study on androgen receptor and triple negative breast cancer

Conditions: Breast Cancer Female; Triple Negative and Androgen Receptor Positive

Summary: 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.