This study aims to evaluate the efficacy of Entinostat combined with Fulvestrant in HR+/HER2- advanced breast cancer patients with recurrence/progression after endocrine therapy (primary endpoint: progression-free survival [PFS]), and explore the correlation between peripheral blood mononuclear cell (PBMC) acetylation levels and treatment response to determine the baseline acetylation threshold .

Inclusion criteria：

1. Signed informed consent form.
2. Female participants aged ≥18 and ≤75 years. 3 .Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

4. Life expectancy ≥3 months. 5.Participants must have histopathologically and molecular pathologically diagnosised HR-positive and HER2-negative breast cancer (based on the most recent report),defined as presence of following criteria:

1. . Hormone receptor positivity is defined by the presence of estrogen receptors (ER), where a threshold of ≥10% positive staining cells is considered indicative of positivity. The status of progesterone receptors (PR) can be either negative or positive, with the same criterion of ≥10% positive staining cells applied to determine receptor positivity.
2. . HER-2 negativity indicates that the immunohistochemical assessment of the pathological specimen yields a result classified as 0 or 1+. Alternatively, a result classified as 2+ may also be deemed HER-2 negative if corroborated by negative findings from ISH or FISH testing.

6. Participants must have received endocrine +CDK4/6 inhibitor treatment and meet any of the following conditions, namely endocrine resistance:

a) Imaging progression occurs during adjuvant/neoadjuvant endocrine therapy; or b) Recurrence/metastasis within ≤12 months after the completion of adjuvant endocrine therapy; or c) Disease progression occurred after first-line endocrine therapy in the advanced stage (RECIST v1.1).

7.Prior chemotherapy history for the participants must meet:

1. For metastatic diseases, having received ≤1 line of chemotherapy (including antibody-drug conjugates) in the past;

2. The period from the end of the last chemotherapy administration to the randomization date is ≥4 weeks;

3. If disease progression occurs within ≤12 months after the end of neoadjuvant or adjuvant chemotherapy, this regimen is regarded as first-line chemotherapy in the metastasis stage.

   8.One week (7 days) before the start of the study administration, the participant must have adequate organ function, as defined below: Hematology: Hemoglobin (HgB) ≥80 g/L, platelet count ≥50×109 /L, absolute neutrophil count ≥1.0×109 /L.

   Note: Before these laboratory tests, platelet transfusion is not allowed within 3 days, red blood cell transfusion is not allowed within 14 days, and hematopoietic growth factor (pegylated G-CSF and erythropoietin within 14 days) is not allowed within 7 days.

   Renal function: Serum creatinine (Cre) ≤1.5× upper limit of normal (ULN), or glomerular filtration rate (eGFR) ≥60 mL/min/1.73m2.

   Liver function: Total bilirubin ≤1.5×ULN; If Gilbert syndrome is present, the total bilirubin is ≤3 mg/dL. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3×ULN; If there is liver metastasis, both ALT and AST should be ≤5×ULN. Alkaline phosphatase (ALP) ≤2.5×ULN; If there is bone metastasis, it should be ≤5×ULN.

   9.Left ventricular ejection fraction (LVEF) ≥50% by echocardiogram and QTc interval ≤480 ms.

   10.Female participants in the premenopausal or perimenopausal stages who consent to the use of concomitant luteinizing hormone-releasing hormone (LHRH) agonists are eligible for enrollment. Participants meeting any of the following criteria may be classified as having reached menopause; those not fulfilling these criteria will be considered to be in the premenopausal or perimenopausal period:

   1)- A history of bilateral oophorectomy; 2）- Age ≥ 60 years; 3）- Age < 60 years, with natural amenorrhea lasting ≥ 12 months, during which no chemotherapy, tamoxifen, torremifene, or ovarian castration was administered. Additionally, blood levels of follicle-stimulating hormone (FSH) and estradiol (E2) must fall within the postmenopausal range (as determined in conjunction with the reference range established by the research center); 11.Participants of childbearing potential must use effective contraception (e.g., spermicidal condoms, vaginal diaphragm, oral/injectable contraceptives) or practice abstinence during and for 3 months after treatment.

   Exclusion criteria：

   1. Presence of current or prior Central Nervous System (CNS) metastases or leptomeningeal disease (LMD).
   2. Prior treatment with Selective Estrogen Receptor Degraders (SERD, e.g., fulvestrant) or Histone Deacetylase (HDAC) inhibitors (e.g., entinostat, chidamide).
   3. Known to be allergic to SERD, entinostat or other drugs with a benzamide structure (such as tyapride, remopilib, cloprapride, etc.).
   4. Pregnant or lactating women.
   5. Combined with other malignant tumors, unless radical treatment has been carried out and there is no evidence of recurrence or metastasis;
   6. Clinically significant effusions requiring drainage (e.g., pericardial, pleural, or ascites with symptoms).
   7. Significant clinical gastrointestinal dysfunction that may affect oral medication intake, transport, or absorption(e.g., dysphagia, chronic diarrhea, intestinal obstruction).
   8. Severe infectious diseases, uncontrolled or severe cardiovascular diseases, or other abnormalities within 14 days before enrollment that the investigators considered might affect the safety and compliance of the subjects and were not suitable for participation in this clinical trial.
   9. Participants deemed by investigators as unsuitable for endocrine therapy.