ETHAN - ET for Male BC

This is an open-label, multicenter, randomized trial for men with stage I-III hormone receptor-positive (HR+)/HER2-negative breast cancer. The trial will have two phases: A 3-week window phase containing endocrine therapy followed by a 4-month treatment phase where participants are treated with one of four endocrine therapy treatment combinations.

Tamoxifen is the standard of care for the treatment of breast cancer in men. Anastrozole is a standard treatment in women with breast cancer and works more effectively than tamoxifen. This study hopes to learn if anastrozole may also be effective in men. Given that gonadal suppression and CDK 4/6 inhibitors have both improved treatment in women with breast cancer, the study hopes to learn how the addition of Degarelix (gonadal suppression) and Abemaciclib (CDK 4/6 inhibitors) work in comparison to standard of care tamoxifen.

The research study procedures include screening for eligibility and study treatment including laboratory evaluations and quality of life questionnaires.

After completion of treatment, participants will be followed for up to 10 years

It is expected that about 60 men will take part in this research study.

Eli Lilly, a pharmaceutical company, is supporting this research study by providing one of the study drugs. This study is also being supported by Johns Hopkins University on behalf of the Translational Breast Cancer Research Consortium (TBCRC).

• Tamoxifen (Drug), also known as Nolvadex, Soltamox: Taken orally
• Anastrozole (Drug), also known as Arimidex: Taken orally
• Degarelix (Drug): Subcutaneous (under the skin) injection
• Abemaciclib (Drug), also known as Verzenio: Taken orally

Primary outcomes

• Change in Ki-67 [At the end of the 3-week window period.]: Ki-67 will be evaluated by ImmunoHistoChemistry (IHC) following consensus recommendations using imaging analysis methods.
• RCB index [At time of surgery.]: RCB will be determined using data from each participating institution pathology department, and will be reviewed by the study team pathologist.

Secondary outcomes

• Changes in estradiol levels [Baseline and at the end of the three-week window period]: To evaluate the physiologic endocrine changes that occur as a result of treatment with tamoxifen, anastrozole and anastrozole and degarelix as measured by estradiol levels at baseline and at the end of the three-week window period
• Changes in testosterone levels [Baseline and at the end of the three-week window period]: To evaluate the physiologic endocrine changes that occur as a result of treatment with tamoxifen, anastrozole and anastrozole and degarelix as measured by testosterone levels at baseline and at the end of the three-week window period
• Preoperative Endocrine Prognostic Index (PEPI) score [At time of surgery]: To evaluate the comparative efficacy of the experimental treatments as measured by PEPI score at surgery.

Other outcomes

• Grade 3 or Higher Treatment-Related Toxicity Rate [Up to 6 months]: All grade 3 or higher adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv5 as reported on case report forms were counted. Rate is the proportion of treated participants experiencing at least one treatment-related grade 3 or higher AE of any type during the time of observation.
• Trial enrollment [3 years]: We will evaluate how many patients we are able to enroll to this trial in a period of 3 years
• Trial completion [3 years]: We will evaluate how many of the enrolled participants successfully complete the study protocol
• EORTC QLC-C30 questionnaire [Up to 6 months]: Patient-reported outcomes (PROs) measures will be conducted using the EORTC QLC-C30 questionnaire.
• Adapted EORTC BR23 questionnaire [Up to 6 months]: Patient-reported outcomes (PROs) measures will be conducted using the EORTC BR23, adapted by replacing female-specific items with male-specific sexual activity/function items from PR25 (Appendix D of protocol) questionnaire.

Sex: Male, ages: 18 Years to any

Inclusion Criteria:

* Men aged 18 years or older, with diagnosis of invasive breast cancer who have not undergone surgical resection of the primary tumor and axillary nodes.
* Stage I, II, or III per American Joint Committee on Cancer (AJCC) staging 8th edition (112).
* Breast cancer must be hormone receptor-positive and HER2-negative according to definition below assessed by local pathology.

  * Hormone receptor-positive is defined as: positivity for at least one of the hormone receptors (estrogen receptor \[ER\] or progesterone receptor \[PR\]) by IHC. ER and PR assays are considered positive if there are > 1% positive tumor nuclei in the samples.
  * HER2-negative is defined per the current American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline (113).
* Patients with multifocal or multicentric disease are eligible if the treating investigator has determined the patient should be treated as ER-positive and HER2-negative.
* Bilateral breast cancers are allowed if the treating investigator has determined the patient should be treated as ER-positive and HER2-negative.
* Patients with a history of ipsilateral or contralateral DCIS or LCIS are eligible.
* ECOG performance status ≤ 2.
* Required laboratory values demonstrating adequate organ function:

  * ANC ≥ 1000/mm3
  * Hemoglobin ≥ 8 g/dl
  * Platelets ≥ 50,000/mm3
  * Serum creatinine ≤ 3.0 x ULN (institutional)
  * Total bilirubin ≤ 2.0 x ULN (institutional).
  * AST and ALT ≤ 5.0 x ULN (institutional)
* Men with partners of childbearing potential must be willing to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner and continue its use for the duration of the study treatment and for 6 months after the last dose of study treatment.
* Non-English-speaking patients are eligible but will be exempt from patient-completed questionnaires.
* Willing and able to sign informed consent.
* Willing to undergo breast biopsy after completion of window phase.
* Patient is able to swallow oral medications.

Exclusion Criteria:

* Prior endocrine therapy, chemotherapy, radiation therapy, or investigational therapy for the current breast cancer diagnosis.
* Prior endocrine therapy, systemic therapy, radiation therapy, or investigational therapy for any other malignancy within the past 12 months.
* Diagnosis of inflammatory breast cancer (T4d).
* Other concurrent serious diseases that may interfere with planned treatment, including severe cardiac disease, congestive heart failure (CHF) of New York Heart Association (NYHA) Class III or higher, severe pulmonary conditions/illness, uncontrolled infections.
* The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment \[e.g. estimated creatinine clearance <30ml/min\], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
* The patient has active systemic bacterial infection (requiring intravenous \[IV\] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C \[for example, hepatitis B surface antigen positive\]. Screening is not required for enrollment.
* The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.

• Jose Pablo Leone, MD, Principal investigator, Dana-Farber Cancer Institute