HR+/HER2- Advanced Breast Cancer and Endocrine Resistance

Inclusion Criteria: 1. Women 18 years or older. 2. Postmenopausal, defined by at least one of the following criteria: 1. Prior bilateral oophorectomy 2. Age ≥60 3. Age \<60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and estradiol in the postmenopausal range according to the local laboratory reference. Note: For women with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol are needed to ensure postmenopausal status. OR Pre/perimenopausal if treated with goserelin that was initiated at least 4 weeks prior to randomization. 3. Locally advanced or metastatic breast cancer deemed not amenable to curative surgery or curative radiation therapy. 4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 5. Known estrogen-receptor positive and/or progesterone receptor positive breast cancer reported by local laboratory. 6. Known HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing. 7. Documented resistance to endocrine therapy (tamoxifen or aromatase inhibitors) defined as: 1. Recurrence while on or within 12 months after the end of adjuvant endocrine treatment OR 2. Progression while on or within 1 month after the end of endocrine treatment for advanced disease 8. Previous chemotherapy for breast cancer including an anthracycline and a taxane (only one line for metastatic disease) is permitted. 9. Radiological or other objective evidence (eg. new skin lesions or new lymph node lesions) of recurrence during or after the most recent systemic therapy for recurrent / metastatic disease prior to randomization. 10. At least one tumor lesion accessible for biopsy that is a non-bone lesion or a predominantly lytic bone lesion, and that measures at least 10 mm in largest diameter. This lesion must not have been treated previously with irradiation (although the area may have been irradiated before the occurrence of the lesion). 11. Patient is interested to participate in the trial, including the obligatory biopsies at a metastatic site/site before the start of study treatment. 12. Clinically and/or radiographically documented measurable disease according to RECIST v1.1 criteria or bone-only disease with at least one predominantly lytic or mixed bone lesion. For measurable disease, at least one site of disease must have largest tumor diameter of at least: 1. 10 mm if measured by CT-scan, ultrasound, or physical exam 2. 20 mm if measured by Chest X-ray 3. 15 mm if suspiciously enlarged lymph node (short axis) see Eisenhauer et al. for more details All radiology studies must be performed within 28 days prior to registration (35 days if negative). 13. Adequate bone-marrow, hepatic and renal function defined as laboratory tests within 7 days prior to enrollment: 1. Hematology: Absolute granulocytes \> 1.5 x 109/L, Platelets \> 100 x 109/L 2. Biochemistry: Bilirubin ≤ 1.5 x upper limit of normal (ULN), Serum creatinine ≤ 1.5 x ULN. 14. 14\. APTT and INR ≤ 1.5 x ULN or institution accepted values for biopsy within 7 days prior to enrollment. 15. Signed written informed consent provided by the patient. Exclusion Criteria: 1. Previous treatment with a CDK4/6 inhibitor, mTOR or PI3K inhibitor, fulvestrant or capecitabine. Short-term (\<28 days) exposure to mTOR or PI3K inhibitor in the (neo)adjuvant setting is allowed. 2. More than one prior chemotherapy lines for metastatic breast cancer. Previous (neo)adjuvant chemotherapy or for radically treated local or regional relapse is allowed in addition to one prior chemotherapy line for metastatic breast cancer Note: A chemotherapy line in advanced disease is an anticancer regimen that contains at least one chemotherapy agent and is given for 21 days or longer. If a cytotoxic chemotherapy regimen was discontinued for a reason other than disease progression and the decision for its discontinuation was taken within 21 days after starting it, then this regimen does not count as a "prior line of chemotherapy". Chemotherapy regimens composed of more than one drug are considered as one line of therapy. 3. No measurable lesions amenable to biopsy (e.g. pleural effusion, ascites, skin rash, sclerotic bone etc). 4. CNS metastases unless asymptomatic and adequately controlled with surgery or radiotherapy. Stable CNS disease is defined as CNS metastases or cord compression that have been definitively treated and the patient is clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization. 5. Leptomeningeal carcinomatosis 6. Advanced, symptomatic visceral spread (visceral crisis) with risk of life-threatening complications in the short term. 7. Concurrent malignancy of any site, except adequately controlled limited basal cell carcinoma or squamous-cell carcinoma of the skin, in situ melanoma or carcinoma in situ of the cervix. 8. Active cardiac disease or a history of cardiac dysfunction including any of the following: 1. History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 12 months prior to study entry 2. History of documented congestive heart failure (New York Heart Association functional classification III-IV) 3. Documented cardiomyopathy 4. QTc \> 480 msec as measured by Bazett's formula, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes. 5. Uncontrolled hypertension. 9. Patients being treated with drugs recognized as strong inhibitors or inducers of the isoenzyme CYP3A (including, but not limited, to - see table 6 - Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazole, Voriconazole, Ritonavir, Telithromycin) continuously for at least 7 days during any time period in the last 2 weeks prior to randomization. 10. Subjects with known dihydropyrimidine dehydrogenase (DHPD) deficiency or previous severe reactions to a fluoropyrimidine. 11. Known abnormalities in coagulation such as bleeding diathesis or ongoing treatment with anticoagulants that preclude intramuscular administration of drugs. 12. Ongoing pregnancy or lactation. 13. 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. 14. A previous metastatic tumor biopsy reported to be negative for both estrogen receptor and progesterone receptor (i.e. \<1% for both), or positive for HER2 status (amplified ERBB2).