Inclusion Criteria:
* Voluntarily participate in the clinical study and provide written informed consent (ICF).
* Aged 18 to 75 years (inclusive) at the time of signing the main ICF, of any sex.
* Histologically and/or cytologically confirmed locally advanced breast cancer (LABC) not amenable to curative surgery or metastatic breast cancer (mBC), with pathology confirming hormone receptor (HR)-positive and HER2-negative disease (based on the most recent test result); per the 2020 ASCO/CAP guidelines, HR-positive is defined as ER-positive and/or PR-positive with ≥1% of tumor cells showing positive staining, and HER2-negative is defined as IHC 0 or 1+, or IHC 2+ with negative ISH.
* Must provide a fresh or archived FFPE tumor tissue block or unstained slides for central laboratory confirmation of PIK3CA mutation status and site.
Postmenopausal women, as well as premenopausal/perimenopausal women, are eligible; male participants and premenopausal/perimenopausal women - - must receive ovarian suppression (e.g., continuous LHRH agonist such as goserelin or leuprorelin) during the study; postmenopausal status in women is defined per NCCN Breast Cancer Guidelines 2026 V2 as age ≥60 years, or age \<60 years with amenorrhea ≥12 months and postmenopausal FSH/estradiol levels (without prior chemotherapy/endocrine therapy/suppression) or chemotherapy-induced amenorrhea ≥12 months with postmenopausal FSH/estradiol, or on tamoxifen with postmenopausal FSH/estradiol, or prior bilateral oophorectomy.
* Prior at least one line of endocrine therapy (monotherapy or combination including AI or SERM) with failure: relapse/progression during (neo)adjuvant endocrine therapy or within 12 months after adjuvant completion counted as first-line, or progression on endocrine therapy in LABC/mBC setting; in LABC/mBC, prior systemic therapy must be endocrine ≤2 lines and chemotherapy ≤1 line; note at least 80% of participants must have received prior CDK4/6 inhibitor.
* At least one measurable lesion per RECIST v1.1, or at least one osteolytic or mixed osteolytic-osteosclerotic bone lesion; sclerotic/osteoblastic-only bone lesions without measurable disease are not eligible; previously locally treated lesions may be target lesions only if documented radiologic progression occurred.
* ECOG performance status 0-1.
* Expected survival ≥6 months.
* Adequate organ function before first dose (no blood products/cytokines/EPO within 14 days, no oral leukocyte boosters within 7 days): ANC \>1.5×10⁹/L, platelets \>100×10⁹/L, hemoglobin \>90 g/L, serum creatinine \<1.5×ULN or CrCl \>50 mL/min (Cockcroft-Gault) if ≥1.5×ULN, total bilirubin \<1.5×ULN, AST/ALT \<2.5×ULN (\<5×ULN with liver mets), APTT and INR \<1.5×ULN, FPG \<7.0 mmol/L, HbA1c \<6.5%.
* Females of childbearing potential must have negative serum pregnancy test within 7 days before first dose; all fertile participants (male and female) must agree to reliable contraception (abstinence, barrier, hormonal, IUD, sterilization, etc.) during treatment and 90 days after last dose.
* Assessed by investigator as suitable for fulvestrant treatment without contraindications.
Exclusion Criteria:
* Presence of PTEN loss or concurrent AKT1 E17K mutation. Prior use of fulvestrant, other selective estrogen receptor degraders (SERDs), or any PI3K/AKT/mTOR inhibitor.
Receipt of any anticancer therapy (including investigational anticancer drugs) within 4 weeks before first study drug administration, with the following exceptions:
1. Nitrosoureas or mitomycin C within 6 weeks before first dose (due to delayed toxicity);
2. Anticancer endocrine therapy, oral fluoropyrimidines, or small-molecule targeted drugs within 2 weeks or 5 half-lives (whichever is shorter) before first dose;
3. Anticancer traditional Chinese medicine/herbal formulations within 2 weeks before first dose;
4. Palliative local radiotherapy (e.g., thoracic spine or rib radiotherapy) within 2 weeks before first dose.
* Failure to recover from any prior anticancer-treatment-related adverse event or complication to baseline or ≤Grade 1, except toxicities judged by the investigator as having no safety risk (e.g., alopecia, hyperpigmentation, Grade 2 peripheral neuropathy, hypothyroidism stable on hormone replacement).
* Known active central nervous system (CNS) metastasis (note: previously treated brain metastases are allowed if radiologically stable \[no progression for ≥4 weeks on imaging performed during screening\], clinically stable, and no steroid requirement for ≥14 days before planned start; any leptomeningeal metastasis/carcinomatous meningitis is excluded).
* Major surgical procedure within 4 weeks before first dose (excluding biopsy, venous access, ureteral stent, etc.), significant trauma, or anticipated major surgery during the study; minor traumatic surgery (biopsy, endoscopy, drainage) within 7 days before first dose.
* History of another malignancy within 3 years before first dose (except cured basal cell or squamous cell skin cancer, superficial bladder cancer, cervical carcinoma in situ, ductal carcinoma in situ of breast, papillary thyroid carcinoma).
* Gastrointestinal disease affecting drug administration/absorption, including but not limited to bowel obstruction, dysphagia/inability to swallow tablets, refractory nausea/vomiting/diarrhea, chronic GI diseases (Crohn's disease, ulcerative colitis).
* Severe cardiovascular or cerebrovascular disease, including but not limited to:
a) Serious cardiac rhythm or conduction abnormality requiring intervention (e.g., ventricular/supraventricular arrhythmia, II-III degree AV block, QTcF ≥470 ms in males or ≥480 ms in females \[QTcF = QT/RR\^0.33; if abnormal at screening, repeat 3 times 2-5 min apart and take mean\]); b) Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other ≥Grade 3 cardio/cerebrovascular event within 6 months before first dose; c) NYHA functional class ≥II, congestive heart failure, or LVEF \<50%; d) Any factor increasing QTc prolongation or arrhythmic risk (e.g., heart failure, hypokalemia, congenital long QT syndrome, family history of long QT, known QT-prolonging concomitant drugs); e) Uncontrolled hypertension (SBP ≥160 mmHg and/or DBP ≥100 mmHg on regular antihypertensives), or history of hypertensive crisis/encephalopathy; f) Arteriovenous thrombosis, pulmonary embolism, or other severe thrombotic event within 6 months before first dose (port catheter or catheter-related thrombosis, superficial venous thrombosis not considered "severe").
* History of type 1 diabetes, type 2 diabetes, or gestational diabetes.
* History of moderate-to-severe pulmonary disease significantly affecting respiratory function or interfering with drug-related pulmonary toxicity assessment/management, including COPD, interstitial lung disease/pneumonitis, radiation pneumonitis, idiopathic pulmonary fibrosis, pulmonary embolism, severe asthma, severe obstructive/restrictive ventilatory defect, any autoimmune/connective tissue/inflammatory disease with pulmonary involvement (e.g., rheumatoid arthritis, Sjögren's, sarcoidosis), prior pneumonectomy; active pulmonary inflammation or interstitial lung disease on screening chest imaging; active tuberculosis or active TB infection within 1 year before first dose regardless of treatment.
* Systemic corticosteroid or immunosuppressant therapy within 14 days before first dose that cannot be discontinued, except: low-dose prednisone ≤10 mg/day (or equivalent), local/ocular/intra-articular/nasal/inhaled corticosteroids, short-term corticosteroids for prophylaxis/treatment (e.g., allergy prevention, edema control).
* Serious systemic active infection within 4 weeks before first dose, or unexplained fever ≥38.5°C with IV antimicrobial requirement within 2 weeks before first dose; prophylactic antibiotics (e.g., for urinary tract infection) allowed.
* Judged by investigator as unsuitable for endocrine anticancer therapy (e.g., inflammatory breast cancer, symptomatic visceral crisis threatening life in short term such as uncontrolled/recurrent pleural/pericardial/ascitic effusion requiring drainage).
* History of Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), or severe skin disease (≥Grade 3).
* HIV antibody positive; active hepatitis B (HBsAg positive and HBV DNA \>2000 IU/mL or \>10\^4 copies/mL); active hepatitis C (HCV antibody positive with detectable HCV RNA); co-infection of HBV and HCV (HBsAg positive and HCV antibody positive); active syphilis (if specific antibody positive and non-specific antibody \[RPR/TRUST\] positive with titer \<1:2 and clinically confirmed inactive, may be screened).
* Allergy or contraindication to any active or inactive component of study drugs (JYP0035 or fulvestrant) and LHRH agonist (only for those requiring LHRH agonist co-therapy).
* Pregnant (or planning pregnancy) or lactating females. History of immunodeficiency including congenital or acquired immunodeficiency, prior organ transplantation, or awaiting organ transplantation.
* In the investigator's judgment, other factors that may affect study results or force premature termination (e.g., alcoholism, drug abuse, other severe diseases including psychiatric or significant CNS abnormalities requiring concomitant treatment, markedly abnormal labs, uncontrolled metabolic disorder, uncontrolled diabetes/hyperglycemia, chronic kidney disease, familial/social factors impairing safety/compliance/data collection).
