Hormone Therapy with or without Radiation for Breast Cancer

(DEBRA Trial)

Recruiting at 830 trial locations

Overseen By Norman Wolmark, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: NRG Oncology

Must be taking: Endocrine therapy

Must not be taking: SERMs, Estrogen replacement

Disqualifiers: Metastatic disease, Mastectomy, Non-breast malignancies, 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: Unknown

Duration: 5 years

1670 Participants Needed

Trial Summary

What is the purpose of this trial?

This Phase III Trial evaluates whether breast conservation surgery and endocrine therapy results in a non-inferior rate of invasive or non-invasive ipsilateral breast tumor recurrence (IBTR) compared to breast conservation with breast radiation and endocrine therapy.

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

The trial requires that you stop any current endocrine therapy, such as tamoxifen or other selective estrogen receptor modulators, before joining. If you are on estrogen replacement therapy, you must also discontinue it before registration.

What data supports the effectiveness of the drugs used in hormone therapy for breast cancer?

Research shows that letrozole, an aromatase inhibitor, is more effective than tamoxifen in improving disease-free survival and reducing the risk of breast cancer recurrence in postmenopausal women. Letrozole has been shown to significantly reduce the risk of distant metastasis and is recommended as an initial adjuvant therapy for breast cancer. ^{1 2 3 4 5}

Is hormone therapy with or without radiation safe for breast cancer treatment?

Research shows that hormone therapies like anastrozole, letrozole, and tamoxifen are generally safe for treating breast cancer in postmenopausal women. Anastrozole has a favorable safety profile compared to tamoxifen, with mild side effects such as hot flashes and joint pain. Letrozole also has mild side effects, including nausea and fatigue. ^{6 7 8 9 10}

How is the drug combination of Anastrozole, Exemestane, Letrozole, and Tamoxifen unique for breast cancer treatment?

This drug combination is unique because it includes third-generation aromatase inhibitors (Anastrozole, Exemestane, Letrozole) and Tamoxifen, which are used to treat hormone receptor-positive breast cancer in postmenopausal women. These drugs work by reducing estrogen levels or blocking estrogen receptors, offering more effective and better-tolerated options compared to older treatments like megestrol acetate, especially for patients who do not respond to Tamoxifen alone. ^{5 7 8 11 12}

Eligibility Criteria

This trial is for individuals with hormone-sensitive, HER-2 negative breast cancer and an Oncotype Recurrence Score of 18 or less. Participants must have had a lumpectomy with clear margins, no metastatic disease, no prior breast radiation, and be able to start treatment within 70 days post-surgery. They should not have received any previous treatments for their current cancer.

Inclusion Criteria

It has been less than 70 days since my last breast cancer surgery.

The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.

My cancer was found to be at an early stage with a small tumor and no spread to nearby lymph nodes.

Exclusion Criteria

Use of any investigational product within 30 days prior to study entry.

Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.

I have had suspicious breast changes checked and they were not cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either breast radiation therapy with endocrine therapy or only endocrine therapy for at least 5 years

5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment, including monitoring for invasive or non-invasive ipsilateral breast tumor recurrence

5 years

Long-term follow-up

Participants are monitored for any breast procedure after the initial surgery or last follow-up, with an average duration of 15 years

15 years

Treatment Details

Interventions

• Anastrozol
• Exemestane
• Letrozole
• Radiation
• Tamoxifen

Trial Overview The DEBRA Phase III Trial is testing if endocrine therapy alone after breast conservation surgery is as effective in preventing tumor recurrence as the combination of endocrine therapy with radiation. The goal is to see if radiation can be safely omitted without increasing the risk of cancer returning.

Participant Groups

Group I: Arm 1: Breast Radiation Therapy + Endocrine Therapy Active Control 1 Intervention

Radiation therapy to the breast and hormonal drug for at least 5 years. Tamoxifen 20 mg daily Anastrozole 1 mg daily Letrozole 2.5 mg daily Exemestane 25 mg daily

Group II: Arm 2: No Breast Radiation Therapy + Endocrine Therapy Active Control 1 Intervention

No radiation therapy, only hormonal drug for at least 5 years. Tamoxifen 20 mg daily Anastrozole 1 mg daily Letrozole 2.5 mg daily Exemestane 25 mg daily

Anastrozol is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Arimidex for:

• Early breast cancer
• Advanced breast cancer

Approved in United States as Arimidex for:

• Postmenopausal women with hormone receptor-positive early breast cancer
• Advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy

Approved in Canada as Arimidex for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer

Approved in Japan as Arimidex for:

• Postmenopausal women with hormone receptor-positive early breast cancer
• Advanced breast cancer in postmenopausal women

Who Is Running the Clinical Trial?

NRG Oncology

Lead Sponsor

Trials

242

Recruited

105,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Letrozole, an aromatase inhibitor, has been shown to significantly improve disease-free survival in breast cancer patients, particularly those at higher risk of relapse, compared to tamoxifen, making it a recommended initial adjuvant therapy.

In addition to its initial use, letrozole also provides benefits when given after 5 years of tamoxifen treatment, with its efficacy increasing with longer treatment durations, highlighting its potential in future combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole: a well-tolerated and effective treatment for breast cancer. Bundred, NJ.[2016]

In a randomized trial, letrozole significantly improved disease-free survival by 19% and reduced the risk of breast cancer recurrence by 28% compared to tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer.

Letrozole is considered cost-effective, providing an additional 0.343 quality-adjusted life years (QALYs) at an incremental cost of Can$ 8,110, resulting in a cost per QALY gained of Can$ 23,662 from the Canadian healthcare perspective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of letrozole versus tamoxifen as initial adjuvant therapy in postmenopausal women with hormone-receptor positive early breast cancer from a Canadian perspective. Delea, TE., El-Ouagari, K., Karnon, J., et al.[2022]

In the BIG 1-98 trial, letrozole demonstrated a 19% reduction in the risk of disease-free survival events compared to tamoxifen, indicating its superior efficacy as an adjuvant therapy for early breast cancer.

Letrozole significantly reduced the risk of distant metastases (hazard ratio 0.73), establishing it as a standard treatment option for postmenopausal women with hormone-sensitive breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving role of letrozole in the adjuvant setting: first results from the large, phase III, randomized trial BIG 1-98. Monnier, A.[2022]

Third-generation aromatase inhibitors, like anastrozole, letrozole, and exemestane, show significant antitumor activity in breast cancer treatment and have fewer side effects compared to tamoxifen.

Anastrozole has been found to be more effective than tamoxifen for postmenopausal women receiving adjuvant endocrine therapy, highlighting its potential as a preferred treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aromatase inhibitors in breast cancer therapy. Buzdar, AU.[2019]

Adjuvant hormonal therapy, particularly with aromatase inhibitors like anastrozole and letrozole, is recommended for postmenopausal women with estrogen receptor-positive early breast cancer, showing better disease-free survival compared to tamoxifen.

Letrozole has demonstrated effectiveness in reducing tumor size before surgery, allowing for more breast-conserving options, and is well tolerated for long-term use in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aromatase inhibitors in early breast cancer treatment. Mauriac, L., Smith, I.[2019]

The ATAC trial, involving over 9,000 postmenopausal women, demonstrated that anastrozole significantly improves disease-free survival and reduces recurrence rates compared to tamoxifen, with benefits continuing even after treatment ends.

Anastrozole also has a favorable safety profile compared to tamoxifen, suggesting it may be a better initial treatment option for early breast cancer, especially when considering long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anastrozole as an adjuvant endocrine treatment for postmenopausal patients with breast cancer: emerging data. Buzdar, AU., Cuzick, J.[2018]

Anastrozole and letrozole are effective oral treatments for advanced breast cancer in postmenopausal women, especially when other therapies like tamoxifen have not worked.

Both drugs are claimed to be more effective and less toxic than the standard treatment, megestrol acetate, although the review assesses the validity of these claims.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New aromatase inhibitors for breast cancer. [2019]

Third-generation aromatase inhibitors (AIs) like anastrozole, letrozole, and exemestane have emerged as effective alternatives to tamoxifen for treating postmenopausal breast cancer, particularly in hormone receptor-positive cases, as shown in the ATAC trial with over five years of follow-up.

Fulvestrant, a new type of estrogen receptor antagonist with no partial agonist activity, represents a promising option in breast cancer treatment, and the review discusses future sequencing strategies for using AIs earlier in treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New developments in the treatment of postmenopausal breast cancer. Howell, A.[2018]

Letrozole is a new non-steroidal aromatase inhibitor approved in Japan for treating postmenopausal women with breast cancer, particularly effective for those with steroid receptor positive or receptor-unknown locally advanced or metastatic cases.

The drug is generally well-tolerated, with mostly mild side effects such as hot flashes and fatigue, and has shown beneficial results in large international studies for post-surgical endocrine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Introduction of new drug: letrozole, a new non-steroidal aromatase inhibitor for the treatment of postmenopausal women with breast cancer]. Tsukagoshi, S.[2018]

In a study of 6241 postmenopausal women with early-stage breast cancer, anastrozole was found to have significantly fewer treatment-related adverse events compared to tamoxifen, indicating better tolerability.

Anastrozole also demonstrated a more favorable risk-benefit profile, with lower rates of serious adverse events and recurrence compared to tamoxifen, making it a preferable option for adjuvant treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Buzdar, A., Howell, A., Cuzick, J., et al.[2022]

Anastrozole and letrozole significantly improve disease-free survival compared to tamoxifen in postmenopausal women with early-stage breast cancer, based on results from Phase III trials.

Switching to an aromatase inhibitor like anastrozole or exemestane after 2 to 3 years of tamoxifen therapy reduces the risk of cancer recurrence more effectively than continuing tamoxifen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are all aromatase inhibitors the same? A review of controlled clinical trials in breast cancer. Berry, J.[2007]

The ATAC trial is one of the few studies that directly compares aromatase inhibitors (AIs) for breast cancer treatment, providing valuable insights into their effectiveness.

Emerging evidence suggests a proposed sequence of hormonal therapies, including anastrozole and tamoxifen, tailored for different patient populations, which could optimize treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hormonal therapy in early and advanced breast cancer. Buzdar, AU.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Letrozole: a well-tolerated and effective treatment for breast cancer. [2016]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of letrozole versus tamoxifen as initial adjuvant therapy in postmenopausal women with hormone-receptor positive early breast cancer from a Canadian perspective. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

The evolving role of letrozole in the adjuvant setting: first results from the large, phase III, randomized trial BIG 1-98. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Aromatase inhibitors in breast cancer therapy. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Aromatase inhibitors in early breast cancer treatment. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Anastrozole as an adjuvant endocrine treatment for postmenopausal patients with breast cancer: emerging data. [2018]

7. England pubmed.ncbi.nlm.nih.gov

New aromatase inhibitors for breast cancer. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

New developments in the treatment of postmenopausal breast cancer. [2018]

9. Japan pubmed.ncbi.nlm.nih.gov

[Introduction of new drug: letrozole, a new non-steroidal aromatase inhibitor for the treatment of postmenopausal women with breast cancer]. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Are all aromatase inhibitors the same? A review of controlled clinical trials in breast cancer. [2007]

12. United States pubmed.ncbi.nlm.nih.gov

Hormonal therapy in early and advanced breast cancer. [2019]