• Patient must be capable to understand the purpose of the study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures.

• Female or male patients ≥ 18 years of age at the time of signing ICF.

• Unresectable locally recurrent or metastatic breast cancer documented by computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to resection with curative intent.

• Histologically confirmed TNBC or HR+/HER2- breast cancer as defined by the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines.

• Note: Patients must have known HR and HER2 status locally determined on the most recent analyzed biopsy or FFPE tumor block prior to study entry.

• All patients must have been previously treated with taxanes regardless of disease stage (adjuvant, neoadjuvant, or advanced), unless contraindicated for a given patient.

• Refractory to at least one, and no more than two, prior standard of care chemotherapy regimens for unresectable locally advanced or metastatic breast cancer. Earlier adjuvant or neoadjuvant therapy for more limited disease will be considered as one of the required prior regimens if the development of unresectable locally advanced or metastatic disease occurred within a 12-month period after completion of chemotherapy.

• HR+/HER2- breast cancer patients must be refractory to at least 1 prior anti-cancer hormonal treatment for advanced disease and must have resistance to CDK4/6 inhibitor defined as:

‣ Disease progression while on, or within 12 months after the end of this treatment in the (neo)adjuvant setting.

⁃ Disease progression to this treatment during advanced disease.

• For phase Ib: evaluable disease according to RECIST v.1.1; for phase II: measurable disease according to RECIST v.1.1.

• Patients with bone-only metastatic disease will be allowed to participate only if they have at least one measurable soft-tissue component ≥10 mm.

⁃ Patients with brain metastasis must have an MRI scan of the brain performed and have had stable CNS disease for at least 4 weeks before entry into the trial.

⁃ Note: low dose corticosteroids for the treatment of brain metastases are permitted provided the dose is stable for 4 weeks.

⁃ Able to provide the most recently available formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks or fresh tumor biopsy at baseline and after detection of disease progression.

⁃ Able to provide liquid biopsy at the established time points.

⁃ ECOG performance status of 0-1.

⁃ Patient must have adequate bone marrow, liver, and renal function.

⁃ Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v.5.0) (except for alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).

⁃ Women of childbearing potential who are sexually active with a non-sterilized male partner must have a negative serum pregnancy test within 14 days before study treatment initiation. In addition, they must agree to use one highly effective method of birth control from the time of screening until 7 months after the last dose of study treatments. Female patients must refrain from egg cell donation and breastfeeding during this same period.

⁃ Male patients who are sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception from the time of screening until 4 months after the last administration of the study drug. Male patients must not donate or bank sperm during the same time period.

⁃ Patient must be accessible for treatment and follow-up visits.