Preoperative Fulvestrant With or Without Enzalutamide in ER+/Her2- Breast Cancer

Study Overview
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Brief Summary
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This is a randomized two arm phase II study to further evaluate the efficacy of fulvestrant plus enza compared to single agent fulvestrant in postmenopausal women with locally advanced AR+/ER+/Her2- BC who will have local surgery after  4 months on treatment.

Detailed Description
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This is a randomized two arm phase II study to further evaluate the efficacy of fulvestrant plus enza compared to single agent fulvestrant in postmenopausal women with locally advanced AR+/ER+/Her2- BC who will have local surgery after  4 months on treatment. After consent, all patients will get a tissue biopsy, and than half the patients will get fulvestrant alone (standard dosing) and the other half of the patients will get fulvestrant plus enzalutamide. At  4 weeks, a biopsy will be done and therapy will be continued. Hormone therapy will continue for  4 months at which point the patients will undergo surgical resection.

Official Title
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Randomized Phase II Trial of Preoperative Fulvestrant With or Without Enzalutamide in ER+/Her2- Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ER+ Her2- breast cancer Stage at least T2 or greater Planned to get local surgery Postmenopausal, or if pre- or peri- menopausal, then will need to have concurrent ovarian suppression. At least 18 years of age Not on anticoagulants PS 0-2 Able to swallow study drug and comply with study requirements ANC >1000/uL, platelets >75,000/uL at screening visit Total bilirubin < 1.5 times upper limit of normal (ULN) at the screening visit unless an alternate nonmalignant etiology exists (eg, Gilbert's disease) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 times ULN or < 5 times ULN if patient has documented liver metastases Creatinine < 1.5 times ULN INR < 1.5 times ULN, or if on warfarin, can safely transition off for biopsy Willing to donate blood for research at 4 time points Willing to undergo core biopsies for research at study entry and at  4 weeks. Willing to donate tissue to research from the surgical specimen Written informed consent obtained prior to biopsies and blood samples Exclusion Criteria: Current or previously treated brain or leptomeningeal metastases History of seizures Prior treatment with an anti-androgen (abiraterone, ARN-509, bicalutamide, enzalutamide, ODM-201, TAK-448, TAK-683, TAK-700, VT-464). Systemic estrogens or androgens within 14 days before initiating therapy. Vaginal estrogens are allowed if necessary for patient comfort.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 101 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Fulvestrant Without Enzalutamide<br>500 mg of Fulvestrant will be given IM on days 1, 15, 28, then every 4 weeks as per standard of care (SOC) | Drug: Fulvestrant<br>* 500mg Fulvestrant will be given IM on days 1, 15, 28, then every 4 weeks as per standard of care (SOC)<br>* Other names: FASLODEX;|
| Experimental: Fulvestrant With Enzalutamide<br>500 mg of Fulvestrant will be given IM on days 1, 15, 28, then every 4 weeks as per standard of care (SOC), plus160mg of Enzalutamide will be given daily. | Drug: Enzalutamide<br>* 160mg of Enzalutamide will be given daily in conjunction with Fulvestrant.<br>* Other names: MDV3100;Drug: Fulvestrant<br>* 500mg Fulvestrant will be given IM on days 1, 15, 28, then every 4 weeks as per standard of care (SOC)<br>* Other names: FASLODEX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With a PEPI Score Equal to Zero at Post Treatment | The preoperative endocrine prognostic index (PEPI) is a validated measure of pathologic response to endocrine therapy. It is a model that combines estrogen receptor (ER) level, pathologic tumor site, nodal status, and Ki67 score at the time of surgery to predict subsequent risk of cancer recurrence. PEPI scoring is typically discretized into three risk groups: 0 (low risk of recurrence and best outcome), 1-3 (intermediate risk), and >= 4 (high risk). This study was concerned only with the distinction between zero and non-zero PEPI scores. Zero is the minimum score, and there is no maximum score. Lower scores are better. | 16 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free Survival | Disease-free survival is defined as the time in months from the start of fulvestrant until documented disease progression or death. Complete and partial response for the single drug arm and combination of enzalutamide/fulvestrant arm separately. | 15 months | 
| Correlation Between PEPI Score and Disease-free Survival, Clinical Benefit Rate, and Overall Response Rate | To assess the association between PEPI score and the clinical, outcomes such as DFS, ORR, clinical benefit for all subjects. | 4 years | 
| Androgen Receptor (AR) Expression | The strength of AR signaling was measured by the percentage of downstream AR-regulated genes that were expressed. | 16 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ER+/Her2 - breast cancer, Preoperative Fulvestrant, Enzalutamide