DNA-Guided Adjuvant Therapy for Breast Cancer

(DARE Trial)

Recruiting at 17 trial locations

Overseen By Bebi Yassin-Rajkumar, MSc

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Criterium, Inc.

Must be taking: Aromatase inhibitors, Tamoxifen

Must not be taking: Fulvestrant, CDK4/6 inhibitors

Disqualifiers: Invasive cancer, HER2 positive, others

Stay on Your Current Meds You can continue your current medications while participating

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

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

Compensation: Varies

Number of Visits: 4

Duration: Up to 2 years

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new methods to treat certain types of breast cancer by using DNA information to guide therapy. It focuses on breast cancer that is estrogen receptor positive (where cancer cells grow in response to estrogen) and HER-2 negative, meaning it lacks excess HER-2 protein. The trial compares a combination of drugs—fulvestrant (Faslodex, a hormone therapy) and palbociclib (Ibrance, a targeted therapy)—against standard treatments. Individuals who have undergone breast cancer surgery and are concerned about recurrence might be suitable candidates, especially if they had large tumors or cancer in the lymph nodes. As a Phase 2 trial, the research measures how well the treatment works in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop your current medications, but it does allow patients who are currently taking an aromatase inhibitor or tamoxifen as adjuvant endocrine therapy. However, you cannot be on a CDK4/6 inhibitor or certain other medications that interact with trial drugs. It's best to discuss your specific medications with the trial team.

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

Research shows that using palbociclib and fulvestrant together is generally safe and well-tolerated for patients with hormone receptor-positive breast cancer. Studies have found that common side effects include low white blood cell counts, tiredness, and nausea, affecting more than 20% of patients. However, the overall safety of palbociclib and fulvestrant is well understood, as the FDA has already approved this combination for other breast cancer treatments. This approval indicates a known level of safety when these drugs are used together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the Palbociclib/Fulvestrant combination therapy for breast cancer because it offers a unique approach by targeting specific molecules involved in cancer cell growth. Unlike traditional chemotherapy, which attacks all rapidly dividing cells, this combination specifically inhibits proteins known as CDK4/6, which are crucial for cancer cell division. This targeted action not only aims to be more effective but also potentially reduces the side effects associated with broader treatments. Additionally, Fulvestrant acts by degrading estrogen receptors, which are often overactive in certain breast cancers, adding another layer of precision in attacking the cancer cells.

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

In this trial, participants in Arm A will receive a combination of palbociclib and fulvestrant. Research has shown that using palbociclib with fulvestrant can delay the progression of certain types of breast cancer. One study found that this combination delayed cancer progression for an average of 9.2 months, compared to 3.8 months with fulvestrant alone. The PALOMA-3 trial found that patients lived longer overall when using both drugs compared to just fulvestrant. However, some studies have shown mixed results, with no clear benefit from adding palbociclib in certain cases. While the evidence is promising, effectiveness can vary depending on the patient's specific condition. ^{2 4 6 7 8}

Who Is on the Research Team?

Lajos Pusztai, MD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for men and women with stage II-III, HER2 negative, ER positive breast cancer who have been on hormone therapy for 6 months to 7 years. They must not show signs of cancer spread and agree to use contraception. Those with high recurrence risk or ctDNA positivity are eligible. Exclusions include intolerance to the drugs being tested, severe health issues, living outside the US, certain cancer histories, or taking specific medications.

Inclusion Criteria

My breast cancer is stage II or III, HER2 negative, and ER positive.

My scans show no cancer spread to other parts of my body.

I agree to use birth control during and after the trial if I am a woman who can still have children or a man.

Exclusion Criteria

I haven't had cancer in the last 5 years, except for skin cancer.

I am on medication that strongly affects liver enzyme levels and cannot switch.

I have been treated with fulvestrant, a CDK4/6 inhibitor, or was in the PENELOPE/PALLAS trials.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

Up to 7 years

Routine follow-up clinic visits every 4 to 6 months

Surveillance/ctDNA Screening

Assess the incidence of ctDNA detection in patients with ER positive HER2- breast cancer receiving standard of care adjuvant endocrine therapy

Enrollment period

Treatment

Randomized patients receive either palbociclib plus fulvestrant or continue standard of care endocrine therapy

Up to 2 years

Regular visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

What Are the Treatments Tested in This Trial?

Interventions

• Fulvestrant
• Palbociclib

Trial Overview The DARE trial tests if adding Palbociclib and Fulvestrant (second line adjuvant therapies) can benefit patients with a high residual risk of breast cancer after initial treatment. It's randomized: some will get standard care while others receive the new combination; decisions are made by chance.

How Is the Trial Designed?

Group I: Arm A Experimental Treatment 2 Interventions

Palbociclib/Fulvestrant Combination

Group II: Arm B Active Control 1 Intervention

Adjuvant Therapy

Who Is Running the Clinical Trial?

Criterium, Inc.

Lead Sponsor

Trials

18

Recruited

730+

Published Research Related to This Trial

In the PALOMA-3 study involving women with advanced estrogen receptor-positive breast cancer, changes in circulating tumor DNA (ctDNA) levels after 15 days of treatment with the CDK4/6 inhibitor palbociclib and fulvestrant were found to strongly predict progression-free survival, indicating a potential biomarker for treatment response.

The study revealed that while ESR1 mutations can be present in tumor subclones, their ctDNA dynamics were less effective in predicting clinical outcomes, suggesting that monitoring ctDNA levels could be more reliable for assessing treatment efficacy in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. O'Leary, B., Hrebien, S., Morden, JP., et al.[2022]

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]

In a study involving 1723 women with HR+/HER2- advanced or metastatic breast cancer, palbociclib combined with aromatase inhibitors or fulvestrant showed low dose-reduction rates (18.9% and 12.3%, respectively), indicating good tolerability.

The treatment demonstrated favorable progression-free rates (PFR) at 12 months, with 88.1% for palbociclib + AI and 79.8% for palbociclib + fulvestrant, along with high survival rates (97.3% and 97.5%, respectively), suggesting its effectiveness in real-world clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world treatment of patients with palbociclib for HR+/HER2-advanced/metastatic breast cancer: the Europe IRIS study. Mycock, K., Zhan, L., Hart, K., et al.[2022]

In a study of 56 patients with advanced breast cancer, a significant reduction in cell-free DNA (cfDNA) mutations was observed after 15 days of treatment with palbociclib and fulvestrant, indicating a biological response to the therapy.

However, this reduction in cfDNA mutations did not correlate with improved progression-free survival, suggesting that while cfDNA changes may reflect treatment effects, they do not necessarily predict clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in cell-free DNA after short-term palbociclib and fulvestrant treatment for advanced or metastatic hormone receptor-positive and human epidermal growth factor 2-negative breast cancer. Iwamoto, T., Niikura, N., Watanabe, K., et al.[2023]

In a study of 201 patients with hormone receptor-positive/HER2-negative metastatic breast cancer, the presence of circulating tumor DNA (ctDNA), particularly TP53 mutations, was linked to poorer progression-free survival (PFS) and overall survival (OS), indicating its potential as a prognostic biomarker.

Dynamic changes in ctDNA levels during treatment could predict treatment efficacy, with higher ctDNA suppression observed in patients treated with capecitabine, suggesting that monitoring ctDNA could help assess how well a treatment is working.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baseline Mutations and ctDNA Dynamics as Prognostic and Predictive Factors in ER-Positive/HER2-Negative Metastatic Breast Cancer Patients. Pascual, J., Gil-Gil, M., Proszek, P., et al.[2023]

In a study of 280 patients with HR+/HER2- breast cancer treated with CDK4/6 inhibitors and endocrine therapy, factors like modified Scarff-Bloom-Richardson (SBR) scores and lack of PR expression were linked to shorter progression-free survival (PFS), highlighting their potential as biomarkers for treatment response.

Gene expression analyses revealed that changes in cell cycle and estrogen receptor signaling during treatment were significant, with certain gene sets associated with shorter PFS, suggesting that understanding these biological features could improve treatment strategies for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determinants of response to CDK4/6 inhibitors in the real-world setting. Witkiewicz, AK., Schultz, E., Wang, J., et al.[2023]

In a study of 61 women with ER+ HER2- metastatic breast cancer, early changes in circulating tumor DNA (ctDNA) levels were found to be predictive of the effectiveness of the combination therapy of palbociclib and fulvestrant, with ctDNA clearance at day 30 associated with significantly longer progression-free survival (PFS).

Patients who showed an increase in ctDNA levels at day 30 had a higher risk of disease progression, indicating that monitoring ctDNA can provide valuable insights into treatment response before traditional radiological evaluations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating tumor DNA as a dynamic biomarker of response to palbociclib and fulvestrant in metastatic breast cancer patients. Darrigues, L., Pierga, JY., Bernard-Tessier, A., et al.[2022]

In a study of 459 patients with estrogen receptor-positive breast cancer, high levels of circulating tumor DNA (ctDNA) were linked to worse progression-free survival (PFS) on both palbociclib plus fulvestrant and placebo plus fulvestrant, indicating that ctDNA can serve as a potential biomarker for early progression risk.

Specific genomic alterations, such as TP53 mutations and FGFR1 amplifications, were also associated with poorer PFS, suggesting that patients with these markers may require more aggressive treatment strategies despite receiving CDK4/6 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating Tumor DNA Markers for Early Progression on Fulvestrant With or Without Palbociclib in ER+ Advanced Breast Cancer. O'Leary, B., Cutts, RJ., Huang, X., et al.[2023]

Palbociclib, when combined with fulvestrant, significantly improves progression-free survival in women with hormone receptor-positive, HER2-negative advanced breast cancer, showing a median PFS of 9.5 months compared to 4.6 months with placebo, based on a study of 521 women.

The safety profile of palbociclib includes common adverse reactions such as neutropenia and infections, which were observed in over 20% of patients, confirming its known side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval of Palbociclib in Combination with Fulvestrant for the Treatment of Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer. Walker, AJ., Wedam, S., Amiri-Kordestani, L., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4570077/

Palbociclib Prolongs Progression-Free Survival in Patients ... The median PFS was 9.2 months (95% confidence interval [CI], 7.5 to not estimable) with the combination of palbociclib plus fulvestrant compared with 3.8 months ...

2. breastcancer.org breastcancer.org/research-news/ibrance-faslodex-combo-continues-to-improve-overal-survival-in-advanced-hr-positive

Ibrance-Faslodex Combo Continues To Improve Overall ... The latest results from the PALOMA-3 trial show that combining Ibrance and Faslodex continues to offer better overall survival than Faslodex alone.

3. cancernetwork.com cancernetwork.com/view/adding-palbociclib-to-fulvestrant-did-not-yield-better-efficacy-in-er-positive-her2-negative-metastatic-breast-cancer

Adding Palbociclib to Fulvestrant Did Not Yield Better ... Patients with estrogen receptor–positive, HER2-negative metastatic breast cancer did not derive further benefit when palbociclib was added to fulvestrant.

4. onclive.com onclive.com/view/inavolisib-plus-palbociclib-and-fulvestrant-improves-os-in-pik3ca-mutant-hr-her2-breast-cancer

Inavolisib Plus Palbociclib and Fulvestrant Improves OS in ... Inavolisib plus palbociclib and fulvestrant improved OS in PIK3CA-mutant, HR-positive, HER2-negative, endocrine-resistant advanced breast cancer.

5. lbbc.org lbbc.org/news/ibrance-adds-no-benefit-over-faslodex-alone

Ibrance adds no benefit over Faslodex alone After one year, this triple-drug combination worked to hold off cancer in 35.6% of people, compared to 17.5% in the fulvestrant only group and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5061543/

Palbociclib in Combination With Fulvestrant in Women ... Treatment with palbociclib in combination with fulvestrant was generally safe and well-tolerated in patients with hormone receptor (HR)-positive metastatic ...

7. facingourrisk.org facingourrisk.org/XRAY/palbociclib-overall-survival-metastatic-breast-cancer

Treating metastatic breast cancer: Analysis of the Paloma-3 ... The PALOMA-3 clinical trial showed that a new CDK4/6 inhibitor in combination therapy improved progression-free survival of women treated for hormone receptor- ...

8. aacrjournals.org aacrjournals.org/clincancerres/article/22/20/4968/124844/FDA-Approval-of-Palbociclib-in-Combination-with

FDA Approval of Palbociclib in Combination with Fulvestrant ... Safety data confirmed the known adverse reaction profile of palbociclib. The most common adverse reactions (>20%) in patients treated with palbociclib were ...