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

Plain English Summary

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) is a Phase 3 clinical trial sponsored by Hoffmann-La Roche studying Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer. Tests the effectiveness and safety of giredestrant compared to fulvestrant combined with a CDK4/6 inhibitor in treating ER+ HER2- advanced breast cancer. For patients who have developed resistance to prior endocrine therapy and are not suitable for curative treatment. Participation involves taking daily medication and regular check-ups at one of the study sites. Alternative treatments include other endocrine therapies or targeted therapies. The trial aims to enroll 1050 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Eligible if you have ER+ HER2- advanced breast cancer, resistance to prior endocrine therapy, and measurable disease. Not eligible if you have had prior systemic therapy for advanced breast cancer or active cardiac disease. Age range: 18+ years. Health requirements: Good overall health, no active visceral spread, and no significant liver disease. This trial is studying Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures focus on progression-free survival, which means how long patients can remain without their cancer getting worse. The specific primary outcome measures are: 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 in the Full Analysis Set (FAS) Population (From randomization to first occurrence of PD or death (up to 5 years)). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial addresses a significant treatment gap for patients with ER+ HER2- advanced breast cancer who have developed resistance to prior endocrine therapy. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer, where improved treatment options are needed.

Investor Insight

Market size is substantial, with a competitive landscape dominated by established players. Approval probability is high given the unmet need in this patient population. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage. The large enrollment target of 1050 participants suggests significant investment in this program.

Is This Trial Right for Me?

Ask your doctor about your eligibility and the potential benefits and risks of participating in the study. Participation involves taking daily medication and regular check-ups at one of the study sites. This trial is currently recruiting participants. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 1,050 participants

Interventions

• 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.
• 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.
• 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.

Primary Outcomes

• 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 in the Full Analysis Set (FAS) Population (From randomization to first occurrence of PD or death (up to 5 years))

Secondary Outcomes

• 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))
• Confirmed Objective Response Rate (cORR) (From randomization until treatment discontinuation (up to 5 years))
• Duration of Response (DOR) (From the first occurrence of a documented objective response to PD or death (up to 5 years))
• Clinical Benefit Rate (CBR) (From randomization until treatment discontinuation (up to 5 years))

Full Eligibility Criteria

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

Trial Locations

• 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
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer
• Endocrine Therapy Resistance
• CDK4/6 Inhibitors
• Circulating Tumor DNA (ctDNA) Testing
• ER+ HER2- Breast Cancer
• Advanced Breast Cancer
• Resistance to Endocrine Therapy
• CDK4/6 Inhibitor Therapy
• ER Targeting Agents
• SERD (Selective Estrogen Receptor Downregulator) Therapy

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