Chemotherapy + Hormone Therapy for Breast Cancer

(OFSET Trial)

Recruiting at 1245 trial locations

Overseen By Rubina Qamar

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding chemotherapy to hormone therapy improves survival in premenopausal women with early-stage, hormone-positive breast cancer. It compares two treatment options: one uses only hormone therapy (Ovarian Function Suppression + Aromatase Inhibitor), while the other combines hormone therapy with chemotherapy (Adjuvant Chemotherapy + Ovarian Function Suppression). Premenopausal women with hormone-sensitive breast cancer that hasn't spread might be suitable candidates. 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.

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.

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

Research has shown that suppressing ovarian function (OFS) with hormone therapy (ET) is generally safe for premenopausal women. In one study involving 2,647 patients, combining OFS with a drug that lowers estrogen levels was well-tolerated. Another study found that using these drugs for five years is usually safe and can reduce breast cancer deaths by 15% compared to tamoxifen, another common treatment.

When additional chemotherapy follows the main treatment, studies have not identified major safety concerns. Although chemotherapy can cause side effects, adding OFS and ET for young breast cancer patients has been linked to better outcomes without new safety issues.

Overall, these treatments have been well-studied and are generally safe. However, like any treatment, side effects can occur, so discussing expectations with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for breast cancer because they combine ovarian function suppression with aromatase inhibitors, potentially enhancing the effectiveness of hormone therapy. This approach is different from traditional treatments that typically focus on one method at a time. By integrating a GnRH agonist with aromatase inhibitors, these treatments aim to more effectively block estrogen production, which is crucial for slowing the growth of hormone receptor-positive breast cancer. Additionally, the choice of drugs and dosing schedules can be tailored to each patient's needs, offering a personalized approach that may improve outcomes.

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

Research has shown that adding adjuvant chemotherapy to treatments that suppress ovarian function and use aromatase inhibitors can improve outcomes for premenopausal women with certain early-stage breast cancers. In this trial, one group of participants will receive this combination of adjuvant chemotherapy, ovarian function suppression, and aromatase inhibitors. Studies have found that combining ovarian function suppression with aromatase inhibitors lowers the chance of cancer recurrence and improves survival rates. Specifically, one study found that patients had a 7.5% better chance of being cancer-free after eight years with these treatments. Another study demonstrated that using ovarian function suppression with aromatase inhibitors or tamoxifen led to better survival outcomes. These findings suggest that this combination of treatments could effectively help patients remain cancer-free longer. ^{2 3 6 7 8}

Are You a Good Fit for This Trial?

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.

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

I have chronic hepatitis B but it's undetectable with my current treatment.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10938175/

Adjuvant Ovarian Function Suppression in Premenopausal ... This cohort study of 2647 individuals with premenopausal, early-stage breast cancer diagnoses found no significant recurrence risk reductions ...

2. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2816030

Adjuvant Ovarian Function Suppression in Premenopausal ... A 2-year duration of OFS was associated with reduced recurrence risk. Meaning This study may provide insights on the use of adjuvant OFS; ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.505

15-year outcomes for women with premenopausal ... The high level 15y final results of the SOFT and TEXT confirm a role for OFS- and aromatase inhibitor-containing adjuvant endocrine therapy for premenopausal ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0960977625004758

Real-world utilization of aromatase inhibitors, tamoxifen, ... This study assessed the use of adjuvant endocrine therapies for premenopausal patients with intermediate/high-risk HRpos/HER2neg eBC.

5. thelancet.com thelancet.com/journals/eclinm/article/PIIS2589-5370(25)00048-3/fulltext

Adjuvant endocrine treatment strategies for non-metastatic ... In the overall population of premenopausal patients, OFS + AI was associated with an absolute improvement in DFS at 8 years of 7.5% compared to ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.507

The impact of ovarian function suppression with adjuvant ... In this global cohort of young BRCA mutation carriers, OFS combined with ET was associated with improved DFS, BCFI and OS versus tam without OFS.

7. sciencedirect.com sciencedirect.com/science/article/pii/S0305737224000987

Revisiting ovarian function suppression with GnRH ... In this review article, we discuss the long-term survival benefit, efficacy in different recurrence risk groups, safety outcomes, and ovarian function ...

8. yalemedicine.org yalemedicine.org/clinical-trials/evaluating-the-addition-of-adjuvant-chemotherapy-to-ovarian-function-suppression-plus-endocrine-ther

A Phase III Adjuvant Trial Evaluating the Addition ... This Phase III Trial will determine whether adjuvant chemotherapy (ACT) added to ovarian function suppression (OFS) plus endocrine therapy (ET) is superior to ...