Giredestrant + Palbociclib vs Letrozole + Palbociclib for Breast Cancer

Not currently recruiting at 560 trial locations

Overseen By Reference Study ID Number: BO41843 https://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Hoffmann-La Roche

Must be taking: LHRH agonists

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: CNS metastases, Cardiac dysfunction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: Up to 78 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two different drug combinations for a specific type of breast cancer that is estrogen receptor (ER)-positive and human epidermal growth factor receptor-2 (HER2)-negative. This means the cancer grows in response to estrogen but does not have an excess of HER2 protein. The trial aims to determine which combination works better: giredestrant (a new potential drug) with palbociclib or letrozole with palbociclib. Individuals with breast cancer that has recurred or spread, but who have not received certain prior treatments, might be suitable for this study. Participants will help researchers learn more about managing advanced breast cancer with these drugs. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I have to stop taking my current medications for the trial?

The trial requires that you stop taking strong CYP3A inhibitors or inducers at least 14 days before starting the study treatment. Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that giredestrant is generally well-tolerated, with safety similar to other hormone treatments, suggesting it likely won't cause unexpected side effects. Most side effects are known and manageable.

Letrozole, another treatment under investigation, has been used for a long time to treat breast cancer. Studies have shown that its side effects are also known and manageable.

Palbociclib, used with both giredestrant and letrozole, is already approved for breast cancer, indicating it is generally safe when used as directed.

Overall, the treatments in this study are considered well-tolerated, with side effects that are usually known and manageable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for breast cancer?

Researchers are excited about Giredestrant because it offers a new approach to treating breast cancer. Unlike traditional hormone therapies like Letrozole, which reduces estrogen production, Giredestrant is a selective estrogen receptor degrader (SERD) that directly targets and degrades estrogen receptors in cancer cells. This novel mechanism can potentially overcome resistance that often develops with existing treatments. Additionally, combining Giredestrant with Palbociclib, a cell cycle inhibitor, may enhance its effectiveness by further disrupting cancer cell growth.

What evidence suggests that this trial's treatments could be effective for breast cancer?

Research has shown that giredestrant, when combined with palbociclib, holds promise for treating certain types of breast cancer. In this trial, one group of participants will receive giredestrant with palbociclib, while another group will receive letrozole with palbociclib. Studies have found that the combination of giredestrant and palbociclib significantly improved progression-free survival, allowing patients to live longer without their cancer worsening. Giredestrant has been well tolerated and demonstrated strong effects against tumors, particularly in patients who previously underwent hormone therapy. In another study, giredestrant reduced Ki67, a marker of cancer cell growth, more effectively than another treatment. Overall, evidence suggests that giredestrant with palbociclib may be effective for estrogen receptor-positive, HER2-negative breast cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

This trial is for adults with ER-positive, HER2-negative advanced or metastatic breast cancer who haven't had systemic anti-cancer therapy for their advanced disease. They should have completed at least 24 months of standard adjuvant endocrine therapy without progression and be over a year since the last treatment. Pre/peri-menopausal women and men must use LHRH agonist therapy.

Inclusion Criteria

I am fully active or can carry out light work.

I am receiving hormone therapy to manage my cancer.

I have cancer that can be measured by scans or have a specific type of bone lesion.

Exclusion Criteria

Pregnant or breastfeeding

Treatment with any investigational therapy within 28 days prior to study treatment

My cancer has spread to vital organs and poses an immediate risk to my life.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive giredestrant combined with palbociclib or letrozole combined with palbociclib

Up to 78 months

Baseline, Days 1 and 15 of Cycles 1 and 2, and Day 1 of each cycle thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Giredestrant
• Letrozole
• Palbociclib

Trial Overview The study compares the effectiveness and safety of two treatments: Giredestrant combined with Palbociclib versus Letrozole combined with Palbociclib. It's a Phase III trial where participants are randomly assigned to either treatment in a double-blind manner, meaning neither they nor the researchers know which group they're in.

How Is the Trial Designed?

Group I: Giredestrant + Letrozole-matched Placebo + Palbociclib Experimental Treatment 4 Interventions

Group II: Letrozole + Giredestrant-matched Placebo + Palbociclib Active Control 4 Interventions

Who Is Running the Clinical Trial?

Hoffmann-La Roche

Lead Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Published Research Related to This Trial

In a study with a median follow-up of about 38 months, palbociclib combined with letrozole significantly improved progression-free survival (PFS) in women with advanced estrogen receptor-positive (ER+)/HER2-negative breast cancer, with a median PFS of 27.6 months compared to 14.5 months for the placebo group.

The treatment not only prolonged PFS but also delayed the need for chemotherapy and maintained a favorable safety profile and quality of life for patients, suggesting that palbociclib-letrozole should be the standard first-line therapy for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Rugo, HS., Finn, RS., Diéras, V., et al.[2023]

Oral palbociclib is an effective treatment for HR-positive, HER2-negative advanced or metastatic breast cancer, significantly prolonging progression-free survival when used with letrozole or fulvestrant in clinical trials involving postmenopausal women.

The most common side effect was neutropenia, which was manageable and rarely led to serious complications, indicating that palbociclib can be safely administered without significantly compromising its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib: A Review in HR-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer. Kim, ES., Scott, LJ.[2022]

Palbociclib is the first CDK4/6 inhibitor approved for treating estrogen receptor-positive, HER2-negative metastatic breast cancer, and it works by selectively inhibiting CDK4 and CDK6, enhancing the effects of anti-estrogens like letrozole and fulvestrant.

Clinical trials show that palbociclib significantly doubles the treatment efficacy of letrozole and fulvestrant while maintaining a manageable safety profile, positively impacting patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of palbociclib in the treatment of metastatic breast cancer. Ettl, J., Harbeck, N.[2017]

In the PALOMA-2 trial involving 666 postmenopausal women with ER+/HER2- advanced breast cancer, the combination of palbociclib and letrozole significantly improved progression-free survival compared to letrozole alone, with a hazard ratio of 0.58.

Neutropenia was the most common adverse event associated with palbociclib, occurring in 95.3% of patients, but it was mostly manageable through dose modifications and did not compromise treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib with Letrozole in Postmenopausal Women with ER+/HER2- Advanced Breast Cancer: Hematologic Safety Analysis of the Randomized PALOMA-2 Trial. Diéras, V., Harbeck, N., Joy, AA., et al.[2020]

In a study of 666 postmenopausal women with advanced breast cancer, Asian patients receiving palbociclib plus letrozole experienced a significantly longer progression-free survival (PFS) of 25.7 months compared to 13.9 months for those on placebo plus letrozole, indicating the efficacy of this combination treatment.

While hematologic toxicities like neutropenia were more common in Asian patients, they were manageable, and quality of life remained stable, suggesting that palbociclib plus letrozole is a safe and effective treatment option for this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib Plus Letrozole as First-Line Therapy in Postmenopausal Asian Women With Metastatic Breast Cancer: Results From the Phase III, Randomized PALOMA-2 Study. Im, SA., Mukai, H., Park, IH., et al.[2023]

Palbociclib, an inhibitor of CDK4 and CDK6, was granted accelerated FDA approval for treating advanced breast cancer in postmenopausal women when combined with letrozole, based on a trial involving 165 patients that showed significant improvement in progression-free survival (PFS).

The trial demonstrated a nearly 50% reduction in the risk of disease progression for patients receiving the combination therapy compared to those on letrozole alone, although the most common side effect noted was neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer. Beaver, JA., Amiri-Kordestani, L., Charlab, R., et al.[2022]

In a phase 3 study involving 666 postmenopausal women with ER-positive, HER2-negative advanced breast cancer, the combination of palbociclib and letrozole significantly improved progression-free survival to 24.8 months compared to 14.5 months with letrozole alone, indicating its efficacy as a treatment option.

While palbociclib plus letrozole showed better outcomes, it also resulted in higher rates of serious side effects, such as neutropenia (66.4% vs. 1.4% in the placebo group), highlighting the need for careful monitoring of patients during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib and Letrozole in Advanced Breast Cancer. Finn, RS., Martin, M., Rugo, HS., et al.[2022]

Citations

1. roche.com roche.com/media/releases/med-cor-2025-09-22

Positive phase III results show Roche's giredestrant ... The study met both co-primary endpoints, demonstrating a statistically significant and clinically meaningful improvement in progression-free ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10870118/

Phase Ia/b Study of Giredestrant ± Palbociclib and ... Giredestrant was well tolerated and clinically active in patients who progressed on prior endocrine therapy. Results warrant further evaluation of giredestrant ...

3. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00268-1/fulltext

Neoadjuvant palbociclib plus either giredestrant or ... The coopERA Breast Cancer study showed a greater relative geometric mean reduction of Ki67 with giredestrant compared with anastrozole after 2 ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04436744

NCT04436744 | A Study to Evaluate the Efficacy, Safety ... This is a randomized, multicenter, open-label, two-arm, Phase II study to evaluate the efficacy, safety, and pharmacokinetics of giredestrant versus ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.01500

Giredestrant for Estrogen Receptor–Positive, HER2- ... Giredestrant is well tolerated, and has shown encouraging antitumor activity in aBC as a monotherapy and in combination with palbociclib, ...

6. dana-farber.org dana-farber.org/newsroom/news-releases/2025/novel-treatment-combination-improves-progression-free-survival-in-metastatic-estrogen-receptor-positive-her-2-negative-breast-cancer

Novel Treatment Combination Improves Progression-Free ... In addition, the safety profile of the giredestrant regimen was manageable and consistent with the known safety profiles of the individual study ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38537155/

Giredestrant for Estrogen Receptor-Positive, HER2- ... Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT05306340

NCT05306340 | A Study Evaluating the Efficacy and Safety ... This Phase III, randomized, open-label, multicenter study will evaluate the efficacy and safety of giredestrant plus everolimus compared with the ...