A strong rationale accumulated over the years suggests that within HR+/HER2-negative breast
cancer, tumors falling into the PAM50 HER2-enriched subtype have androgen receptor
(AR)-dependency. To test this hypothesis directly in patients' tumors, we propose an
exploratory, open-label, non-randomized, two-cohort, multicenter, prospective, phase II study
which evaluates the effect of enzalutamide on proliferation after 2 weeks (14-21 days) of
treatment in patients with endocrine-resistant, locally advanced or metastatic
HR+/HER2-negative breast cancer. After 2 weeks (14-21 days) of treatment, patients will
continue enzalutamide. Exemestane will be allowed to be added to enzalutamide per
investigator discretion and will be administered until progression or unacceptable toxicity.
- Written informed consent for all study procedures according to local regulatory
requirements prior to beginning specific protocol procedures.
- Subjects with progression on or following at least 1 prior standard of care systemic
- Female and male patients.
- Performance status of 0-2.
- Age ≥18 years.
- Pre/peri-menopausal and post-menopausal women are allowed; menopausal status is
relevant for the requirement of goserelin, triptorelin or leuprolide to be used
concomitantly with enzalutamide. Post-menopausal status is defined either by:
- Prior bilateral oophorectomy or
- Age ≥60 or
- Age < 60 and amenorrhea for ≥ 12 months (in the absence of chemotherapy,
tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the
post-menopausal range per local standards.
- If a patient is taking tamoxifen or toremifene and is aged < 60, then FSH and
plasma estradiol levels should be in post-menopausal range per local values.
- For women with therapy-induced amenorrhea, measurement of FSH and/or estradiol
are needed to ensure menopausal status.
- Life expectancy ≥ 12 weeks.
- Locally advanced or metastatic breast cancer not amenable to curative intent.
- Histologically confirmed HR-positive/HER2-negative disease based on the most recent
biopsy before signing the informed consent.
- HER2 negativity is defined as either of the following by local laboratory
assessment: IHC 0, IHC 1+ or IHC2+/in situ hybridisation (ISH/FISH) negative as
per American Society of Clinical Oncology (ASCO)-College of American Pathologists
Guideline (CAP) guideline(73).
- ER and/or PR positivity are defined as >1% of cells expressing HR via IHC
analysis as per ASCO-CAP guideline (74)
- Patients must have a site of disease amenable to safely perform a biopsy, as per
Investigator's assessment, and be a candidate for tumor biopsy according to the
treating institution's guidelines.
- Possibility of performing a biopsy prior to the start of treatment and its repetition
after 2 weeks (14-21 days) on the same location. It will be provided formalin-fixed
paraffin-embedded (FFPE) tumor block. The tumor tissue should be of good quality based
on total and viable tumor content and must be evaluated centrally for PAM50 analysis
prior to enrollment. Patients whose tumor tissue is not evaluable for central testing
are not eligible. It is recommended to send the biopsy directly to the central lab
after confirming the existence of a tumor, so as not to delay the inclusion, without
the need to carry out IHC studies in the same.
- Acceptable samples include core needle biopsies for deep tumor tissue or
excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous,
or mucosal lesions or biopsies from bone metastases.
- Fine needle aspiration, brushing, cell pellet from pleural effusion and lavage
samples are not acceptable.
- Patient must be willing to provide biopsy prior to the start of treatment and its
repetition after 2 weeks (14-21 days) on the same location.
- The following subtypes identified in the pre-treatment tumor biopsy, as assessed by
PAM50 assay at the Central Laboratory:
- HER2-E (Cohort A)
- Luminal A and Luminal B (Cohort B).
- No more than 4 prior lines of chemotherapy regimens for recurrent, locally advanced or
metastatic breast cancer.
- Endocrine resistant disease, defined as the presence of disease recurrence while
receiving adjuvant endocrine therapy for early stage breast cancer or disease
progression of locally advanced/metastatic BC under ongoing endocrine therapy. There
is no limit of previous received hormonal agents.
- Measurable and non-measurable (but evaluable) disease per RECIST 1.1 criteria.
- Adequate organ function, as determined by the following laboratory tests, within 28
days prior to enrollment:
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
- Hemoglobin (Hb) ≥ 9 g/dL (red blood cell transfusion and/or erythropoietin
allowed 7 days before study treatment).
- Platelets ≥ 75,000/mm3.
- International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN and
activated partial thromboplastin time (aPTT) within therapeutic range
- Serum creatinine ≤ 1.5x upper limit of normal (ULN)
- AST or ALT ≤ 3 x ULN.
- Serum bilirubin ≤ 1.5 upper limit of normal (ULN) unless the patient has
documented non-malignant disease (e.g. Gilbert´s syndrome).
- Ability to swallow study drug and comply with study requirements.
- Resolution of all acute toxic effects of prior therapy or surgical procedures to
baseline or Grade ≤ 1 (except alopecia or other toxicities not considered to be a
safety risk for the patient) according to NCI CTCAE version 5.0.
- History of current or previously treated CNS metastases or leptomeningeal disease.
Testing for CNS metastasis is not mandatory.
- History of seizure or any condition that may predispose to seizure.
- Clinically significant cardiovascular disease within 6 months prior to enrolment
- Myocardial infarction.
- Inadequately controlled angina or serious cardiac arrhythmia not controlled by
- Congestive heart failure (CHF) New York Health Association (NYHA) Class ≥ II.
- History of clinically significant ventricular arrhythmias (eg, ventricular
tachycardia, ventricular fibrillation, torsade de pointes).
- History of Mobitz II second-degree or third-degree heart block without a
permanent pacemaker in place.
- Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury
(mmHg) on 2 consecutive measurements at the screening visit.
- Bradycardia as indicated by a heart rate of < 50 beats per minute on the
screening electrocardiogram (ECG) recording.
- Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or
diastolic blood pressure > 105 mmHg on 2 consecutive measurements at the
- Inability to swallow tablets, extensive reduction surgery of the stomach or small
bowel or any active gastrointestinal disorder which may impair the absorption of the
trial treatment (e.g. active peptic ulcer disease; uncontrolled celiac disease).
- Major surgical procedure within 4 weeks prior to allocation or anticipation of the
need for major surgery during the course of study treatment.
- Use of medications that could reduce seizure threshold or concomitant treatment with
potent CYP3A4 inducers.
- Treatment with warfarin and coumarin-like anticoagulants. Prophylactic use of low
molecular weight heparin (LMWH) is allowed.
- Fructose intolerance.
- Treatment with any anticancer commercially available or investigational drug within 14
days prior to commencing trial treatment.
- Hypersensitivity reaction to the active pharmaceutical ingredient or any of the
capsule components, including Labrasol, butylated hydroxyanisole, and butylated
- Current severe disease, infection, or systemic condition that renders the patient
inappropriate for enrollment in the opinion of the investigator.
- Presence of any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule; those
conditions should be discussed with the patient before registration in the trial.
- Has a known history of Human Immunodeficiency Virus (HIV).
- Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is
detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required
unless mandated by local health authority.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of enzalutamide.
- Treatment with any approved or investigational agent that blocks androgen synthesis or
targets the AR (eg, abiraterone acetate, ARN-509, bicalutamide, enzalutamide, ODM-201,
TAK-448, TAK-683, TAK-700); or patients who progressed on Exemestane in
adjuvant/advanced setting are not allowed; patients who received treatment for < 28
days or placebo on an investigational study are acceptable