A Study to Evaluate Efficacy and Safety of Giredestrant Compared With Fulvestrant (Plus a CDK4/6 Inhibitor), in Participants With ER-Positive, HER2-Negative Advanced Breast Cancer Resistant to Adjuvant Endocrine Therapy (pionERA Breast Cancer)

Study Overview
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Brief Summary
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This is a Phase III, randomized, open-label multicenter study that will evaluate the efficacy and safety of giredestrant compared with fulvestrant, both in combination with the investigator's choice of a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib), in participants with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer who have developed resistance to adjuvant endocrine therapy.

Official Title
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A Phase III Randomized, Open-Label Study Evaluating Efficacy and Safety of Giredestrant Compared With Fulvestrant, Both Combined With a CDK4/6 Inhibitor, in Patients With Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer With Resistance to Prior Adjuvant Endocrine Therapy

Conditions
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Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer

Intervention / Treatment
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* Drug: Giredestrant
* Drug: Fulvestrant
* Drug: Abemaciclib
* Drug: Palbociclib
* Drug: Ribociclib
* Drug: LHRH Agonist
* Diagnostic Test: FoundationOne Liquid CDx Assay (F1LCDx)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally advanced or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent Documented estrogen receptor-positive (ER+), HER2-negative (HER2-) tumor assessed locally on the most recent tumor biopsy (or archived tumor sample) Confirmed ESR1 mutation status (ESR1m vs. ESR1nmd) in baseline circulating tumor DNA (ctDNA) through central laboratory testing Resistance to prior adjuvant endocrine therapy (ET). Prior use of neo/adjuvant CDK4/6i is allowed. No prior systemic anti-cancer therapy for advanced disease Measurable disease as defined per RECIST v.1.1 or non-measurable bone-only disease Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1 For pre/perimenopausal women and for men: treatment with LHRH agonist therapy (as per local guidelines) for the duration of study treatment is required Exclusion Criteria: Prior systemic therapy (e.g., prior chemotherapy, immunotherapy, or biologic therapy) for locally advanced unresectable or metastatic breast cancer Prior treatment with another SERD (e.g., fulvestrant, oral SERDs) or novel ER-targeting agents Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term Active cardiac disease or history of cardiac dysfunction Clinically significant history of liver disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Giredestrant + Investigator's Choice of CDK4/6i<br>Participants in the experimental arm will receive giredestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib. | Drug: Giredestrant<br>* Giredestrant 30 milligrams (mg) orally (PO) once a day (QD) on Days 1-28 of each 28-day cycle until progressive disease (PD) or unacceptable toxicity.<br>* Other names: GDC-9545;Drug: Abemaciclib<br>* If chosen by the investigator as the CDK4/6i, participants will receive abemaciclib 150 mg PO twice per day (BID) on Days 1-28 of each 28-day cycle until PD or unacceptable toxicity.<br>Drug: Palbociclib<br>* If chosen by the investigator as the CDK4/6i, participants will receive palbociclib 125 mg PO QD on Days 1-21 of each 28-day cycle until PD or unacceptable toxicity.<br>Drug: Ribociclib<br>* If chosen by the investigator as the CDK4/6i, participants will receive ribociclib 600 mg PO QD on Days 1-21 of each 28-day cycle until PD or unacceptable toxicity.<br>Drug: LHRH Agonist<br>* Only pre/perimenopausal female participants and male participants will receive a luteinizing hormone-releasing hormone (LHRH) agonist locally approved for use in breast cancer on Day 1 of each 28-day treatment cycle.<br>Diagnostic Test: FoundationOne Liquid CDx Assay (F1LCDx)<br>* F1LCDx is a next-generation sequencing (NGS)-based in vitro diagnostic test that detects and analyses genomic alterations in circulating cell-free DNA (cfDNA) isolated from plasma derived from the anti-coagulated peripheral whole blood of cancer patients. It will be used to determine the eligibility of participants requiring confirmation of ESR1 mutation status (mutation detected [ESR1m] vs. no mutation detected [ESR1nmd]).<br>* Other names: F1LCDx;|
| Active Comparator: Fulvestrant + Investigator's Choice of CDK4/6i<br>Participants in the control arm will receive fulvestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib. | Drug: Fulvestrant<br>* Fulvestrant 500 mg intramuscularly (IM) on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle until PD or unacceptable toxicity.<br>Drug: Abemaciclib<br>* If chosen by the investigator as the CDK4/6i, participants will receive abemaciclib 150 mg PO twice per day (BID) on Days 1-28 of each 28-day cycle until PD or unacceptable toxicity.<br>Drug: Palbociclib<br>* If chosen by the investigator as the CDK4/6i, participants will receive palbociclib 125 mg PO QD on Days 1-21 of each 28-day cycle until PD or unacceptable toxicity.<br>Drug: Ribociclib<br>* If chosen by the investigator as the CDK4/6i, participants will receive ribociclib 600 mg PO QD on Days 1-21 of each 28-day cycle until PD or unacceptable toxicity.<br>Drug: LHRH Agonist<br>* Only pre/perimenopausal female participants and male participants will receive a luteinizing hormone-releasing hormone (LHRH) agonist locally approved for use in breast cancer on Day 1 of each 28-day treatment cycle.<br>Diagnostic Test: FoundationOne Liquid CDx Assay (F1LCDx)<br>* F1LCDx is a next-generation sequencing (NGS)-based in vitro diagnostic test that detects and analyses genomic alterations in circulating cell-free DNA (cfDNA) isolated from plasma derived from the anti-coagulated peripheral whole blood of cancer patients. It will be used to determine the eligibility of participants requiring confirmation of ESR1 mutation status (mutation detected [ESR1m] vs. no mutation detected [ESR1nmd]).<br>* Other names: F1LCDx;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) in the ESR1 mutation (ESR1m) Subgroup | PFS is defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), or death from any cause during the study. | From randomization to first occurrence of progressive disease (PD) or death (up to 5 years) | 
| PFS in the Full Analysis Set (FAS) Population |  | From randomization to first occurrence of PD or death (up to 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS in the ESR1 no-mutation-detected (ESR1nmd) Subgroup |  | From randomization to first occurrence of PD or death (up to 5 years) | 
| Overall Survival (OS) | OS is defined as the time from randomization to death from any cause. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups. | From randomization until death from any cause (up to 5 years) | 
| Confirmed Objective Response Rate (cORR) | The cORR is defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions at least 4 weeks apart, as determined by the investigator according to RECIST v1.1. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups. | From randomization until treatment discontinuation (up to 5 years) | 
| Duration of Response (DOR) | DOR is defined as the time from the first occurrence of a documented objective response to PD, as determined by the investigator according to RECIST v1.1, or death from any cause (whichever occurs first). It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups. | From the first occurrence of a documented objective response to PD or death (up to 5 years) | 
| Clinical Benefit Rate (CBR) | The CBR is defined as the percentage of participants with stable disease for at least (≥)24 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups. | From randomization until treatment discontinuation (up to 5 years) | 
| Time to Chemotherapy | Time to chemotherapy is defined as the time from randomization until the start date of the first chemotherapy or death from any cause (whichever occurs first). It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups. | From randomization until the start of chemotherapy or death (up to 5 years) | 
| Time to Confirmed Deterioration (TTCD) in Pain Severity | TTCD in pain severity is defined as the time from randomization to the first documentation of ≥2-point increase from baseline on the worst pain item score of the Brief Pain Inventory-Short Form (BPI-SF). It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups. | From randomization until end of follow-up (up to 5 years) | 
| TTCD in Pain Presence and Interference | TTCD in pain presence and interference is defined as the time from randomization to the first documentation of ≥10-point increase in pain score, as determined using the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) questionnaire. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups. | From randomization until end of follow-up (up to 5 years) | 
| TTCD in Physical Functioning | TTCD in physical functioning (PF) is defined as the time from randomization to the first documentation of ≥10-point decrease in PF score, as determined using the EORTC QLQ-C30 questionnaire. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups. | From randomization until end of follow-up (up to 5 years) | 
| TTCD in Role Functioning | TTCD in role functioning (RF) is defined as the time from randomization to the first documentation of ≥10-point decrease in RF score, as determined using the EORTC QLQ-C30 questionnaire. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups. | From randomization until end of follow-up (up to 5 years) | 
| TTCD in Global Health Status/Quality of Life | TTCD in in Global Health Status/Quality of Life (GHS/QoL) is defined as the time from randomization to the first documentation of ≥10-point decrease in GHS/QoL score, as determined using the EORTC QLQ-C30 questionnaire. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups. | From randomization until end of follow-up (up to 5 years) | 
| Incidence and Severity of Adverse Events | Incidence will be reported as the number of participants with at least one adverse event, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5 (NCI CTCAE v5.0). | From Baseline until 28 days after the final dose of study treatment (up to 5 years) | 
| Number of Participants with Vital Sign Abnormalities Over the Course of the Study | Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature. | From Baseline until 28 days after the final dose of study treatment (up to 5 years) | 
| Number of Participants with Clinical Laboratory Test Abnormalities for Hematology and Biochemistry Parameters Over the Course of the Study |  | From Baseline until 28 days after the final dose of study treatment (up to 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oral Selective Estrogen Receptor Degrader (SERD), CDK4/6 inhibitor (CDK4/6i), ESR1 mutation