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 within the previous five years, 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 four years at the time of study enrolment with an additional three years of ET planned. At least 12 months prior to enrolment on the same ET treatment (AI or tamoxifen). For pre-menopausal women and men LHRH is required.~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, 1,260 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: Control Arm (N=10) • Patients must continue the same standard ET, prescribed as per standard practice, used in the surveillance phase. Changes in ET are not allowed.~Arm B: Experimental Arm with giredestrant (N=10)~• Giredestrant: 30 mg will be administered PO QD on Days 1 to 28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/study discontinuation (whichever occurs first).~Arm C: Experimental Arm with giredestrant + abemaciclib (N=10)~Giredestrant: 30 mg will be administered PO QD on Days 1 to 28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/study discontinuation (whichever occurs first).~Abemaciclib 150 mg will be taken PO BID (two intakes for a total daily dose of 300 mg) during each 28-day cycle up to two years or until disease recurrence, unacceptable toxicity, or treatment/study discontinuation (whichever occurs first).~Arm D: Experimental Arm with giredestrant + inavolisib (N=10)~Giredestrant: 30 mg will be administered PO QD on Days 1 to 28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/study discontinuation (whichever occurs first).~Inavolisib: 9 mg will be administered PO QD on Days 1 to 28 of each 28-day cycle up to two years or until disease recurrence, unacceptable toxicity, or treatment/study discontinuation (whichever occurs first).~Note I: In addition to the treatments described on each of the treatment arms, LHRH agonist will be administered to male participants and premenopausal/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.~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.
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 of1,260 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.