• Participant 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 participants 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).

⁃ Pre-menopausal / peri-menopausal women and men must be concurrently receiving a luteinizing hormone-releasing hormone (LHRH) agonist starting at least 3-4 weeks before the start of trial therapy and is planning to continue LHRH during the study.

• Participant 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, participants 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 participants 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 demonstrating unequivocal progression in the opinion of the treating investigator 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, the longest diameter must be ≥10 millimeters \[mm\] by computed tomography \[CT\] or magnetic resonance imaging \[MRI\]).

⁃ 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.

• Participants 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.

• Participants have experienced no more than one seizure within 4 weeks prior to starting trial therapy.

• Participants' prior therapy received in the metastatic setting includes:

‣ At least one endocrine therapy

⁃ Up to two chemotherapy regimens

⁃ Up to two lines of prior cyclin-dependent kinase (CDK) 4/6 inhibitor, not including abemaciclib

• Note 1: Toxicity from prior therapy must be resolved to NCI CTCAE version 5.0 Grade ≤1, with the exception of alopecia and peripheral sensory neuropathy (Grade ≤2).

• Note 2: Chemotherapy refers to not targeted cytotoxic agents (for example, alkylating agents, taxanes, nucleotide analogs, platinum-based drugs, vinca alkaloids, etc) and antibody drug conjugates (ADCs). Targeted therapies (for example, kinase inhibitors) are not considered chemotherapy for eligibility purposes. Not targeted cytotoxic agents administered for less than 1 cycle will not be counted as a prior chemotherapy regimen.

• Participant has documented intracranial and/or extracranial radiological progression or recurrence while on or after the most recent therapy.

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

⁃ Participant has a life expectancy ≥ 12 weeks.

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

• Absolute neutrophil count (ANC) ≥1.5 × 10\^9/liter (L)

∙ Platelets ≥100 × 10\^9/L

∙ Hemoglobin ≥9.0 grams (g)/deciliter (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; participants may receive appropriate supplementation or treatment prior to reassessment)

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

∙ 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 participant has liver metastases, ALT and AST ≤5.0 × ULN.

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

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