per RECIST version 1.1.

‣ Any of the following qualifies brain metastases as active:

⁃ Newly diagnosed brain metastasis in patients who never received prior central nervous system (CNS)-directed therapy.

• Newly diagnosed brain metastasis outside any area that was previously subjected to CNS-directed therapy.

• Brain metastases that are clearly progressing in an area that has previously been subjected to CNS-directed therapy.

⁃ For lesions, including brain metastases, to qualify as measurable, and possibly be selected as target lesions, per RECIST version 1.1 (Appendix C), the longest diameter must be ≥10 mm by CT or MRI).

⁃ In Phase 1b, the presence of brain metastases is allowed but not required for eligibility, in this case, at least 1 measurable lesion outside the brain is required.

• Patients receiving concomitant corticosteroids must be on a stable or decreasing dose for at least 7 days prior to baseline and not receiving doses higher than 4 mg of dexamethasone per day or equivalent.

• Any neurological symptoms of brain metastases must be stable for at least 2 weeks before starting trial therapy. Fluctuations of the previously known symptoms deemed to be due to clinical intercurrent processes (e.g., electrolytes alterations, fever) are admissible if fully resolved before the first dose of study drugs.

• Patient prior therapy received in the metastatic setting includes:

‣ At least one endocrine therapy

⁃ Up to two chemotherapy regimens

⁃ Up to two prior CDK 4/6 inhibitors, not including abemaciclib Note 1: Toxicity from prior therapy must be resolved to National Cancer Institute (NCI) CTCAE version 5.0 Grade ≤1, with the exception of alopecia and peripheral sensory neuropathy (Grade ≤2).

• Patient has documented intra- and/or extra-cranial radiological progression or recurrence while on or after the most recent therapy.

• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2

⁃ Patient has adequate bone marrow and organ function, as defined by the following laboratory values:

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

∙ Platelets ≥100 × 109/L

∙ Hemoglobin ≥9.0 g/dL

∙ Potassium, sodium, calcium (corrected for serum albumin) and magnesium CTCAE Grade ≤1 (if screening assessments are abnormal, these assessments may be repeated up to 2 times; subjects may receive appropriate supplementation or treatment prior to reassessment)

∙ Creatinine clearance (per Cockcroft-Gault formula) ≥50 mL/min

∙ Serum albumin ≥3.0 g/dL (≥30 g/L)

∙ Liver function tests:

• In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × upper limit of normal (ULN). If the patient has liver metastases, ALT and AST ≤5 × ULN.

∙ Total serum bilirubin \<1.5 × ULN except for patients with Gilbert's syndrome who may be included if the total serum bilirubin is ≤3.0 × ULN or direct bilirubin ≤ 1.5 × ULN

⁃ The patient is willing and able to adhere to the study visit schedule and other protocol requirements.