RecruitingInterventionalPhase 3

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

NCT ID: NCT06065748Sponsor: Hoffmann-La RocheLast updated: 2026-06-04

Summary

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.

Arms & interventions

DrugGiredestrant
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.
DrugFulvestrant
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.
DrugAbemaciclib
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.
DrugPalbociclib
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.
DrugRibociclib
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.
DrugLHRH Agonist
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.
Diagnostic TestFoundationOne Liquid CDx Assay (F1LCDx)
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 \[ESR1nmd\]).

Outcome measures

Primary

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.
Time frame: From randomization to first occurrence of progressive disease (PD) or death (up to 5 years)
PFS in the Full Analysis Set (FAS) Population
Time frame: From randomization to first occurrence of PD or death (up to 5 years)

Secondary

PFS in the ESR1 no-mutation-detected (ESR1nmd) Subgroup
Time frame: From randomization to first occurrence of PD or death (up to 5 years)
Overall Survival (OS)
Time frame: From randomization until death from any cause (up to 5 years)
Confirmed Objective Response Rate (cORR)
Time frame: From randomization until treatment discontinuation (up to 5 years)
Duration of Response (DOR)
Time frame: From the first occurrence of a documented objective response to PD or death (up to 5 years)
Clinical Benefit Rate (CBR)
Time frame: From randomization until treatment discontinuation (up to 5 years)
Time to Chemotherapy
Time frame: From randomization until the start of chemotherapy or death (up to 5 years)
Time to Confirmed Deterioration (TTCD) in Pain Severity
Time frame: From randomization until end of follow-up (up to 5 years)
TTCD in Pain Presence and Interference
Time frame: From randomization until end of follow-up (up to 5 years)
TTCD in Physical Functioning
Time frame: From randomization until end of follow-up (up to 5 years)
TTCD in Role Functioning
Time frame: From randomization until end of follow-up (up to 5 years)
TTCD in Global Health Status/Quality of Life
Time frame: From randomization until end of follow-up (up to 5 years)
Incidence and Severity of Adverse Events
Time frame: 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
Time frame: 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
Time frame: From Baseline until 28 days after the final dose of study treatment (up to 5 years)

Eligibility criteria

Sex: AllAge: 18 Years and olderHealthy volunteers: No

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 an archived tumor sample if a recent tumor sample is not available for testing) * Confirmed ESR1 mutation status (ESR1m versus ESR1nmd) in baseline circulating tumor DNA (ctDNA) through central laboratory testing * Resistance to prior adjuvant endocrine therapy (ET), which is defined as having relapsed with prior standard adjuvant ET, on-treatment after \>/=12 months or off-treatment within 12 months of completion. Prior use of adjuvant CDK4/6i is allowed (if relapse occurred \>/=12 months since completion). * No prior systemic anti-cancer therapy for advanced disease * Measurable disease as defined per RECIST v.1.1 or non-measurable (including bone-only) disease * Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1 * For pre/perimenopausal women and for men: willing to undergo and maintain treatment with approved LHRH agonist therapy (as per local guidelines) for the duration of study treatment 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

Study locations (61)

Southern Cancer Center

Daphne, Alabama, 36526

Recruiting

Sutter Auburn Faith Hospital

Auburn, California, 95602

Withdrawn

La Hematology Oncology Medical Group

Glendale, California, 91260

Recruiting

Marin Cancer Care Inc

Greenbrae, California, 94904

Recruiting

Kaiser Permanente - Harbor City

Harbor City, California, 90710

Recruiting

USC Norris Comprehensive Cancer Center

Los Angeles, California, 90033

Recruiting

USC Norris Cancer Center

Newport Beach, California, 92663

Recruiting

Sutter Medical Group, Roseville Clinic

Roseville, California, 95661

Withdrawn

Sutter Health Medical Center

Sacramento, California, 95816

Withdrawn

The Lundquist Institute for BioMedical Innovation at Harbor-UCLA Medical Cente

Torrance, California, 90502

Recruiting

Rocky Mountain Cancer Centers

Littleton, Colorado, 80120-4413

Recruiting

Georgetown University Medical Center

Washington D.C., District of Columbia, 20007

Recruiting

MedStar Washington Hosp Center

Washington D.C., District of Columbia, 20010

Recruiting

AdventHealth Altamonte

Altamonte Springs, Florida, 32701

Recruiting

Florida Cancer Specialists - Broadway

Fort Myers, Florida, 33901

Recruiting

Cancer Specialists of North Florida

Jacksonville, Florida, 32256

Recruiting

Florida Cancer Specialists - North;725 6th Ave South (St. Petersburg)

St. Petersburg, Florida, 33701-4553

Recruiting

Comprehensive Hematology Oncology

St. Petersburg, Florida, 33709

Recruiting

Florida Cancer Specialists - EAST - SCRI - PPDS

West Palm Beach, Florida, 33401-3406

Recruiting

Grady Health System

Atlanta, Georgia, 30303

Recruiting

Winship Cancer Institute of Emory University

Atlanta, Georgia, 30329

Recruiting

Advocate Lutheran General Hospital

Park Ridge, Illinois, 60068

Recruiting

Springfield Clinic

Springfield, Illinois, 62702

Recruiting

Mission Cancer + Blood - IMMC

Des Moines, Iowa, 50309

Recruiting

Baptist Health Lexington

Lexington, Kentucky, 40503

Recruiting

Baptist Health Hamburg

Lexington, Kentucky, 40509

Recruiting

Baptist Health Louisville

Louisville, Kentucky, 40207

Recruiting

New England Cancer Specialists

Scarborough, Maine, 04074

Recruiting

Maryland Oncology Hematology

Annapolis, Maryland, 21401

Recruiting

Frederick Health Hospital

Frederick, Maryland, 21702

Withdrawn

Dana Farber Cancer Institute

Boston, Massachusetts, 02215

Recruiting

Henry Ford Hospital

Detroit, Michigan, 48202

Recruiting

HCA Midwest Division

Kansas City, Missouri, 64132

Recruiting

Cancer Care Center of O'Fallon

O'Fallon, Missouri, 62269

Recruiting

Oncology Hematology West - Grand Island

Grand Island, Nebraska, 68803

Recruiting

Oncology Hematology West - Legacy

Omaha, Nebraska, 68130-2042

Recruiting

Astera Cancer Care East Brunswick

East Brunswick, New Jersey, 08816

Recruiting

Capital Health Regional Medical Center

Pennington, New Jersey, 08534

Withdrawn

Queens Hospital Cancer Center

Jamaica, New York, 11432

Recruiting

Duke Women Cancer Care

Raleigh, North Carolina, 27607

Recruiting

Oncology Hematology Care

Cincinnati, Ohio, 45242

Withdrawn

Asante Rogue Regional Medical Center

Medford, Oregon, 97504-8332

Recruiting

Alliance Cancer Specialists

Bensalem, Pennsylvania, 19020

Recruiting

Ann B. Barshinger Cancer Institute

Lancaster, Pennsylvania, 17604

Recruiting

Abramson Cancer Center; Univ of Pennsylvania; Clinical Research Unit

Philadelphia, Pennsylvania, 19106

Recruiting

WellSpan Oncology Research

York, Pennsylvania, 17403

Withdrawn

Brown University Health

Providence, Rhode Island, 02905

Recruiting

Medical University of South Carolina

Charleston, South Carolina, 29425

Recruiting

Avera Cancer Institute - Aberdeen

Aberdeen, South Dakota, 57401

Recruiting

Avera Cancer Institute

Sioux Falls, South Dakota, 57105

Recruiting

West Cancer Center

Germantown, Tennessee, 38138

Recruiting

SCRI Oncology Partners

Nashville, Tennessee, 37203

Recruiting

Texas Oncology Cancer Center

Austin, Texas, 78731

Recruiting

JPS Oncology & Infusion Center

Fort Worth, Texas, 76104

Recruiting

Texas Oncology - DFW

Irving, Texas, 75063

Recruiting

Virginia Cancer Specialists, PC

Fairfax, Virginia, 22031

Recruiting

Virginia Commonwealth University - Massey Cancer Center

Richmond, Virginia, 23219

Recruiting

Northwest Medical Specialties

Tacoma, Washington, 98405

Recruiting

West Virginia University Hospitals Inc

Morgantown, West Virginia, 26056

Recruiting

Aurora BayCare Medical Center

Green Bay, Wisconsin, 54311

Recruiting

Aurora St Lukes Medical Center

Milwaukee, Wisconsin, 53215

Recruiting