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)

Phase 3

Recruiting

• Conditions: Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer
• Interventions: Drug: Fulvestrant; Drug: Giredestrant; Drug: Abemaciclib; Drug: Palbociclib; Drug: Ribociclib; Drug: LHRH Agonist; Diagnostic Test: FoundationOne Liquid CDx Assay (F1LCDx)

• Registration Number: NCT06065748
• Lead Sponsor: Hoffmann-La Roche

Brief 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-09-26
• Study First Submitted QC: 2023-09-26
• Study First Posted: 2023-10-04
• Study Start: 2023-12-11
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-24
• Last Update Posted: 2025-07-25
• Primary Completion: 2026-07-30
• Study Completion: 2028-12-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1050

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fulvestrant + Investigator's Choice of CDK4/6i	Fulvestrant	Participants in the control arm will receive fulvestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.
Fulvestrant + Investigator's Choice of CDK4/6i	LHRH Agonist	Participants in the control arm will receive fulvestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.
Giredestrant + Investigator's Choice of CDK4/6i	LHRH Agonist	Participants in the experimental arm will receive giredestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.
Giredestrant + Investigator's Choice of CDK4/6i	FoundationOne Liquid CDx Assay (F1LCDx)	Participants in the experimental arm will receive giredestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.
Giredestrant + Investigator's Choice of CDK4/6i	Ribociclib	Participants in the experimental arm will receive giredestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.
Fulvestrant + Investigator's Choice of CDK4/6i	FoundationOne Liquid CDx Assay (F1LCDx)	Participants in the control arm will receive fulvestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.
Fulvestrant + Investigator's Choice of CDK4/6i	Palbociclib	Participants in the control arm will receive fulvestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.
Giredestrant + Investigator's Choice of CDK4/6i	Giredestrant	Participants in the experimental arm will receive giredestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.
Giredestrant + Investigator's Choice of CDK4/6i	Abemaciclib	Participants in the experimental arm will receive giredestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.
Giredestrant + Investigator's Choice of CDK4/6i	Palbociclib	Participants in the experimental arm will receive giredestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.
Fulvestrant + Investigator's Choice of CDK4/6i	Abemaciclib	Participants in the control arm will receive fulvestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.
Fulvestrant + Investigator's Choice of CDK4/6i	Ribociclib	Participants in the control arm will receive fulvestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS) in the ESR1 mutation (ESR1m) Subgroup	From randomization to first occurrence of progressive disease (PD) or death (up to 5 years)	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.
PFS in the Full Analysis Set (FAS) Population	From randomization to first occurrence of PD or death (up to 5 years)

Secondary Outcome Measures

Name	Time	Method
Time to Confirmed Deterioration (TTCD) in Pain Severity	From randomization until end of follow-up (up to 5 years)	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.
Duration of Response (DOR)	From the first occurrence of a documented objective response to PD or death (up to 5 years)	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.
Incidence and Severity of Adverse Events	From Baseline until 28 days after the final dose of study treatment (up to 5 years)	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).
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)
Confirmed Objective Response Rate (cORR)	From randomization until treatment discontinuation (up to 5 years)	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.
Clinical Benefit Rate (CBR)	From randomization until treatment discontinuation (up to 5 years)	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.
Time to Chemotherapy	From randomization until the start of chemotherapy or death (up to 5 years)	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.
TTCD in Pain Presence and Interference	From randomization until end of follow-up (up to 5 years)	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.
TTCD in Role Functioning	From randomization until end of follow-up (up to 5 years)	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.
Number of Participants with Vital Sign Abnormalities Over the Course of the Study	From Baseline until 28 days after the final dose of study treatment (up to 5 years)	Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature.
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)	From randomization until death from any cause (up to 5 years)	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.
TTCD in Physical Functioning	From randomization until end of follow-up (up to 5 years)	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.
TTCD in Global Health Status/Quality of Life	From randomization until end of follow-up (up to 5 years)	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.

Trial Locations

Locations (341)

Southern Cancer Center; 🇺🇸 Daphne, Alabama, United States

Sutter Auburn Faith Hospital; 🇺🇸 Auburn, California, United States

La Hematology Oncology Medical Group; 🇺🇸 Glendale, California, United States

Marin Cancer Care Inc; 🇺🇸 Greenbrae, California, United States

Kaiser Permanente - Harbor City; 🇺🇸 Harbor City, California, United States

USC Norris Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

USC Norris Cancer Center; 🇺🇸 Newport Beach, California, United States

Sutter Medical Group, Roseville Clinic; 🇺🇸 Roseville, California, United States

Sutter Health Medical Center; 🇺🇸 Sacramento, California, United States

The Lundquist Institute for BioMedical Innovation at Harbor-UCLA Medical Cente; 🇺🇸 Torrance, California, United States

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