This trial is a multicenter, open-label, non-comparative, phase II, biomarker-driven adjuvant treatment study involving the periodic collection and analysis of blood samples from patients with HR-positive/HER2-negative early-stage BC at higher risk of relapse, who have undergone surgery within the previous five years, with no evidence of locoregional, contralateral, or distant disease.

The study design is composed by an initial pre-screening phase, a molecular follow-up phase (ctDNA surveillance phase), and an interventional therapeutic phase (treatment phase).

After informed consent is obtained, a total of 976 eligible patients will enter a ctDNA surveillance in which primary tumor tissue and matched normal blood will be collected from each patient to obtain a patient-specific somatic mutations panel (tumor signature).

At the event of ctDNA positivity, patients will be screened to enter the treatment phase of the study. Upon confirmed eligibility, a total of 40 patients will be allocated in one of the following trial's arms adopting a sequential recruitment strategy:

Arm A: Control Arm (N=10) Arm B: Experimental Arm with giredestrant (N=10) Arm C: Experimental Arm with giredestrant + abemaciclib (N=10) Arm D: Experimental Arm with giredestrant + inavolisib (N=10)

If the strategy of ctDNA monitoring enables physicians to identify patients at high risk of relapse and assess whether treatment at molecular relapse can improve outcome, new cohorts may be added to the study.

This is a multicenter, open-label, non-comparative, phase II, biomarker-driven adjuvant treatment Study involving the periodic collection and analysis of blood samples from patients with HR-positive/HER2- negative early-stage BC at higher risk of relapse, who have undergone surgery, have received radiotherapy if indicated as per local guidelines, with no evidence of locoregional, contralateral, or distant disease. Patients must be on adjuvant treatment with ET for at least two years and no more than seven years at the time of Study enrolment with an additional three years of ET planned. At least 6 months prior to enrolment on the same ET treatment (AI or tamoxifen). LHRH is mandatory for men and premenopausal women receiving AI, as well as for premenopausal women treated with tamoxifen, except in cases of bilateral oophorectomy).

The trial design entails an initial pre-screening phase, a molecular follow-up phase (ctDNA surveillance phase), and an interventional therapeutic phase (treatment phase). After informed consent is obtained, 976 eligible patients will enter a ctDNA surveillance in which primary tumor tissue and matched normal blood will be collected from each patient to obtain a patient-specific somatic mutations panel (tumor signature).

Note: Additional patients may enter the ctDNA surveillance phase if needed, for example if additional arms are opened.

Then, blood will be collected, processed, and analyzed to detect the presence or absence of ctDNA at predefined time points for longitudinal surveillance. ctDNA analysis will occur every three months from Study inclusion during the first year and every six months thereafter until positive result or end of accrual. At the event of ctDNA positivity, patients will be screened to enter the treatment phase of the Study. Upon confirmed eligibility, a total of 40 patients will be allocated in one of the following trial's arms adopting a sequential recruitment strategy.

Arm A: Experimental Arm with standard treatment followed by change in treatment (N=10) Arm B: Experimental Arm with giredestrant (N=10) Arm C: Experimental Arm with giredestrant + abemaciclib (N=10) Arm D: Experimental Arm with giredestrant + inavolisib (N=10)

Note I: In addition to the treatments described on each of the treatment arms, LHRH agonist will be administered to male participants and pre-menopausal/perimenopausal participants according to local prescribing information. The patient should be supplied with the previous LHRH they were taking.

Note II: During the length of the study, additional treatment arms may open to stay up to date with the most recent advances in oncology, and to be able to provide the best treatment options to patients in this study. Because of that, the N of patients screened to enter the treatment phase may increase.

Note III: For patients eligible to receive inavolisib with a creatinine clearance between 30 and <60 mL/min, as estimated by the 2021 CKD-EPI creatinine equation (National Kidney Foundation, 2021), the starting dose is 6 mg orally once daily (PO QD) on Days 1-28 of each 28-day cycle.

In the meanwhile, serial assessment of ctDNA will be continuously performed every three months during the first year and every six months thereafter until EoS to correlate any ctDNA variations with response. Patients discontinuing the Study treatment period will enter a post-treatment follow-up period during which survival and new anti-cancer therapy information will be collected every three months (±14 days) from the last dose of Study treatment up to the EoS. Telephone contact is acceptable (in some countries medical information can only be shared directly in person with the patient).

Arm extensions

After initiation of Study treatments, data obtained from serial assessment of ctDNA will also be used to confirm feasibility of eventual arms extensions, with maximum two arms that could be expanded (10 additional patients will be enrolled in each of the selected arms). The expansion will be approved when the arm complies with the following criteria:

• If at three months, a 90% ctDNA decrease is observed in at least 30% patients and if after three additional months, a 90% ctDNA decrease is maintained in at least 20% patients In this case, 10 additional patients will be enrolled in the specific experimental arms that meet these requirements (N=20).
• If all three experimental arms fulfill the criteria, the two arms with the highest proportion of patients with the highest proportion of 90% decrease will be the ones expanded.
• If cohorts remain too similar (no clear "winners"), the decision will be taken by the Steering Committee based on the duration of the response and the safety and toxicity of each specific treatment.
• If none of the arms fulfill the specific expansion criteria, the Steering Committee will evaluate the data further and may nominate the two arms with the strongest signal of ctDNA decreases for further expansion. If the strategy of ctDNA monitoring enables physicians to identify patients at high risk of relapse and assess whether treatment at molecular relapse can improve outcome, new cohorts may be added to the study

Eligibility criteria for the surveillance phase:

Note: Patients who have not participated in the surveillance phase but have a positive ctDNA test (conducted under other circumstances) will be allowed to enter directly into the treatment phase after confirmation of ctDNA positivity by the study test. Therefore, these patients will not need to meet all the inclusion criteria for the surveillance phase but will need to meet all the inclusion criteria for the treatment phase.

Inclusion criteria for surveillance phase:

1. Signed informed consent form (ICF) prior to participation in any Studyrelated activities.
2. Male or female patients aged 18 years or older.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
4. Histologically proven primary HR-positive according to the updated American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) 2020 guidelines and HER2-negative BC as per ASCO/CAP 2018 criteria based on local testing on the most recent analyzed biopsy.
5. Patients with high-risk early-stage BC according to at least one of the following criteria: a. If there is no previous neoadjuvant chemotherapy: i. pN2-N3 or ii. pN1 (including micrometastasis - pN1mi) if:

1. pT3-T4, or 2. pT2 and high genomic risk and/or histological grade III and/or Ki 67≥30%. b. If patients have received previous neoadjuvant chemotherapy, they must have had residual invasive disease defined as at least one of the following: i. Residual invasive disease in lymph nodes (ypN+, including ypN1mi) ii. ypN0 with residual invasive disease in breast if:

1. cT3-4, or
2. cT2 and high genomic risk and / or histological grade III and / or Ki67≥30%. Note: Genomic risk using platforms such as Oncotype Dx, Prosigna or Mammaprint won't be assessed for the screening to participate in the Study. However, patients with the detailed scores assessed prior to Study inclusion, may be eligible.

6. On adjuvant treatment with ET for at least two years and no more than seven years at the time of Study enrolment with an additional three years of ET planned, and at least 6 months prior to enrolment on the same ET treatment with AI or tamoxifen (LHRH is mandatory for men and premenopausal women receiving AI, as well as for premenopausal women treated with tamoxifen, except in cases of bilateral oophorectomy.) Note: Pre-menopausal patients treated with tamoxifen alone are excluded.

7. Prior treatment with cyclin-dependent kinases 4/6 (CDK4/6) inhibitors will be allowed in the case of an interval of at least 12 months between the last dose and inclusion in the trial.

8. No prior treatment with SERDs will be allowed.

9. Willingness and ability to provide tissue from one archival tumor tissue sample (either from diagnostic biopsy, primary surgery, or where available from a residual disease post-neoadjuvant therapy).

Note: Patients with multifocal BC may be enrolled, if archival tissue samples from at least two tumors are available and after histopathological examination, all tumors meet pathologic criteria for HR-positive and HER2-negative BC.

10. Absence of metastatic disease by routine clinical assessment (computed tomography [CT] scan of the thorax and abdomen, and bone scan or positron emission tomography [PET] scan). confirmed no longer than three months prior to Study inclusion.

11. Patients must have had surgery for their primary BC with documented clear margins (as per local guidelines) and they must have received radiotherapy if indicated (as per local guidelines).

12. Patients must be able and willing to adhere to Study procedures.

Exclusion criteria for surveillance phase:

1. Patients with pathological complete response (pCR) after neoadjuvant treatment.

2. Any concurrent or planned treatment for the current diagnosis of BC other than adjuvant ET except for denosumab or zoledronic acid, which are allowed.

3. Diagnosis of an alternative cancer in the five years prior to primary BC diagnosis other than for non-melanoma carcinoma of the skin or cervical carcinoma in situ. Other stage I tumors will be discussed case by case prior to inclusion with the Medical Monitor of the Study.

4. Active or prior documented inflammatory bowel disease (i.e., Crohn's disease, ulcerative colitis, or a preexisting chronic condition resulting in baseline grade ≥1 diarrhea) that may significantly alter the absorption of oral drugs.

5. Active cardiac disease or history of cardiac dysfunction including any of the following:

   1. History (within two years from screening) or presence of idiopathic bradycardia or resting heart rate <50 beats per minute at screening.
   2. History of angina pectoris or symptomatic coronary heart disease within 12 months prior to Study entry.
   3. QT interval corrected through use of Fridericia's formula (QTcF) > 450 ms for women and > 470 ms for men by at least three electrocardiograms (ECGs) > 30 minutes apart.
   4. History or presence of an abnormal ECG that is clinically significant in the investigator's opinion,
   5. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy cardiomyopathy, infiltrative cardiomyopathy, moderate-to-severe valve disease), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of long QT syndrome within 12 months.

6. History of pneumonitis, interstitial lung disease (ILD), or pulmonary fibrosis.

7. Known history of Human Immunodeficiency Virus (HIV) infection (testing not required as part of Study screening).

8. Clinically significant liver disease consistent with Child-Pugh C, including active hepatitis (e.g., hepatitis B virus [HBV] or hepatitis C virus [HCV]), current alcohol abuse, cirrhosis, or positive test for viral hepatitis

9. Active bleeding diathesis venous thrombo-embolism, previous history of bleeding diathesis, or chronic anti-coagulation treatment, or any indications or history of Disseminated Intravascular Coagulation (DIC) or Deep vein thrombosis (DVT). Low molecular weight heparin (LMWH), low dose aspirin or clopidogrel are permitted.

10. Creatinine clearance < 30mL/min.

11. Participants with renal dysfunction who require dialysis.

12. Patient who has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator' opinion cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol.

13. Females who are known to be breastfeeding or pregnant as determined by a serum pregnancy test, Human chorionic gonadotropin (β-HCG), prior to the administration of any trial treatment (once during the treatment phase). Since β-HCG over expression can also be elevated in some tumor types, a positive result should be confirmed with a validated alternative test (e.g., ultrasound).

14. Female or male participants planning a pregnancy.

Eligibility criteria for the treatment phase:

Patients will be considered eligible to enter to the treatment phase and to be allocated to standard ET only followed by change in treatment after a 90-day period , giredestrant monotherapy, giredestrant plus abemaciclib, or giredestrant plus inavolisib if they fulfill all the inclusion and none of the exclusion criteria listed below.

Inclusion criteria for treatment phase:

1. Signed treatment ICF prior to Study inclusion.

2. Male or female patients aged 18 years or older.

3. ctDNA positivity with no evidence of clinical or radiologic recurrence by standard assessments (e.g.: breast ultrasound, staging scans, RMN).

4. ECOG performance status 0 or 1.

5. Patients must have received the same ET during at least the last 6 months. A temporary discontinuation of < 90 days during the surveillance phase is allowed.

6. Receiving LHRH agonist therapy alongside the same ET treatment for at least 90 days prior to initiation of one of the available Study treatments if male or pre-menopausal.

7. Prior treatment with cyclin-dependent kinases 4/6 (CDK4/6) inhibitors will be allowed in the case of an interval of at least 12 months between the last dose and inclusion in the trial.

8. No prior treatment with SERDs will be allowed.

9. Absence of metastatic disease by routine clinical assessment (computed tomography [CT] scan of the thorax and abdomen, and bone scan or positron emission tomography [PET] scan). confirmed no longer than three months prior to Study inclusion.

10. Patients must have had surgery for their primary BC with documented clear margins (as per local guidelines) ) and they must have received radiotherapy if indicated (as per local guidelines).

11. Willingness and ability to provide tissue from one archival tumor tissue sample (either from diagnostic biopsy, primary surgery, or where available from a residual disease post-neoadjuvant therapy).

12. Female of reproductive potential and male patients with female partners of childbearing potential, must remain abstinent and truly abstain from sexual activity (refrains from heterosexual intercourse) or use locallyrecognized adequate methods of contraception (described as that with a failure rate <1%) for the duration of trial treatment. In addition, patients must follow these guidelines for a certain period of time after the last dose of trial treatment, specified in the protocol depending on which treatment arm the patient is allocated in. During this indicated period of time, female and male patients must as well refrain from donating eggs or sperm.

    Note: Female patients will be deemed not of childbearing potential if they are post-menopausal or have had irreversible sterilization. Well-defined pre-menopausal status refers to women who have not reached the postmenopausal state because they are not permanently infertile due to prior bilateral oophorectomy, age ≥60 years or age <60 years with amenorrhea for ≥12 months and estradiol and follicle-stimulating hormone (FSH) levels in the post-menopausal range.

13. Resolution of all acute toxic effects of prior anti-cancer therapy to Grade ≤1 as determined by the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v) 5.0 (except for alopecia, or other toxicities not considered a safety risk for the patient at investigator's discretion). Adverse events (AEs) of current ET treatment are not included.

14. Adequate hematologic and organ function within 14 days before the first Study treatment on Day 1 of Cycle 1, defined by the following:

    • Hematological (without platelet, red blood cell (RBC) transfusion, and/or granulocyte colony-stimulating factor support within 7 days before first Study treatment dose): White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 9.0 g/dL (≥ 5.6 mmol/L).
    • Hepatic: Serum albumin ≥ 3 g/dL; Bilirubin ≤ 1.5 times the upper limit of normal (ULN) (≤ 3 x ULN in the case of Gilbert's disease); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN; alkaline phosphatase (ALP) ≤ 2 × ULN.
    • Renal: serum creatinine level ≤ 1.5 × the upper limit of normal (ULN) or an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m², as calculated using the 2021 CKD-EPI creatinine equation (National Kidney Foundation, 2021).

    Note: eGFR should be determined using the following standardized CKDEPI 2021 formula (without race adjustment): eGFR (mL/min/1.73 m²) = 142 × min(Scr/κ, 1)^α × max(Scr/κ, 1)^-1.200 × 0.9938^Age × 1.012 [if female]. Scr = serum creatinine in mg/dL, κ = 0.7 for females; 0.9 for male; α = - 0.241 for females; -0.302 for males; min(Scr/κ, 1) = the lesser of Scr/κ or 1; max(Scr/κ, 1) = the greater of Scr/κ or 1; Age = age in years; The multiplication factor 1.012 is applied only for females.

15. Participants who are able and willing to swallow, retain, and absorb oral medication.

16. Patients must be able and willing to adhere to Study procedures.

Additional inclusion criteria for Arm C (giredestrant + abemaciclib arm):

1. Patients with prior diagnosis of thrombosis might be included as long as they are under stable anti-coagulation regimen therapy 28 days prior to starting treatment with abemaciclib.

Additional inclusion criteria for Arm D (giredestrant + inavolisib arm):

1. Confirmation of biomarker eligibility (detection of specified mutation(s) of PIK3CA via specified test: Qiagen therascreen PIK3CA RGQ PCR PCR kit - CE-IVD). This determination will be done in tumor tissue.
2. No prior treatment with any phosphatidylinositol 3-kinase (PI3K), Akt, or mammalian target of rapamycin (mTOR) inhibitors, or any agent whose mechanism of action is to inhibit the PI3K/Akt/mTOR pathway.

Exclusion criteria for treatment phase:

1. Known hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances.
2. Undergoing any other simultaneous anti-cancer treatment since enrolling in the Study, other than hormonal therapy or a bisphosphonate (or denosumab).
3. Major surgery (defined as requiring general anesthesia) or significant traumatic injury within 28 days of start of Study drug, or patients who have not recovered from the side effects of any major surgery.
4. Treatment with strong Cytochrome P450 3A4 (CYP3A4) inhibitors or strong CYP3A4 inducers within 14 days or five drug-elimination halflives, whichever is longer, prior to initiation of one of the available Study treatments.
5. Patient has a history of non-compliance to medical regimen.

Additional exclusion criteria for Arm D (giredestrant + inavolisib arm):

1. Type 2 diabetes requiring ongoing systemic treatment at the time of Study entry; or any history of Type 1 diabetes.
2. Fasting glucose ≥126 mg/dL or ≥7.0 mmol/L and hemoglobin A1C (HbA1c) ≥ 6.0%.
3. Any concurrent ocular or intraocular condition excluding cataracts (e.g., diabetic retinopathy) that, in the opinion of the investigator, would require medical or surgical intervention during the Study period to prevent or treat vision loss that might result from that condition.
4. Active inflammatory (e.g., uveitis or vitritis) or severe infectious conditions (e.g., keratitis, scleritis, or endophtalmitis) in either eye or history of idiopathic or autoimmune-associated uveitis in either eye.
5. Inability to confirm biomarker eligibility based on valid results from either central testing of blood or local testing of blood or tumor tissue that documents one of the protocol-defined PIK3CA mutations.