Inclusion Criteria:
* Patients must meet all of the following criteria:
1. Signed informed consent form (ICF).
2. Female, aged ≥18 years at the time of signing the ICF.
3. Must meet one of the following definitions of postmenopausal status:
1. Age ≥60 years; OR
2. Age \<60 years with amenorrhea for ≥12 consecutive months in the absence of oral contraceptives, hormone replacement therapy, or gonadotropin-releasing hormone (GnRH) agonists/antagonists, and with follicle-stimulating hormone (FSH) and plasma estradiol levels in the postmenopausal range per local laboratory assessment; OR
3. Documented bilateral oophorectomy performed ≥14 days before Cycle 1 Day 1 (first treatment), with recovery to baseline status.
For premenopausal or perimenopausal women (i.e., those not meeting postmenopausal criteria), the following is also required:
4. Ongoing treatment with a luteinizing hormone-releasing hormone (LHRH) agonist (e.g., goserelin or leuprorelin) initiated at least 2 weeks before Cycle 1 Day 1 and continued throughout study treatment.
4. Histologically or cytologically confirmed adenocarcinoma of the breast that is locally advanced or metastatic and not amenable to curative surgery or radiotherapy.
5. Estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive tumor per ASCO/CAP guidelines, defined as ≥1% of tumor cells showing positive staining on the most recent tumor biopsy.
6. HER2-negative per ASCO/CAP guidelines, defined as: HER2 IHC score 0 or 1+, or IHC 2+ with negative ISH (FISH/CISH/SISH), or HER2/CEP17 ratio \<2.0 on the most recent biopsy, based on local laboratory assessment.
7. Biomarker eligibility: PIK3CA mutation status must be determined by PCR or NGS testing of blood or tumor tissue at a local or regional laboratory. Blood samples should represent metastatic disease and be collected after the most recent anticancer therapy; tumor tissue should preferably be from metastatic lesions.
8. Disease progression during or within 12 months after completion of adjuvant endocrine therapy (aromatase inhibitor or tamoxifen). If CDK4/6 inhibitor was used in neoadjuvant/adjuvant setting, time from completion of CDK4/6 inhibitor to progression must be \>12 months.
9. At least one measurable lesion per RECIST v1.1. Patients with only bone metastases are not eligible, even if lesions are measurable.
10. Women of childbearing potential must agree to abstinence or use effective non-hormonal contraception (failure rate \<1% per year) during treatment and for specified post-treatment periods (depending on study drug), and must not donate oocytes.
11. ECOG performance status 0-1.
12. Life expectancy \>6 months.
13. Adequate hematologic and organ function within 14 days prior to treatment initiation, including:
ANC ≥1500/μL Hemoglobin ≥9 g/dL Platelets ≥100,000/μL Fasting glucose \<126 mg/dL and HbA1c \<6.0% Total bilirubin ≤1.5×ULN (≤3×ULN for Gilbert syndrome) Albumin ≥2.5 g/dL AST/ALT ≤2.5×ULN (≤5×ULN with liver metastases) ALP ≤2.5×ULN (≤5×ULN with liver/bone metastases) Creatinine clearance ≥60 mL/min (Cockcroft-Gault) INR \<1.5×ULN and aPTT \<1.5×ULN (with specified exceptions for anticoagulation)
14. Ability and willingness to comply with study procedures as judged by the investigator.
Exclusion Criteria:
1. Metaplastic breast carcinoma.
2. Any history of leptomeningeal disease or carcinomatous meningitis.
3. Prior systemic therapy for metastatic breast cancer (mBC).
4. Prior treatment with fulvestrant or other selective estrogen receptor degraders (SERDs), except neoadjuvant use ≤6 months.
5. Prior exposure to PI3K, AKT, or mTOR inhibitors, or any drugs targeting the PI3K-AKT-mTOR pathway.
6. Requirement for cytotoxic chemotherapy at study entry (e.g., visceral crisis as per local guidelines).
7. Type 2 diabetes requiring ongoing systemic treatment at enrollment, or history of type 1 diabetes.
8. Inability or unwillingness to take oral medication or receive intramuscular injections.
9. Malabsorption syndrome or any condition affecting gastrointestinal absorption.
10. Untreated or active CNS metastases (progressive disease or requiring anticonvulsants or corticosteroids for symptom control).
11. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring drainage more frequently than every 2 weeks.
12. Severe infection requiring intravenous antibiotics within 7 days prior to enrollment.
13. Any concurrent ocular or intraocular disease requiring intervention during the study to prevent or treat potential vision loss.
14. Active inflammatory or infectious ocular disease, or history of autoimmune/idiopathic uveitis.
15. Requirement for daily supplemental oxygen therapy.
16. Symptomatic active pulmonary disease, including pneumonia.
17. Active inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), or current immunosuppressive treatment for such disease.
18. Any active intestinal inflammation, including diverticulitis.
19. Symptomatic hypercalcemia requiring ongoing bisphosphonate or denosmab therapy.
20. Clinically significant active liver disease, including severe hepatic impairment (Child-Pugh B/C), viral hepatitis, cirrhosis, or current alcohol abuse.
21. Known HIV infection.
22. Any severe, uncontrolled systemic disease (e.g., significant cardiopulmonary, metabolic, or infectious disease) that may affect study safety or interpretation.
23. Anticancer therapy within 2 weeks prior to first dose.
24. Investigational drug use within 4 weeks prior to first dose.
25. Prior irradiation of ≥25% of bone marrow, or prior stem cell/bone marrow transplantation.
26. Unresolved toxicities from prior therapy (except alopecia, hot flashes, or peripheral neuropathy ≤Grade 2).
27. Other malignancy within 5 years prior to screening, except low-risk cancers (e.g., treated cervical carcinoma in situ, non-melanoma skin cancer, or stage I uterine cancer).
28. Significant cardiovascular disease, including:
* Stroke or TIA within 6 months
* Myocardial infarction within 6 months
* NYHA class III-IV heart failure or clinically significant CHF
* Uncontrolled arrhythmias or ventricular arrhythmias requiring treatment
* Clinically significant coronary artery disease or unstable angina
* QTc prolongation (\>470 ms using Fridericia formula) or history of long/short QT syndrome, Brugada syndrome, or torsades de pointes
* Clinically significant ECG abnormalities (e.g., complete LBBB, high-grade AV block)
* Evidence of prior myocardial infarction on ECG
29. Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia).
30. Chronic use of ≥10 mg/day prednisone equivalent or other systemic corticosteroids/immunosuppressants.
31. Known hypersensitivity to inavolisib, ribociclib, or fulvestrant components.
32. Use of strong CYP3A4 inhibitors or inducers within 1 week or 5 half-lives (whichever is longer) prior to treatment initiation.
33. Pregnancy, breastfeeding, or planning pregnancy during study or within defined post-treatment periods (inavolisib 7 days, ribociclib 21 days, fulvestrant up to 2 years).
34. Major surgery or significant trauma within 28 days prior to Cycle 1 Day 1, or expected need for major surgery during the study.
35. Minor surgery within 7 days prior to first dose without adequate recovery (including proper wound healing).
