• This study was an open, multicenter phase II clinical trial that enrolled 118 patients with HR+/HER2- with recurrent or progressive advanced breast cancer treated with CDK4/6 inhibitors;
• The study adopted the Simon phase 2 design, and all 20 eligible patients were treated with entinostat + fulvestrant; The study was terminated if no more than 2 patients achieved objective response and continued to enter Phase 2 if no more than 3 patients achieved objective response. In Phase 2, qualified patients were randomly assigned at a ratio of 1:1.5 to either the entestasta + fluvestrus group (Group 1) or the anlotinib + entestasta + fluvestrus group (Group 2), with 39 patients enrolled in group 1 and 59 patients enrolled in group 2; All patients were treated until the subjects' treatment would continue until the subjects experienced disease progression, intolerable toxicity, active withdrawal from treatment, or other conditions specified in the protocol, whichever occurred first.
• During the study period, efficacy evaluations will be conducted every 8 weeks in accordance with the Solid Tumor Efficacy Evaluation Criteria (RECIST) v1.1 until disease progression, the initiation of a new anti-tumor treatment by the subject, or the withdrawal of informed consent, whichever occurs first.
• Continuous safety evaluations will be conducted during the study treatment period. All subjects who have received at least one study treatment will be required to undergo end-of-treatment visits and safety follow-up visits within 7 days and 30±2 days after the last study treatment, respectively.
• The end of the study was defined as the occurrence of disease progression or the end of the study treatment in all subjects, or the early termination of the study for other reasons, whichever occurred first.

Inclusion Criteria:

1. Sign an informed consent form;

2. Female, aged 18 or above;

3. The patient's Eastern Tumor Collaboration Group (ECOG) physical status is 0-1;

4. The patient's expected survival time is ≥3 months;

5. Breast cancer patients diagnosed as HR-positive and HER-2 negative by tumor histopathological and molecular pathological typing (based on the most recent report); 1) Hormone receptor positive refers to estrogen receptor (ER) positive, progesterone receptor (PR) negative or positive (≥1% positive staining cells are considered receptor positive); 2) HER-2 negative means: the immunohistochemical result of the pathological specimen test is 0 or 1+; Or an immunohistochemical result of 2+ and a negative ISH or FISH test.

6. The subject has received at least one line of endocrine therapy as well as CDK 4/6 inhibitor therapy at an unresectable stage of locally advanced recurrence or metastasis; Or disease recurrence occurred during ET combined with CDK4/6 inhibitors as adjuvant therapy or within 12 months after the end of treatment.

7. The subject has not received chemotherapy or ADC therapy for metastatic disease

8. At least one measurable target lesion was evaluated by the investigator in accordance with RECIST 1.1

9. No known active brain metastases or leptomeningeal disease

10. The patient must have adequate organ function within 1 week (7 days) prior to the initiation of study administration, as defined below:

    • Hematology: Hemoglobin (HgB) ≥80 g/L, platelet count ≥100×109 /L, absolute neutrophil count ≥1.0×10 /L.

Note: Platelet transfusion is not allowed within 3 days before these laboratory tests, red blood cell transfusion is not allowed within 14 days, and hematopoietic growth factor (pegylated G-CSF, 14 days for erythropoietin) is not allowed within 7 days. No blood transfusion or use of auxiliary white blood cell, platelet increase drugs such as cytokines or erythropoietin drugs within 2 weeks prior to the screening test

• Renal function: Serum creatinine (Cre) ≤1.5× upper limit of normal (ULN), or glomerular filtration rate (eGFR) ≥60 mL/min/1.73m2. Urine protein <2+ or 24-hour urine protein quantification <1g

• Liver function: Total bilirubin ≤1.5×ULN; If Gilbert syndrome is present, total bilirubin ≤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. Echocardiography shows left ejection fraction (LVEF) ≥50% and QTc interval ≤480 ms.

  10. Female patients in the premenopausal or perimenopausal period who agree to use the concomitant luteinizing hormone-releasing hormone (LHRH) agonist can be enrolled. Those who meet any of the following criteria may be considered to have reached menopause, but those who do not meet the criteria for being considered premenopausal or perimenopausal:

• Having undergone bilateral oophorectomy in the past;

• Age ≥60 years;

• Age <60 years old, natural menopause ≥12 months, no chemotherapy, tamoxifen, torremifen or ovarian function castration during this period, blood follicle-stimulating hormone (FSH) and estradiol (E2) levels within postmenopausal range (judged in combination with the reference range of the research center); 11. Patients who are fertile must agree to use recognized effective methods of contraception (including condoms with inactivated sperm, vaginal separators, oral or injectable contraceptives, etc.) or abstain from sexual activity during their participation in the study and for 3 months after the cessation of study treatment.

Exclusion Criteria:

• Patients should not be enrolled if any of the following conditions occur:

  1. Symptomatic visceral metastases or other conditions, visceral crisis, or the investigator deems it inappropriate to use endocrine therapy;
  2. The patient has a past or present central nervous system metastases, or leptomeningeal disease, brain metastases;
  3. Previous use of selective estrogen receptor degraders (SERD, such as fulvestrant) or histone deacetylase (HDAC) inhibitors (such as entectamine, chidamide, etc.) or small molecule multi-target tyrosine kinase inhibitors (such as apatinib, anlotinib, etc.) or PAM pathway inhibitors (such as PI3K inhibitor Alpelisib, AKT inhibitor Capivasertib, MTOR inhibitor everolimus, etc.
  4. Known allergy to SERD, entinostat, or other drugs with a benzamide structure (such as typapride, remopilib, cloprapride, etc.), anlotinib;
  5. Pregnant or lactating women;
  6. Coexisting with other malignant tumors, unless radical treatment has been administered and there is no evidence of recurrence or metastasis;
  7. There is pericardial effusion requiring drainage, pleural effusion with obvious clinical symptoms or ascites;
  8. Other circumstances that the investigator deems unsuitable for inclusion.