Randomized, Open, Controlled, Multicenter Phase III Clinical Study of Fluzoparib in Combination With Apatinib Versus Investigator-Selected Chemotherapy for HRD-Positive/HER2-negative Advanced Breast Cancer

This study develops a new therapeutic approach for HER2-negative advanced breast cancer patients without precise treatment targets. The trial aims at extending the combination target therapy involving PARP inhibitors and anti-angiogenesis from only BRCA mutation carriers to all patients with homologous recombination repair defects (HRD-positive). The phase III randomized clinical study will investigate the effectiveness of the combination therapy of PARP inhibitor "fludzoparib" and anti-angiogenic "apatinib" in treating HRD-positive/HER2-negative advanced breast cancers.

Breast cancer is the most prevalent malignant tumor in the world, and 30% of breast cancer patients will enter the advanced stage due to treatment failure. 80% of these patients have HER2-negative subtype breast cancer, which has not yet been found the similar target as HER2, with the median survival time of only 6-20 months. In the past, ovarian cancer patients faced the dilemma of poor survival due to the lack of precise targeted therapy. However, through a series of clinical studies, experts in the field of ovarian cancer have successfully expanded the indications of PARP inhibitor-based combination targeted therapy from the small population of BRCA mutation(20%) to the large population of HRD-positive (Homologous recombination deficiency) (50%), which has significantly prolonged the survival time of patients. Because causes other than BRCA mutations can also cause tumor cells to be "HRD" and thus sensitive to PARP inhibitors, so that HRD-positive patients are likely to benefit. The HRD-positive profile of nearly 50% of the patients could be a potential beneficiary of PARP inhibitor-based targeted therapy. The synergistic effect of PARP inhibitor and anti-angiogenic combination therapy has already been confirmed in preliminary cellular experiments and clinical studies related to ovarian cancer. Further cell-based experiments and preclinical studies have also confirmed the feasibility of the combination targeted therapy in the HRD-positive/HER2-negative subtype of breast cancer. Therefore, we intend to further validate the efficacy and safety of the PARP inhibitor fluazoparib in combination with the antiangiogenic abatinib in a Phase III, randomized, controlled clinical study, in order to provide HRD-positive/HER2-negative breast cancer patients with a better choice of precision targeted therapy.

Eligibility Criteria:
Inclusion Criteria:

1. Adult female patients (age 18-70 years) with metastatic breast cancer confirmed by pathology or imaging;
2. Pathological diagnosis of HER-2 was negative (definition: immunohistochemical results were 0、+ or ++ and in situ hybridization results were negative);
3. Patient tested positive for HRD (defined by: BRCA 1 / 2 mutation, or HRD score is ≥ 42);
4. HR+/HER2- patients were required to have received endocrine therapy during the metastatic phase;
5. ECOG physical status score ≤ 2 and expected survival of not less than 3 months;
6. According to RECIST 1.1, patients with at least one target lesion or simple bone metastasis can be evaluated;
7. Prior treatment-related toxicity should be reduced to NCI CTCAE (version 5.0) ≤ 1 degree (except for hair loss or other toxicity which is considered as no risk to patient's safety according to the investigator's judgment) 8）LVEF≥50%；
8. Sufficient functional reserve of bone marrow

   1. White blood cell count (WBC) ≥ 3.0 × 10 \^ 9 / L,
   2. Neutrophil count (ANC) ≥ 1.5 × 10 \^ 9 / L,
   3. Platelet count (PLT) ≥ 100 × 10 \^ 9 / L
9. Previous treatment-related toxicity should be relieved as NCI CTCAE (version 5.0) ≤ 1 degree, total bilirubin (TBIL) ≤ 1.5 × upper limit of normal value (ULN), alanine aminotransferase (ALT / AST) ≤ 2.5 × ULN (liver metastasis patients ≤ 5xuln), serum creatinine ≤ 1.5 × ULN or creatinine clearance rate (CCR) ≥ 60 ml / min;
10. Left ventricular ejection fraction (LVEF) ≥ 55%, QTcF(Fridericia correction) ≤ 470 ms.
11. Be able to understand the research process, volunteer to participate in the study, and sign informed consent.

Exclusion Criteria:

1. HR+/HER2- MBC patients with no prior endocrine therapy;
2. No treatment for metastatic breast cancer was received;
3. Patients who are known to be allergic to active or other components of the study drug.
4. They received radiotherapy, chemotherapy, endocrine therapy within 4 weeks before enrollment, or were participating in any clinical trials of intervention drugs;
5. Pregnant or lactating women, women of childbearing age who refused to take effective contraceptive measures during the study period.
6. Any other situation in which the researcher considers that the patient is not suitable for the study may interfere with the concomitant diseases or conditions involved in the study, or there are any serious medical barriers that may affect the safety of the subjects (e.g., uncontrollable heart disease, hypertension, active or uncontrollable infection, active hepatitis B virus infection)