GB491 Combined With Fulvestrant for HR+ HER2- Locally Advanced or Metastatic Breast Cancer

Key Inclusion Criteria:

• Females or males of 18 years of age or older and less than 75 years of age at study screening
• Histologically or cytologically confirmed locally advanced or metastatic breast cancer that is not amenable to curative surgical resection or radiation therapy
• Patients have been diagnosed with ER-positive breast cancer in the local laboratory
• Patents have been diagnosed with HER2-negative breast cancer in the local laboratory
• Menopausal status is not limited (including Premenopausal/perimenopausal/postmenopausal state)
• Prior endocrine therapy and chemotherapy, the following are permitted:

• Prior endocrine adjuvant therapy: a) Radiologic evidence of progressive disease (PD) during or within 12 months following (neo)adjuvant therapy with an aromatase inhibitor (AI) or an anti-estrogen such as tamoxifen, and no subsequent endocrine therapy for locally advanced or metastatic breast cancer; b) Radiologic evidence of PD during or within 12 months following (neo)adjuvant therapy with an AI or an anti-estrogen such as tamoxifen, after receiving the first-line endocrine therapy for locally advanced or metastatic breast cancer, and who developed radiologically documented PD after receiving therapy for ≥ 6 months; c) Radiologically documented PD more than 12 months following the end of adjuvant therapy with AIs or anti-estrogens such as tamoxifen, followed by radiographic progression following first-line therapy with AIs or anti-estrogens for locally advanced or metastatic breast cancer; 2) Progression with radiographic evidence of disease following prior first-line endocrine therapy for locally advanced or metastatic breast cancer in subjects who have not received prior (neo) adjuvant therapy; 3) Prior chemotherapy: In addition to endocrine therapy, subjects are eligible if they received a maximum of 1 prior line of chemotherapy for locally advanced or metastatic breast cancer and discontinued treatment for at least 28 days prior to randomization; 7.According to RECIST V1.1, the patient has at least one measurable lesion that has not been irradiated by radiotherapy and can be evaluated by CT/MRI; If there is no measurable lesion, there must be at least one osteolytic bone lesion that can be evaluated by CT/MRI 8.ECOG performance status of 0 or 1 9.Adequate organ and marrow function.

Key Exclusion Criteria:

• Previous treatment with fulvestrant, everolimus or any other CDK4/6 inhibitors
• Patients with known hypersensitivity to any component of GB491 or Fulvestrant
• Known active, uncontrolled, or symptomatic central nervous system metastasis, carcinomatous meningitis, or clinically manifested leptomeningeal disease, cerebral edema, spinal compression or/and tumor progressive growth
• Visceral crisis
• Patients with skin lesion only and radiographically non-measurable at baseline
• Persistent toxicities (CTCAE Grade >2) caused by previous anticancer therapy, excluding alopecia
• Patients who have been on bisphosphonates and denosumab therapy at a stable dose for less than 7 days prior to randomization
• Patients who have received limited field radiotherapy in 2 weeks or extended field radiotherapy in 4 weeks before randomization or radiation with more than 30% of the bone marrow
• Patients use drugs or fruits containing strong inducers or inhibitors of CYP3A4/5, or drugs with narrow therapeutic window that are mainly metabolized by CYP3A4/5 in 14 days before randomization
• Patients with long-term systematic use of corticosteroids
• Any severe and/or uncontrollable medical conditions
• Patients with severely impaired lung function
• Known history of HIV infection or history of HIV seropositivity
• Patients have significant hepatic disease