• Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.

• Patients must be male or female (pre/peri or postmenopausal) ≥ 18 years of age.

• ECOG performance status of 0 or 1(see Appendix 1).

• Histologically or cytologically confirmed breast cancer with evidence of locally advanced disease, not amenable to resection or radiation therapy with curative intent or metastatic disease.

• HR+/HER2- BC by local testing, not amenable to surgical therapy will be enrolled in this study.

∙ HER2 negativity is defined as either of the following by local laboratory assessment: IHC 0, IHC 1+ or IHC2+/in situ hybridization (ISH) negative as per the most recent American Society of Clinical Oncology (ASCO)-College of American Pathologists Guideline (CAP) guideline. If a patient has had multiple HER2 results after metastatic disease, the most recent test result prior screening period will be used to confirm eligibility.

‣ ER and/or PR positivity are defined as \>1% of cells expressing HR via IHC analysis as per most recent ASCO-CAP guideline. If a patient has had multiple ER/PgR results after metastatic disease, the most recent test result prior screening period will be used to confirm eligibility.

• Disease refractory to CDK4/6 inhibitors, defined as recurrence during or within 12 months after the end of adjuvant treatment or progression during or within 6 months after the end of treatment for advanced/metastatic disease.

• No more than 1 prior systemic chemotherapy or antibody-drug conjugate (ADC) regimens for metastatic disease. Adjuvant or neoadjuvant therapy for early-stage disease will qualify as one of the required prior chemotherapy regimens if the development of unresectable, locally advanced, or metastatic disease occurred within a 12-month period of time of the therapy. Note: treatments for bone metastases (eg, bisphosphonates, denosumab, etc.), targeted therapies (eg, PARP inhibitors, CDK 4/6 inhibitors, immunotherapy etc.) and hormonal therapy are not considered as prior systemic chemotherapy treatments for advanced disease.

• Radiologic or objective evidence of disease progression on or after the last systemic therapy prior to starting study treatment

• Measurable or non-measurable disease but evaluable (identification of target and/or non-target lesions by RECIST Vs1.1).

⁃ Patients must have a site of disease amenable to safely perform a biopsy, as per Investigator's assessment, and be a candidate for tumor biopsy according to the treating institution's guidelines.

⁃ Possibility of performing a biopsy prior to the start of treatment and its repetition after 2 weeks (14-21 days) and at End of Treatment (EOT) on the same location. It will be provided formalin-fixed paraffin-embedded (FFPE) tumor block. The tumor tissue should be of good quality based on total and viable tumor content and must be evaluated centrally for quality prior to enrollment. Patients whose tumor tissue is not evaluable for central testing are not eligible. It is recommended to send the biopsy directly to the central lab after confirming the existence of a tumor, so as not to delay the inclusion, without the need to carry out IHC studies in the same sample.

∙ Acceptable samples include core needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, bone or mucosal lesions or biopsies from bone metastases. Lymph node biopsies are also permitted.

‣ Fine needle aspiration, brushing, cell pellet from pleural effusion and lavage samples are not acceptable.

⁃ Patients must have normal organ and bone marrow function measured within 35 days prior to administration of study treatment as defined below:

∙ Haemoglobin ≥ 9.0 g/dL \*

‣ Absolute neutrophil count (ANC) ≥ 1.5 x 109/L\*

‣ Platelet count ≥ 100 x 109/L\*

‣ Total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia).

‣ AST (SGOT) / ALT (SGPT) ≤ 2.5 x ULN unless liver metastases are present in which case, they must be ≤ 5x ULN

‣ Creatinine ≤ 1.5 x ULN or Creatinine clearance estimated of ≥30mL/min using the Cockcroft-Gault equation.

‣ Serum albumin \>3 g/dL

‣ International normalized ratio (INR) or prothrombin time (PT) and either partial thromboplastin or activated partial thromboplastin time (aPTT) ≤ 1.5 ×ULN \*Without transfusional or growth factor support within 1 week of study treatment initiation.

⁃ Patients must have a life expectancy ≥ 16 weeks.

⁃ Male patients and female patients of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception as described in Appendix 2.

⁃ Willing and able to comply with the requirements and restrictions in this protocol.