Phase III Study to Evaluate the Safety, Efficacy, and Impact on Quality of Life of Capivasertib Alongside Standard-of-care Endocrine Treatment in Patients With HR+/HER2- Advanced Breast Cancer and Progression on Prior Endocrine-based Treatment

This is a multicentre phase-III-trial to evaluate the use of capivasertib in patients with HR+/HER2- advanced breast cancer and progression on prior endocrine-based treatment. The goal of this study is 1. To evaluate benefit of capivasertib regarding time to next treatment (TTNT1) - i.e., time "on treatment" with capivasertib. 2. To evaluate the benefits of patient reported outcome(PRO)-adherence regarding the deterioration of quality of life (DQoL)-free interval. There is no active comparison group but a historical control group consisting of data of patients treated within the CAPItello-291-study.. Participants will take capivasertib accompanied by standard of care endocrine treatment and are asked to document ther quality of life on standardised questionnaires. Optionally, patients can use eHealth support via their own smart phones.

Inclusion Criteria: 1. Females (≥18 years, pre-, peri- or post-menopausal) and males (≥18 years) at the time of signing the informed consent form a. Pre-menopausal (and peri-menopausal, i.e., those that do not meet the criteria for post menopausal defined below) women can be enrolled if amenable to treatment with an GNRH agonist. Patients are to have commenced concomitant treatment with GNRH agonist prior to or on Cycle 1, Day 1 and must be willing to continue it for the duration of the study. b. Post-menopausal women are defined as: i. aged ≥60 years of age, OR ii. aged \1.5 × ULN concurrent with creatinine clearance \1.5 × ULN 11. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, or active infection including tuberculosis, hepatitis B, hepatitis C, and human immunodeficiency virus (HIV), including those who have confirmed COVID 19 and any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent. Screening for chronic conditions is not required. Note: Known active hepatitis B or C infection, positive hepatitis C antibody, positive hepatitis B virus surface antigen. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients receiving antiretroviral therapies which are strong inhibitors or inducers of CYP3A4 will be excluded due to the potential for drug-drug interaction with capivasertib 12. Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant or subcutaneous injections of GNRH agonist (if applicable) 13. Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection, or other condition that would preclude adequate absorption of capivasertib 14. Previous allogenic bone marrow or solid organ transplant 15. History of another primary malignancy 16. Known immunodeficiency syndrome 17. Mean resting corrected QT interval \>470 ms, obtained from triplicate ECGs performed at screening. History of QT prolongation associated with other medications that required discontinuation of that medication \[Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.\] 18. Medical history significant for arrhythmia (e.g., multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted to enter the study based on the Investigator judgement with cardiologist consultation recommended. 19. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, hypokalaemia of Grade \>1, potential for Torsades de Pointes, congenital long QT syndrome 20. Experience of any of the following procedures or conditions in the preceding 3 months: coronary artery bypass graft, angioplasty, myocardial infarction, unstable angina pectoris. Congestive heart failure New York Heart Association (NYHA) ≥grade 2. 21. History of hypersensitivity to active or inactive excipients of capivasertib, fulvestrant and GNRH agonists (if applicable, i.e., concomitant GNRH agonist required in this study) or drugs with a similar chemical structure or class to capivasertib, fulvestrant or GNRH agonists (if applicable) 22. Radiotherapy within 14 days prior to first dose of capivasertib 23. Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study. 24. Evidence of dementia altered mental status or any psychiatric condition that would prohibit understanding or rendering of informed consent 25. Pregnancy or breastfeeding 26. Patients who at time of data collection for this study are participating in or have participated in an interventional study that remains blinded 27. More than 2 lines of endocrine-based therapy for inoperable locally advanced or mBC 28. More than 1 line of chemotherapy for inoperable locally advanced or mBC. Adjuvant and neoadjuvant chemotherapy are not classed as lines of chemotherapy for mBC 29. Prior treatment with any of the following: 1. AKT, PIK3 and mTOR inhibitors 2. ngSERD (Note: prior treatment with fulvestrant (=SERD) is allowed!) 3. Nitrosourea or mitomycin C within 6 weeks prior to study treatment initiation 4. Any other chemotherapy, immunotherapy, immunosuppressant medication (other than corticosteroids) or anticancer agents within 3 weeks prior to study treatment initiation. A longer washout period may be required for drugs with a long half-life (e.g., biologics) as agreed by the sponsor 5. Potent inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose of study treatment (3 weeks for St John's wort) or drugs that are sensitive to CYP3A4 inhibition within 1 week prior to study treatment initiation. 6. Any concomitant medication that may interfere with capivasertib or fulvestrant safety and efficacy based on the Investigator´s Brochure of capivasertib and the prescribing information of fulvestrant and local clinical guidelines, e.g., that are known to be associated with Torsade de Pointes or potent inducers of cytochrome P450 3A4 (CYP3A4).