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 3RecruitingNCT06065748

Hoffmann-La Roche1,050 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

1,050

Conditions

Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer

Interventions

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.

FulvestrantDRUG

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.

AbemaciclibDRUG

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.

PalbociclibDRUG

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.

RibociclibDRUG

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.

LHRH AgonistDRUG

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.

FoundationOne Liquid CDx Assay (F1LCDx)DIAGNOSTIC_TEST

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 \[ESR1nmd\]).

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (351)

Southern Cancer Center

Daphne, Alabama, United States

RECRUITING

Sutter Auburn Faith Hospital

Auburn, California, United States

WITHDRAWN

La Hematology Oncology Medical Group

Glendale, California, United States

RECRUITING

Marin Cancer Care Inc

Greenbrae, California, United States

Outcomes

Primary Outcomes

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 Outcomes

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)

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.