Breast Cancer Clinical Trials

⁃ Signed surveillance phase ICF prior to participation in any Study-related activities.

⁃ Male or female participants aged 18 years or older.

⁃ Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

⁃ Histologically proven primary HR-positive according to the updated American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2020 guidelines and HER2-negative BC as per ASCO/CAP 2018 criteria based on local testing on the most recent analyzed biopsy.

⁃ Participants with high-risk early-stage BC according to at least one of the following criteria:

‣ If no previous neoadjuvant chemotherapy:

⁃ i. pN2-N3, or ii. pN1 (including micrometastasis - pN1mi) if:

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⁃ pT3/T4, or

⁃ pT2 and high genomic risk, and/or histological grade III, and/or Ki 67 ≥ 30%. b. If participants 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:

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⁃ cT3/T4, or

⁃ 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, participants 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 six months prior to enrolment on the same ET treatment with AI or tamoxifen (LHRH agonist is mandatory for male and premenopausal participants receiving AI or tamoxifen, except in cases of bilateral oophorectomy).

∙ Note: Premenopausal and male participants treated with tamoxifen alone are excluded.

∙ 7\. Prior treatment with cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) in the adjuvant setting 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 selective estrogen receptor degraders (SERDs) will be allowed.

∙ 9\. Availability and willingness to provide the most recently available (archival formalin-fixed paraffin-embedded \[FFPE\]) tumor tissue sample (either from diagnostic biopsy, primary surgery, or where available from a residual disease post-neoadjuvant therapy) at the time of Study inclusion.

∙ Note I: Participants 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.

∙ Note II: Participants with bilateral carcinoma of the breast may be included as long as at least one of the tumors meets the criteria established by the protocol and both are HR-positive and HER2-negative tumors.

∙ 10\. Successful ctDNA assay designability, defined as the ability to generate a personalized, tumor-informed ctDNA assay based on sequencing of tumor tissue and matched germline DNA, enabling longitudinal ctDNA assessment.

∙ 11\. 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.

∙ 12\. Participants 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).

∙ 13\. Participants must be able and willing to adhere to Study procedures.

∙ A. Inclusion criteria for direct-to-treatment-phase entry:

∙ Participants who have not participated in the molecular surveillance phase but have a positive ctDNA test (conducted under other circumstances) will be considered eligible to enter to the treatment phase directly if they fulfill all the inclusion criteria listed below:

⁃ Signed treatment phase ICF prior to participation in any Study-related activities.

⁃ Male or female participants aged 18 years or older.

⁃ Histologically proven primary HR-positive according to the updated ASCO/CAP 2020 guidelines and HER2-negative BC as per ASCO/CAP 2018 criteria based on local testing on the most recent analyzed biopsy.

⁃ Availability and willingness to provide the most recently available (archival FFPE) tumor tissue sample (either from diagnostic biopsy, primary surgery, or where available from a residual disease post-neoadjuvant therapy) at the time of Study inclusion.

∙ Note I: Participants 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.

∙ Note II: Participants with bilateral carcinoma of the breast may be included as long as at least one of the tumors meets the criteria established by the protocol and both are HR-positive and HER2-negative tumors.

∙ 5\. Successful ctDNA assay designability, defined as the ability to generate a personalized, tumor-informed ctDNA assay based on sequencing of tumor tissue and matched germline DNA, enabling longitudinal ctDNA assessment.

∙ 6\. Confirmation of ctDNA positivity by the Study test. Note: Only participants who are confirmed as ctDNA-positive by the SignateraTM Genome test will be eligible to enter the treatment phase. External ctDNA results may be used to identify potential candidates, but eligibility will be based solely on the ctDNA status determined by the SignateraTM Genome test.

∙ 7\. Participants 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).

∙ 8\. Fulfillment of all general treatment phase eligibility criteria listed below.

∙ 9\. No participation in another interventional clinical trial within 28 days prior to screening or concurrent participation in another interventional clinical trial.

∙ B. Inclusion criteria for all participants to treatment phase entry:

∙ Participants will be considered eligible to enter to the treatment phase if they fulfill all the eligibility criteria listed below:

∙ I. General inclusion criteria for all Study arms:

∙ 1\. Signed treatment phase ICF prior to participation in any Study treatment phase-related activities.

∙ 2\. ctDNA positivity with no evidence of locoregional or contralateral clinical or radiologic recurrence by standard assessments (breast staging scans, e.g.: mammogram, breast ultrasound, breast magnetic resonance imaging \[MRI\]).

∙ 3\. ECOG performance status 0 or 1. 4. 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. Participants must have received the same ET treatment with AI or tamoxifen during at least the last six months. A temporary discontinuation of \< 90 days during the surveillance phase is allowed.

∙ 5\. 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 premenopausal female participant.

∙ 6\. Prior treatment with CDK4/6i in the adjuvant setting will be allowed in the case of an interval of at least 12 months between the last CDK4/6i dose and Study inclusion in the trial.

∙ 7\. No prior treatment with SERDs will be allowed. 8. Female of reproductive potential and male participants with female partners of childbearing potential, must remain abstinent and truly abstain from sexual activity (refrains from heterosexual intercourse) or use locally recognized adequate methods of contraception (described as that with a failure rate \< 1%) for the duration of trial treatment. In addition, participants 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 participant is allocated in.

∙ During this period of time, female and male participants must as well refrain from donating eggs or sperm.

∙ Note: Female participants will be deemed not of childbearing potential if they are postmenopausal or have had irreversible sterilization. Well-defined premenopausal 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 postmenopausal range.

∙ 9\. 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 version 5.0 (NCI-CTCAE v.5.0) (except for alopecia, or other toxicities not considered a safety risk for the participant at investigator's discretion). Adverse events (AEs) of current ET treatment are not included.

∙ 10\. 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 seven 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 ≤ 1.5x the upper limit of normal (ULN) (≤ 3x ULN in the case of Gilbert's disease); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5x ULN; alkaline phosphatase (ALP) ≤ 2 × ULN.

• Renal: serum creatinine level ≤ 1.5x the ULN or an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m², as calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation (National Kidney Foundation \[NKF\], 2021).

∙ Note: eGFR should be determined using the recommended standardized 2021 CKD-EPI Creatine Equation (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.

∙ 11\. Participants who are able and willing to swallow, retain, and absorb oral medication.

∙ 12\. Participants must be able and willing to adhere to Study procedures.

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

⁃ Participants 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.

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

∙ 1\. Central confirmation of biomarker eligibility (detection of specified PIK3CA mutation(s) via Qiagen therascreen® PIK3CA RGQ PCR kit \[CE-IVD\]) in tumor tissue sample.

∙ 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.