A PoC Study to Evaluate Treatments' Efficacy by Monitoring MRD Using ctDNA in HR-positive/HER2-negative EBC Population

This is a multicenter, open-label, non-comparative, phase II, biomarker-driven adjuvant treatment Study. Men and pre- and postmenopausal women aged ≥ 18 years with early stage HR-positive/HER2-negative BC at high risk of relapse, but with no evidence of locoregional, contralateral, or distant disease, who have undergone surgery, have received radiotherapy if indicated as per local guidelines and are on adjuvant treatment with endocrine therapy (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 with aromatase inhibitors (AI) or tamoxifen (luteinizing hormone-releasing hormone \[LHRH\] agonist is mandatory for male and premenopausal participants receiving AI, as well as for premenopausal participants treated with tamoxifen, except in cases of bilateral oophorectomy). Note: Premenopausal and male participants treated with tamoxifen alone are excluded. After signing the ICF and confirmed eligibility, 976 participants will first enter the surveillance phase in which blood will be collected 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 end of surveillance phase, which is defined as ctDNA positive result, permanent discontinuation (or temporally discontinuation ≥ 90 days) of the adjuvant hormonal treatment, or the end of accrual of the treatment phase upon Steering Committee decision, whichever occurs first. Surveillance phase participants should be followed up in line with standard practice every six months (± two weeks) to assess for disease recurrence. Participants should continue to receive ET according to standard treatment (with tamoxifen or AI \[letrozole, anastrozole, exemestane\]); the use of LHRH agonist treatment is mandatory for male and premenopausal participants receiving either AI or tamoxifen , except in cases of bilateral oophorectomy. Changes in ET during the ctDNA surveillance period are generally not allowed, however, justified changes such as anastrozole and letrozole switch may be discussed with the Medical Monitor. Changes in LHRH agonist treatment may also be discussed with the Medical Monitor. Participants who permanently discontinue or temporally discontinued (≥ 90 days) standard ET during the surveillance phase are not eligible to enter the treatment phase of the Study. Following completion of surveillance phase, participants who were not allocated in any arm will continue to be followed up in line with standard practice outside of the trial, and the collection of samples for ctDNA analysis will be halted. Note: Participants who had not participated in the surveillance phase but have a positive ctDNA test (conducted under other circumstances) will be eligible for direct-to-treatment phase entry if they fulfill all the matching eligibility requirements. Therefore, these participants will not need to meet all the eligibility criteria for the surveillance phase. Upon confirmed eligibility, a total of 40 participants will be allocated to four treatment arms as follows: Arm A: Experimental Arm with the same standard ET that was prescribed during the surveillance phase for a period of 90 days, followed by change in treatment to giredestrant, giredestrant plus abemaciclib or giredestrant plus inavolisib, as determined by the investigator´s choice (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 premenopausal participants according to local prescribing information. The participant should be supplied with the previous LHRH agonist they were taking. Note II: During the length of the Study, additional treatment arms may be opened to stay up to date with the most recent advances in oncology, and to be able to provide the best treatment options to participants in this Study. Note III: For participants eligible to receive inavolisib with a creatinine clearance between 30 and \< 60 mL/min, as estimated by the 2021 CKD-EPI Creatinine Equation (NKF, 2021), the starting dose is 6 mg orally once daily (PO QD) on Days 1-28 of each 28-day cycle. After allocation, serial assessment of ctDNA will be continuously performed every three months during the first year and every six months thereafter until end of treatment (EoT) to correlate any ctDNA variations with response. These data will also be used to confirm feasibility of eventual arm extensions, with maximum two arms that could be expanded across the four experimental 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% participants and if after three additional months, a 90% ctDNA decrease/clearance is maintained in at least 20% participants. In this case, 10 additional participants will be enrolled in the selected experimental arm (being completed with a total of 20 participants). * If all experimental arms fulfill these criteria, the two arms with the highest proportion of participants with 90% ctDNA 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 further evaluate the data and may nominate the two arms with the strongest signal of ctDNA decrease for further expansion. If the strategy of ctDNA monitoring permits to identify participants at high risk of relapse and to assess whether treatment at molecular relapse can improve outcome, potentially new cohorts may be added. Note: In addition, a maximum of two arms could be expanded, depending on the number of participants with PIK3CAmut tumors included in arms B and C. In this case, up to 10 participants (maximum of five participants per arm) with these mutations may be added to the specific treatment arms in order to have a similarly balanced background in terms of PIK3CA mutational status (i.e., a comparable distribution of participants with PIK3CAmut and PIK3CAwt tumors across treatment arms) (as an extension), depending on the Steering Committee decision, and if specific criteria to extend those cohorts are fulfilled. The amended CSP will be resubmitted to the pertinent regulatory agencies for approval of every arm extension and/or new arm addition After treatment discontinuation (EoT), all participants will have a safety visit scheduled 28 days (± 7 days) after the last dose of Study treatment, in order to follow up toxicities and changes in concomitant medication. After the safety visit, all participants will enter a post treatment follow-up period during which survival status and subsequent anticancer therapy information will be collected every 3 months (± 7 days) until death, lost to follow-up, elective withdrawal from the Study, or the EoS, whichever occurs first. This information may be collected by telephone call. Participants who discontinue treatment without evidence of disease recurrence will be followed for tumor assessments (according to the planned schedule before treatment discontinuation) until documented recurrence, elective withdrawal from the Study, the start of new anti-cancer treatment, or Study completion or termination.