Chemotherapy + Hormone Therapy for Breast Cancer

(OFSET Trial)

Recruiting at 1159 trial locations

Overseen By Norman Wolmark, MD

Age: 18 - 65

Sex: Female

Trial Phase: Phase 3

Sponsor: NRG Oncology

Must be taking: Endocrine therapy

Must not be taking: Hormonally based contraceptives

Disqualifiers: Metastatic disease, Cardiac disease, 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)

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 5 years

3960 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing if adding additional cancer-fighting drugs to treatments that stop certain body functions is better than just using the treatments that stop those functions alone. It targets younger women with early-stage breast cancer who have a higher risk of dying from the disease. The treatment works by stopping certain body functions and using drugs to kill cancer cells.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does require that hormonally based contraceptives be discontinued before joining. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Adjuvant Chemotherapy + Ovarian Function Suppression for breast cancer?

Research shows that ovarian function suppression (OFS) with tamoxifen or aromatase inhibitors (AIs) can improve disease-free survival in premenopausal women with breast cancer, especially those at higher risk of recurrence. ^{1 2 3 4 5}

Is the combination of chemotherapy and hormone therapy generally safe for humans?

The research indicates that aromatase inhibitors (a type of hormone therapy) can lead to ovarian function recovery in women who experienced ovarian failure due to chemotherapy. This recovery can affect hormone levels, but the studies do not report severe safety concerns related to the combination of chemotherapy and hormone therapy. ^{2 3 4 5 6}

How is the treatment Ovarian Function Suppression + Aromatase Inhibitor unique for breast cancer?

This treatment is unique because it combines ovarian function suppression (which stops the ovaries from producing hormones) with aromatase inhibitors (which block estrogen production) to improve disease-free survival in premenopausal women with breast cancer, especially those at higher risk of recurrence. ^{1 2 3 7 8}

Eligibility Criteria

This trial is for premenopausal women at least 18 years old with early-stage, ER-positive/HER2-negative breast cancer and a low to intermediate recurrence score. They must have had surgery for breast cancer within the last 16 weeks and be eligible for radiation therapy. Women can't join if they are pregnant, breastfeeding, have severe heart issues, other non-breast cancers that could affect the study's safety or results, or any metastatic disease.

Inclusion Criteria

I have another cancer type, but it won't affect this cancer treatment's safety or results.

I have breast cancer in more than one location, but only the largest tumor needs treatment according to the trial's criteria.

I have breast cancer in one or both breasts, but only the highest stage tumor qualifies for this trial and the other tumors don't need chemotherapy or HER2 therapy.

Exclusion Criteria

Your recent lab test results show any of the following values.

I have a heart condition or have been treated with heart-toxic drugs and need a heart function assessment.

My breast cancer is not the common type; it's a rare form like sarcoma or lymphoma.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive adjuvant chemotherapy followed by ovarian function suppression and endocrine therapy

5 years

Monthly or every-three-months visits for GnRH agonist administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

11 years

Treatment Details

Interventions

• Adjuvant Chemotherapy + Ovarian Function Suppression
• Ovarian Function Suppression + Aromatase Inhibitor

Trial Overview The trial is testing if adding adjuvant chemotherapy to ovarian function suppression plus endocrine therapy improves survival without invasive breast cancer returning in patients with certain types of early-stage breast cancer compared to just ovarian function suppression plus endocrine therapy.

Participant Groups

Group I: Arm 2 Adjuvant Chemotherapy + Ovarian Function Suppression + Aromatase Inhibitor Active Control 2 Interventions

Adjuvant chemotherapy of investigator's choice followed by an aromatase inhibitor (AI) co-administered with an GnRH agonist for 5 years. The choice of AI is per investigator discretion. The choice of GnRH agonist and dosing schedule is per investigator's discretion. Options commonly include goserelin, leuprolide, or triptorelin given monthly or every-three-months. The dose and schedule of AI should be consistent with the drug package insert. Endocrine treatment beyond 5 years is at the investigator's discretion. Bilateral oophorectomy may substitute for ovarian suppression if desired.

Group II: Arm 1: Ovarian Function Suppression + Aromatase Inhibitor Active Control 1 Intervention

Aromatase inhibitor co-administered with a GnRH agonist (gonadotropin releasing hormone) for 5 years. The choice of AI is per investigator discretion. The choice of GnRH agonist and dosing schedule is per investigator's discretion. Options commonly include goserelin, leuprolide, or triptorelin given monthly or every-three-months. The dose and schedule of AI should be consistent with the drug package insert. Endocrine treatment beyond 5 years is at the investigator's discretion. Bilateral oophorectomy may substitute for ovarian suppression if desired.

Ovarian Function Suppression + Aromatase Inhibitor is already approved in United States, European Union for the following indications:

Approved in United States as Ovarian Function Suppression + Aromatase Inhibitor for:

• Hormone receptor-positive, HER2-negative breast cancer in premenopausal women

Approved in European Union as Ovarian Function Suppression + Aromatase Inhibitor for:

• Early-stage hormone receptor-positive, HER2-negative breast cancer in premenopausal 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

In a study of 1717 premenopausal women with hormone receptor-positive breast cancer, the use of ovarian function suppression (OFS) increased significantly after 2014, particularly in combination with aromatase inhibitors (AIs).

Patients receiving OFS showed a better overall survival rate compared to those who did not, with an adjusted hazard ratio of 0.44, indicating a 2.1% absolute survival benefit at 5 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of Adjuvant Ovarian Function Suppression in Premenopausal Women With Early Breast Cancer: A Multicenter Cohort Study. Ferreira, AR., Ribeiro, J., Miranda, A., et al.[2021]

In a study of 329 postmenopausal women with chemotherapy-induced ovarian function failure, the rate of ovarian function recovery during treatment with aromatase inhibitors (AIs) was found to be 12.4% over 30 months, indicating a notable risk of recovery even in older patients.

Women who experienced ovarian function recovery had significantly higher estradiol levels during AI treatment compared to those who did not, suggesting that higher estradiol levels may impact the efficacy of AIs in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ovarian Function Recovery During Anastrozole in Breast Cancer Patients With Chemotherapy-Induced Ovarian Function Failure. van Hellemond, IEG., Vriens, IJH., Peer, PGM., et al.[2022]

In a study of 45 women with hormone receptor-positive breast cancer, 28.9% experienced recovery of ovarian function during aromatase inhibitor therapy after a median of 2.1 months, indicating that some women may regain ovarian function even after chemotherapy-induced ovarian failure.

Younger age at the start of chemotherapy was a significant predictor of ovarian function recovery, with those regaining function having a median age of 43 compared to 49 for those who remained postmenopausal, highlighting the importance of age in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of recovery of ovarian function during aromatase inhibitor therapy. Henry, NL., Xia, R., Banerjee, M., et al.[2022]

In a study of estrogen receptor-positive breast cancer patients who had experienced chemotherapy-induced amenorrhea, switching from tamoxifen to the aromatase inhibitor exemestane resulted in a 30-32% incidence of ovarian function recovery (OFR) after about 5-6 months.

Younger patients (under 48 years) were more likely to experience OFR, but those with OFR had significantly lower disease-free survival rates, suggesting that switching to an AI may not be beneficial for this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and predictors of ovarian function recovery (OFR) in breast cancer (BC) patients with chemotherapy-induced amenorrhea (CIA) who switched from tamoxifen to exemestane. Guerrero, A., Gavilá, J., Folkerd, E., et al.[2022]

In a study of 177 women aged 40 to 49 with estrogen receptor-positive breast cancer, 39% regained ovarian function after 2 years of aromatase inhibitor therapy, highlighting a significant chance of ovarian function recovery in this group.

The study suggests that aromatase inhibitors should be avoided in premenopausal women undergoing chemotherapy-induced amenorrhea, as the risk of ovarian function recovery is considerable, particularly in those under 45 years of age.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and Predictive Factors for Recovery of Ovarian Function in Amenorrheic Women in Their 40s Treated With Letrozole. Krekow, LK., Hellerstedt, BA., Collea, RP., et al.[2018]

In a study of 207 breast cancer patients aged 36 to 56, 10.7% of those on aromatase inhibitors (AIs) experienced ovarian function recovery (OFR), indicating a potential risk for breast cancer outcomes during treatment.

Younger age (under 50) and previous chemotherapy were identified as significant risk factors for OFR, highlighting the need for careful monitoring of menopausal status and ovarian activity in patients undergoing adjuvant AI therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Measurable Serum Estradiol and Estrone in Women 36-56 Years During Adjuvant Treatment With Aromatase Inhibitors for a Hormone Receptor-Positive Breast Cancer. Case Studies and Cross-sectional Study Using an Ultra-sensitive LC-MS/MS-Method. Van Houdt, M., Han, SN., Pauwels, S., et al.[2023]

Aromatase inhibitors (AIs) are effective in treating breast cancer in postmenopausal women, with steroidal AIs like exemestane potentially having unique androgenic effects, though their clinical significance is still unclear.

Switching between steroidal and nonsteroidal AIs can provide modest benefits, indicating that these two classes may not fully overlap in effectiveness, but more research is needed to determine the best treatment sequences and the impact of combining AIs with estrogen-receptor blockers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aromatase inhibitors: are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter? Miller, WR., Bartlett, J., Brodie, AM., et al.[2008]

Aromatase inhibitors, which block the production of estrogens, are a promising treatment strategy for hormone-dependent cancers, particularly breast cancer.

4-hydroxyandrostenedione, a steroidal aromatase inhibitor, has been approved for use in advanced breast cancer patients in the UK, and several new non-steroidal inhibitors are currently in clinical trials, expanding treatment options for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aromatase, its inhibitors and their use in breast cancer treatment. Brodie, AM.[2019]

References

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

Effectiveness of Adjuvant Ovarian Function Suppression in Premenopausal Women With Early Breast Cancer: A Multicenter Cohort Study. [2021]

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

Ovarian Function Recovery During Anastrozole in Breast Cancer Patients With Chemotherapy-Induced Ovarian Function Failure. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Predictors of recovery of ovarian function during aromatase inhibitor therapy. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Incidence and predictors of ovarian function recovery (OFR) in breast cancer (BC) patients with chemotherapy-induced amenorrhea (CIA) who switched from tamoxifen to exemestane. [2022]

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

Incidence and Predictive Factors for Recovery of Ovarian Function in Amenorrheic Women in Their 40s Treated With Letrozole. [2018]

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

Measurable Serum Estradiol and Estrone in Women 36-56 Years During Adjuvant Treatment With Aromatase Inhibitors for a Hormone Receptor-Positive Breast Cancer. Case Studies and Cross-sectional Study Using an Ultra-sensitive LC-MS/MS-Method. [2023]

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

Aromatase inhibitors: are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter? [2008]

8. England pubmed.ncbi.nlm.nih.gov

Aromatase, its inhibitors and their use in breast cancer treatment. [2019]