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)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer
• Intervention / Treatment: Drug: Giredestrant; Drug: Abemaciclib; Drug: Palbociclib; Drug: Ribociclib; Drug: LHRH Agonist; Diagnostic test: FoundationOne Liquid CDx Assay (F1LCDx); Drug: Fulvestrant

• Study Type: Interventional
• Enrollment (Estimated): 1050
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Reference Study ID Number: CO44657 https://forpatients.roche.com/; Phone Number: 888-662-6728 (U.S. Only); Email: global-roche-genentech-trials@gene.com

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1125ABD
    • Recruiting
    • Fundación CENIT para la Investigación en Neurociencias
  • Buenos aires, Argentina, C1417DTB
    • Recruiting
    • Inst. de Oncologia Angel H. Roffo ; Oncology Dept
  • Ciudad Autonoma Buenos Aires, Argentina, C1426AGE
    • Recruiting
    • Centro Oncologico Korben; Oncology
  • Cordoba, Argentina, X5000JHQ
    • Recruiting
    • Sanatorio Allende
  • La Rioja, Argentina, F5300COE
    • Recruiting
    • Centro Oncologico Riojano Integral (CORI)
  • Recoleta, Argentina, C1118AAT
    • Recruiting
    • Hospital Aleman
  • Rosario, Argentina, S2000KZE
    • Recruiting
    • Instituto de Oncología de Rosario
  • Rosario, Argentina, S2002KDS
    • Recruiting
    • Hospital Provincial del Centenario
  • Rosario, Argentina, S2000QGB
    • Recruiting
    • Sanatorio Parque S.A.
  • San Juan, Argentina, J5402BGA
    • Recruiting
    • Centro Oncológico de Excelencia
• Australia
  • New South Wales
    • Frenchs Forest, New South Wales, Australia, 2086
      • Recruiting
      • Northern Beaches Hospital
    • Kingswood, New South Wales, Australia, 2747
      • Recruiting
      • Nepean Hospital; Nepean Cancer Care Centre
    • North Sydney, New South Wales, Australia, 2060
      • Recruiting
      • Mater Hospital; Patricia Ritchie Centre for Cancer Care and Research
  • Queensland
    • Sippy Downs, Queensland, Australia, 4556
      • Recruiting
      • University of the Sunshine Coast
    • South Brisbane, Queensland, Australia, 4101
      • Recruiting
      • Mater Misericordiae Limited
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Recruiting
      • Cancer Research Sa
  • Victoria
    • Geelong, Victoria, Australia, 3220
      • Recruiting
      • Barwon Health
    • St Albans, Victoria, Australia, 3021
      • Recruiting
      • Sunshine Hospital
    • Warrnambool, Victoria, Australia, 3280
      • Recruiting
      • South West Healthcare
• Belgium
  • Bruxelles, Belgium, 1200
    • Recruiting
    • Cliniques Universitaires St-Luc
  • Gent, Belgium, 9000
    • Recruiting
    • UZ Gent
  • Leuven, Belgium, 3000
    • Recruiting
    • UZ Leuven Gasthuisberg
  • Liège, Belgium, 4000
    • Recruiting
    • CHU Sart-Tilman
  • Namur, Belgium, 5000
    • Recruiting
    • Clinique Ste-Elisabeth
  • Wilrijk, Belgium, 2610
    • Recruiting
    • Sint Augustinus Wilrijk
• Brazil
  • BA
    • Salvador, BA, Brazil, 40415-006
      • Recruiting
      • Obras Sociais Irma Dulce - Osid
  • CE
    • Fortaleza, CE, Brazil, 60336-232
      • Recruiting
      • Crio - Centro Regional Integrado de Oncologia
  • ES
    • Vitoria, ES, Brazil, 29055-450
      • Recruiting
      • CEDOES - Diagnóstico e Pesquisa
  • GO
    • Goiania, GO, Brazil, 74605-070
      • Recruiting
      • Hospital Araujo Jorge; Departamento de Ginecologia E Mama
  • PE
    • Recife, PE, Brazil, 50040-000
      • Recruiting
      • Hospital do Cancer de Pernambuco - HCP
  • RS
    • Ijui, RS, Brazil, 98700-000
      • Recruiting
      • Oncosite - Centro de Pesquisa Clínica em Oncologia Ltda
    • Porto Alegre, RS, Brazil, 90610-000
      • Recruiting
      • Hospital Sao Lucas - PUCRS
    • Porto Alegre, RS, Brazil, 90035-000
      • Recruiting
      • Hospital Moinhos de Vento
    • Porto Alegre, RS, Brazil, 90020-090
      • Recruiting
      • Santa Casa de Misericordia de Porto Alegre
  • SP
    • Barretos, SP, Brazil, 14784-400
      • Recruiting
      • Hospital de Cancer de Barretos
    • Sao Paulo, SP, Brazil, 01317-001
      • Recruiting
      • Clinica de Pesquisa e Centro de Estudos em Oncologia Ginecologica e Mamaria Ltda
    • Sao Paulo, SP, Brazil, 01308-050
      • Recruiting
      • Hospital Sirio-Libanes
    • Sao Paulo, SP, Brazil, 01509-010
      • Recruiting
      • Hospital A. C. Camargo; Oncologia
• Canada
  • Ontario
    • Barrie, Ontario, Canada, L4M 6M2
      • Recruiting
      • Royal Victoria Regional Health Centre
    • Oshawa, Ontario, Canada, L1G 2B9
      • Recruiting
      • Lakeridge Health Oshawa
    • Toronto, Ontario, Canada, M5G 2M9
      • Recruiting
      • Princess Margaret Cancer Center
    • Toronto, Ontario, Canada, M2K 1E1
      • Recruiting
      • North York General Hospital
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 5H6
      • Recruiting
      • CIUSSS du Saguenay Lac-Saint-Jean, Chicoutimi Hospital
    • Levis, Quebec, Canada, G6V 3Z1
      • Recruiting
      • CISSS Chaudière-Appalaches
    • Montreal, Quebec, Canada, H4A 3J1
      • Recruiting
      • McGill University Health Centre - Glen Site
    • Montreal, Quebec, Canada, H2X 0C1
      • Recruiting
      • Centre Hospitalier de l'Université de Montréal (CHUM)
    • Quebec City, Quebec, Canada, G1S 4L8
      • Recruiting
      • CHU de Québec - Hôpital du Saint-Sacrement
    • Saint-jerome, Quebec, Canada, J7Z 5T3
      • Recruiting
      • Hopital regional de saint jerome
• Chile
  • Puerto Montt, Chile, 5500243
    • Recruiting
    • Clínica Puerto Montt
  • Santiago, Chile
    • Recruiting
    • Icegclinic
  • Santiago, Chile, 7510032
    • Recruiting
    • Oncovida
  • Santiago, Chile, 8330032
    • Recruiting
    • Centro De Cancer Universidad Catolica
• China
  • Beijing, China, 100142
    • Recruiting
    • Beijing Cancer Hospital
  • Changchun City, China, 130021
    • Recruiting
    • the First Hospital of Jilin University; Cancer Center
  • Chengdu, China, 610072
    • Recruiting
    • Sichuan Provincial People's Hospital
  • Chengdu City, China, 610041
    • Recruiting
    • West China Hospital of Sichuan University
  • Chongqing, China, 400016
    • Recruiting
    • The First Affiliated Hospital, Chongqing Medical University
  • Fuzhou City, China, 350001
    • Recruiting
    • Fujian Medical University Union Hospital
  • Fuzhou City, China, 350009
    • Recruiting
    • No. 900 Hospital (Fuzhou General Hospital)
  • Guangzhou City, China, 510060
    • Recruiting
    • Cancer Center, Sun Yat-sen University of Medical Sciences; Department of Medical Oncology
  • Hangzhou, China, 310009
    • Recruiting
    • The Second Affiliated Hospital of Zhejiang University College
  • Harbin, China, 150081
    • Recruiting
    • Harbin Medical University Cancer Hospital
  • Jinan, China, 250117
    • Recruiting
    • Shandong Cancer Hospital
  • Jinan City, China, 250013
    • Recruiting
    • Jinan Central Hospital
  • Kunming City, China, 650034
    • Recruiting
    • The First People's Hospital of Yunnan Province
  • Luoyang City, China, 471031
    • Recruiting
    • The First Affiliated Hospital to Henan University of Science and Technology
  • Nanning City, China, 530021
    • Recruiting
    • Guangxi Cancer Hospital of Guangxi Medical University
  • Shanghai City, China, 200120
    • Recruiting
    • Fudan University Shanghai Cancer Center
  • Taiyuan City, China, 030013
    • Recruiting
    • Shanxi Province Cancer Hospital
  • Taizhou, China
    • Recruiting
    • Taizhou Hospital of Zhejiang Province
  • Tianjin, China, 300000
    • Recruiting
    • Tianjin Cancer Hospital; Department of Breast Oncology
  • Urumqi, China, 830000
    • Recruiting
    • The Tumor Hospital of Xinjiang Medical University
  • Wuhan, China, 430079
    • Recruiting
    • Hubei Cancer Hospital
  • Wuhan City, China, 430023
    • Recruiting
    • Union Hospital Tongji Medical College Huazhong University of Science and Technology
  • Xi'an City, China, 710004
    • Recruiting
    • The Second Affiliated Hospital of Xi'an Jiao Tong University
  • Xian, China, 710100
    • Recruiting
    • Xi'an International Medical Center Hospital
  • Xuzhou, China
    • Recruiting
    • The Affiliated Hospital Of XuZhou Medical University
  • Zhejiang, China, 310022
    • Recruiting
    • Zhejiang Cancer Hospital
• Colombia
  • Bogota, D.C., Colombia, 110131
    • Recruiting
    • Fundación CTIC - Centro de Tratamiento e Investigación sobre Cáncer Luis Carlos Sarmiento Angulo
  • Monteria, Colombia, 230002
    • Recruiting
    • Oncomedica S.A.
  • Valledupar, Colombia, 200001
    • Recruiting
    • Sociedad de Oncología y hematología del Cesar Ltda
• Costa Rica
  • San José, Costa Rica, 10103
    • Recruiting
    • Clinica CIMCA
  • San José, Costa Rica, 10108
    • Recruiting
    • ICIMED Instituto de Investigación en Ciencias Médicas
  • San José, Costa Rica, 11303
    • Recruiting
    • Proclinical Pharma
• France
  • La Rochelle, France, 17019
    • Recruiting
    • Centre Hospitalier Saint Louis; Oncologie Medicale
  • Lyon, France, 69373
    • Recruiting
    • Centre Leon Berard; Departement Oncologie Medicale
  • Montpellier, France, 34070
    • Recruiting
    • Centre Cancerologie Grand Montpellier
  • Reims CEDEX, France, 51056
    • Recruiting
    • Institut Jean Godinot; Oncologie Medicale
  • Villejuif, France, 94805
    • Recruiting
    • Gustave Roussy
• Guatemala
  • Ciudad de Guatemala, Guatemala, 01010
    • Recruiting
    • Celan S.A.
  • Ciudad de Guatemala, Guatemala, 01010
    • Recruiting
    • INTEGRA Cancer Institute
  • Ciudad de Guatemala, Guatemala, 01016
    • Recruiting
    • Sanatorio MEDIK-Cayala
  • Guatemala, Guatemala, 01010
    • Recruiting
    • Oncomedica
  • Guatemala City, Guatemala, 01015
    • Recruiting
    • Grupo Angeles
  • Quetzaltenango, Guatemala, 09001
    • Recruiting
    • Centro Medico Integral de Cancerologia CEMIC
• Hungary
  • Miskolc, Hungary, 3526
    • Recruiting
    • B-A-Z Vármegyei Központi Kórház és Egyetemi Oktatókórház; Klin. Onkológiai és Sugárterápiás Centrum
  • Salgótarján, Hungary, 3100
    • Recruiting
    • Nograd Varmegyei Szent Lazar Korhaz; Onkologiai es Sugarterapias Centrum
• India
  • Maharashtra
    • Pune, Maharashtra, India, 411001
      • Recruiting
      • Grant Medical Foundation, Ruby Hall Clinic
• Israel
  • Petah Tikva, Israel, 4910000
    • Recruiting
    • Rabin Medical Center; Oncology Dept
  • Tel-Aviv, Israel, 6423900
    • Recruiting
    • Sourasky Medical Center; Oncology Department
• Italy
  • Campania
    • Avellino, Campania, Italy, 83100
      • Recruiting
      • Azienda Ospedaliera di Rilievo Nazionale e di Alta Specialita San Giuseppe Moscati
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
      • Recruiting
      • Policlinico S.Orsola-Malpighi; Istituto Oncologia R. Addarii
    • Meldola, Emilia-Romagna, Italy, 47014
      • Recruiting
      • I.R.S.T Srl IRCCS; Oncologia Medica
  • Lazio
    • Roma, Lazio, Italy, 00168
      • Active, not recruiting
      • Policlinico Universitario Agostino Gemelli
    • Roma, Lazio, Italy, 128
      • Recruiting
      • Università Campus Bio-Medico di Roma; Oncologia Medica
  • Lombardia
    • Brescia, Lombardia, Italy, 25123
      • Recruiting
      • ASST DEGLI SPEDALI CIVILI DI BRESCIA; Oncologia Medica
    • Rozzano, Lombardia, Italy, 20089
      • Recruiting
      • Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia
  • Piemonte
    • Novara, Piemonte, Italy, 28100
      • Recruiting
      • A.O.U. Maggiore della Carità
  • Puglia
    • Brindisi, Puglia, Italy, 72100
      • Recruiting
      • Presidio Ospedaliero di Summa-Perrino; Oncologia Medica
  • Sicilia
    • Misterbianco (CT), Sicilia, Italy, 95045
      • Recruiting
      • Humanitas Centro Catanese Di Oncologia; Oncologia Medica
  • Toscana
    • Florence, Toscana, Italy, 50134
      • Recruiting
      • Azienda Ospedaliera Universitaria Careggi
• Korea, Republic of
  • Daegu, Korea, Republic of, 41404
    • Recruiting
    • Kyungpook National University Chilgok Hospital
  • Seongnam-si, Korea, Republic of, 463-707
    • Active, not recruiting
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of, 03080
    • Recruiting
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 06351
    • Active, not recruiting
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 05505
    • Recruiting
    • Asan Medical Center
  • Seoul, Korea, Republic of, 06273
    • Recruiting
    • Gangnam Severance Hospital
  • Seoul, Korea, Republic of, 02841
    • Recruiting
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of, 07985
    • Recruiting
    • Ewha Womans University Mokdong Hospital
  • Seoul, Korea, Republic of, 03722
    • Recruiting
    • Severance Hospital, Yonsei University Health System; Clinical Pharmacy
  • Ulsan, Korea, Republic of, 44033
    • Recruiting
    • Ulsan University Hosiptal
• New Zealand
  • Palmerston North, New Zealand, 4442
    • Recruiting
    • Palmerston North Hospital; Regional Cancer Treatment Service
• Poland
  • ?ód?, Poland, 93-338
    • Recruiting
    • Instytut "Centrum Zdrowia Matki Polki"; Klinika Onkologii
  • Gdynia, Poland, 81-519
    • Recruiting
    • Szpital Morski Im. Pck; Oncology & Radiotherapy Dept
  • Konin, Poland, 62-500
    • Recruiting
    • Przychodnia Lekarska KOMED, Roman Karaszewski
• Portugal
  • Coimbra, Portugal, 3000-075
    • Recruiting
    • IPO de Coimbra; Servico de Oncologia Medica
  • Lisboa, Portugal, 1500-650
    • Recruiting
    • Hospital da Luz; Departamento de Oncologia Medica
  • Lisboa, Portugal, 1495-005
    • Recruiting
    • Hospital de S. Francisco Xavier; Unidade de Oncologia Medica
  • Porto, Portugal, 4200-072
    • Recruiting
    • IPO do Porto; Servico de Oncologia Medica
  • Vila Nova de Gaia, Portugal, 4434-502
    • Recruiting
    • CHVNG/E_Unidade 1; Servico de Oncologia Medica
• Spain
  • Barcelona, Spain, 08028
    • Recruiting
    • Hospital Universitari Dexeus - Grupo Quironsalud; Servicio de Oncologia Medica
  • Huelva, Spain, 21005
    • Recruiting
    • Hospital Juan Ramon Jimenez;Servicio de Oncologia
  • Jaen, Spain, 23007
    • Recruiting
    • Complejo Hospitalario de Jaen-Hospital Universitario Medico Quirurgico; Servicio de Oncologia
  • Madrid, Spain, 28033
    • Recruiting
    • Centro Oncologico MD Anderson Internacional; Servicio de Oncologia
  • Madrid, Spain, 28050
    • Recruiting
    • HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio de Oncologia
  • Sevilla, Spain, 41013
    • Recruiting
    • Hospital Universitario Virgen del Rocio; Servicio de Oncologia
  • Sevilla, Spain, 41009
    • Recruiting
    • Hospital Universitario Virgen Macarena; Servicio de Oncologia
  • Valencia, Spain, 46009
    • Recruiting
    • Instituto Valenciano Oncologia; Oncologia Medica
  • Valencia, Spain, 46015
    • Recruiting
    • Hospital Arnau de Vilanova (Valencia) Servicio de Oncologia
  • Barcelona
    • Sant Andreu de La Barca, Barcelona, Spain, 08740
      • Recruiting
      • Hospital Univ Vall d'Hebron; Servicio de Oncologia
  • Cadiz
    • Jerez de La Frontera, Cadiz, Spain, 11407
      • Recruiting
      • Hospital de Jerez de la Frontera; Servicio de Oncologia
  • Madrid
    • Pozuelo de Alarcon, Madrid, Spain, 28223
      • Recruiting
      • Hospital Quiron de Madrid; Servicio de Oncologia
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Recruiting
      • Hospital Universitario Virgen de La Arrixaca; Servicio De Oncologia
  • Pontevedra
    • Vigo, Pontevedra, Spain, 36213
      • Recruiting
      • Hospital Alvaro Cunqueiro; Servicio de Oncologia
• Taiwan
  • Hsinchu City, Taiwan, 300
    • Recruiting
    • Hsin-Chu Branch of National Taiwan University Hospital
  • Taichung, Taiwan, 404
    • Recruiting
    • China Medical University Hospital; Surgery
  • Taipei, Taiwan, 00112
    • Recruiting
    • VETERANS GENERAL HOSPITAL; Department of General Surgery
  • Taipei, Taiwan, 100
    • Recruiting
    • National Taiwan Uni Hospital; Dept of Oncology
  • Taipei City, Taiwan, 11259
    • Recruiting
    • Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology
  • Xitun Dist., Taiwan, 40705
    • Recruiting
    • Veterans General Hospital - Taichung
• Thailand
  • Muang Chiang MAI Delivery Branch 3, Thailand, 50200
    • Recruiting
    • Maharaj Nakorn Chiang Mai Hospital; Depart of Radiology; Divis of Therapeutic Radiology and Oncology
• United States
  • California
    • Harbor City, California, United States, 90710
      • Recruiting
      • Kaiser Permanente - Harbor City
    • Los Angeles, California, United States, 90033
      • Recruiting
      • USC Norris Comprehensive Cancer Center
    • Newport Beach, California, United States, 92663
      • Recruiting
      • USC Norris Cancer Center; Oncology/Hematology - Newport Beach Treatment Center
    • Torrance, California, United States, 90502
      • Recruiting
      • The Lundquist Institute for BioMedical Innovation at Harbor-UCLA Medical Cente
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Recruiting
      • Georgetown University Medical Center
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • MedStar Washington Hosp Center
  • Maine
    • Scarborough, Maine, United States, 04074
      • Recruiting
      • New England Cancer Specialists
  • Maryland
    • Frederick, Maryland, United States, 21701
      • Recruiting
      • Frederick Health Hospital
  • New Jersey
    • East Brunswick, New Jersey, United States, 08816
      • Recruiting
      • Astera Cancer Care East Brunswick
  • Oregon
    • Medford, Oregon, United States, 97504-8332
      • Recruiting
      • Asante Rogue Regional Medical Center
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17604
      • Recruiting
      • Ann B. Barshinger Cancer Institute
  • South Dakota
    • Aberdeen, South Dakota, United States, 57401
      • Recruiting
      • Avera Cancer Institute - Aberdeen
    • Sioux Falls, South Dakota, United States, 57105
      • Recruiting
      • Avera Cancer Institute
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Recruiting
      • West Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Giredestrant + Investigator's Choice of CDK4/6i; 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; 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.; Other Names: GDC-9545; RO7197597; RG6171; Drug: Abemaciclib; 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.; Drug: Palbociclib; 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.; Drug: Ribociclib; 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.; Drug: LHRH 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 test: FoundationOne 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]).; Other Names: F1LCDx
Active Comparator: Fulvestrant + Investigator's Choice of CDK4/6i; Participants in the control arm will receive fulvestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.	Drug: Abemaciclib; 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.; Drug: Palbociclib; 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.; Drug: Ribociclib; 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.; Drug: LHRH 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 test: FoundationOne 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]).; Other Names: F1LCDx; Drug: Fulvestrant; 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.

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2023
• Primary Completion (Estimated): July 30, 2026
• Study Completion (Estimated): December 30, 2028

Study Registration Dates

• First Submitted: September 26, 2023
• First Submitted That Met QC Criteria: September 26, 2023
• First Posted (Actual): October 4, 2023

Study Record Updates

• Last Update Posted (Actual): April 25, 2024
• Last Update Submitted That Met QC Criteria: April 24, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: ESR1 mutation; oral Selective Estrogen Receptor Degrader (SERD); CDK4/6 inhibitor (CDK4/6i)
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protein Kinase Inhibitors; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Fulvestrant; Palbociclib
• Other Study ID Numbers: CO44657; 2022-502980-39-00 (Registry Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

For eligible studies, qualified researchers may request access to individual patient level data through the request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/).

For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/innovation/process/clinical-trials/data-sharing/).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes