Study on Androgen Receptor and Triple Negative Breast Cancer

This is a multicenter uncontrolled, open-label, prospective, non-comparative randomized, phase II study. Patients will be randomized between darolutamide in Arm n°1 (two-stage Simon's design) and capecitabine in Arm n°2 with two patients randomized in Arm n°1 for one patient randomized in Arm n°2.

The trial population is composed of women over 18 years old with triple-negative and androgen receptor positive, locally recurrent (unresectable) or metastatic breast cancer.


Eligibility Criteria:
Inclusion Criteria:

1. Woman, ≥18 years old;
2. Histologically confirmed locally recurrent (unresectable) or metastatic breast cancer;
3. Triple negative breast cancer:

   Estrogen receptor (ER)-negative and Progesterone receptor (PgR)-negative, as defined by a \<10 % tumor stained cells by immunohistochemistry (IHC); HER2 negative status (i.e. IHC score 0 or 1+, or IHC score 2+ and FISH/SISH/CISH negative), confirmed centrally before inclusion with FFPE tissue from the primary tumour;
4. Androgen receptor (AR)-positive, as defined centrally by a ≥ 10% tumor stained cells by IHC Note: AR assessment by local pathologist before inclusion is not mandatory;
5. Patients with a relapse or progressive disease should be chemotherapy naïve or have received a maximum of one line of chemotherapy for advanced disease (providing they are not presenting with life-threatening metastasis); patients could have received adjuvant or neo-adjuvant therapy;
6. In the exceptional situation of pre-menopausal patient, the addition of a LHRH analog is recommended (androgens might act as an estrogen antagonist in premenopausal patients);
7. Presence of measurable or evaluable disease according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1)
8. Eastern cooperative oncology group (ECOG) ≤1;
9. Normal hematological function: Absolute neutrophile count (ANC) ≥1,500/mm³; platelets count ≥100,000/mm³; hemoglobin \>10 g/dL; Note: subject must not have received any growth factor within 4 weeks or blood transfusion within 7 days of the hematology laboratory sample obtained at screening)
10. Normal hepatic function: total bilirubin ≤ 1.5 upper normal limit (UNL) unless this increase is due to a known Gilbert's disease; aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤2.5 UNL (or ≤5 UNL in case of hepatic metastasis);
11. Creatinine clearance (MDRD formula) ≥50 mL/min;
12. Systolic blood pressure (BP) \<160 mm Hg and diastolic BP \<95 mm Hg, as documented on day of registration/consent (Hypertension allowed provided it is currently controlled);
13. Cardiac ejection fraction ≥50% measured by multigated acquisition (MUGA) or echocardiography (ECHO) done within 4 weeks before inclusion;
14. For premenopausal patients, patient agreeing to use effective contraception during and for ≥6 months after completion of study treatment;
15. Patient able to comply with the protocol;
16. Patient must have signed a written informed consent form prior to any study specific procedures;
17. Patient must be affiliated to a Social Health Insurance.

Exclusion Criteria:

1. HER2-positive status (positivity defined as IHC3+ and/or FISH amplification ≥2);
2. Other concurrent malignancies, except adequately treated cone-biopsied in situ carcinoma of the cervix or basal cell or squamous cell carcinoma of the skin; patients who have undergone potentially curative therapy for a prior malignancy are eligible provided there is no evidence of disease for ≥5 years and patient is deemed to be at low risk for recurrence;
3. Active brain metastases or leptomeningeal disease; history of brain metastases allowed provided lesions are stable for at least 3 months as documented by head CT scan or Magnetic resonance Imaging (MRI) of the brain;
4. Non-malignant systemic disease, including active infection or concurrent serious illness that would make the patient a high medical risk;
5. Significant cardiovascular disease, including any of the following:

   1. NYHA class III-IV congestive heart failure
   2. Stroke, unstable angina pectoris or myocardial infarction within the past 6 months
   3. Severe valvular heart disease
   4. Ventricular arrhythmia requiring treatment;
6. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not be included;
7. Persistent toxicities grade ≥2 from any cause, except chemotherapy-induced alopecia and grade 2 peripheral neuropathy;
8. Any gastrointestinal disorder interfering with absorption of the study drug;
9. Difficulties with swallowing tablets;
10. An active viral hepatitis, known human immunodeficiency virus infection with detectable viral load, or chronic liver disease requiring treatment;
11. PREVIOUS TREATMENT IN THE METASTATIC SETTING: Previous treatment with: capecitabine (MET SETTING), first generation (bicalutamide) or second-generation AR inhibitors (enzalutamide, ARN-509, darolutamide) or other investigational AR inhibitors CYP17 enzyme inhibitor such as abiraterone (capecitabine in the adjuvant setting is allowed provided the last administration was at least ≥12 months prior to study entry)
12. Patients with known deficit of dihydropyrimidine dehydrogenase (DPD) activity; or in case of hypersensitivity to capecitabine or to any of its excipients or to fluorouracil;
13. Prior anticancer therapy within the last 3 weeks including radiotherapy, endocrine therapy, immunotherapy; chemotherapy (6 weeks for nitrosoureas and mitomycin C), or other investigational agents; concurrent palliative radiotherapy is allowed;
14. Concurrent enrolment in another clinical trial in which investigational therapies are administered;
15. Pregnant women, women who are likely to become pregnant or are breast-feeding;
16. Patients with 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;
17. Patients with history of non-compliance to medical regimens or unwilling or unable to comply with the protocol;
18. Individual deprived of liberty or placed under the authority of a tutor.