Olaparib Maintenance Therapy in Metastatic Breast Cancer

Inclusion Criteria:

1. Patients must have a life expectancy ≥ 16 weeks.
2. Provision of informed consent prior to any study specific procedures
3. 20 years of age or older; gender includes female and male
4. ECOG 0-1
5. Patients should be diagnosed as metastatic breast cancer ER(+)Her2(-) or TNBC,diagnosis could be by local hospital
6. HER2 negative [IHC 0, 1+ or IHC 2+ with corresponding ISH non-amplified of ratio lessthan 2.0 or ISH nonamplified ratio less than 2.0] as per ASCO-CAP HER2 guidelinerecommendations 2013 (ASCO-CAP).
7. At least one lesion, not previously irradiated, that can be accurately measured atbaseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have shortaxis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI)
8. Postmenopausal or evidence of non-childbearing status for women of childbearingpotential: negative urine or serum pregnancy test within 28 days of study treatmentand confirmed prior to treatment on day 1. Postmenopausal is defined at least one ofthe followings: (a) Amenorrheic for 1 year or more following cessation of exogenoushormonal treatments; (b) Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50; (c) radiation- inducedoophorectomy with last menses >1 year ago; (d) chemotherapy-induced menopause with >1year interval since last menses; (f) surgical sterilisation (bilateral oophorectomy orhysterectomy)
9. Male patients must use a condom during treatment and for 3 months after the last doseof olaparib when having sexual intercourse with a pregnant woman or with a woman ofchildbearing potential. Female partners of male patients should also use a highlyeffective form of contraception ([see appendix H for acceptable methods]) if they areof childbearing potential
10. No more than previous 0-1 line of chemotherapy after metastasis confirmed
11. For ER(+) breast cancer, patients should fail at least 1-line of hormone therapy (either in adjuvant setting or in metastatic cancer) before entering this study
12. Patients should undergo 4-cycles of platinum-based chemotherapy and have a CR, PS orSD prior to randomisation.
13. At least one measurable lesion that can be accurately assessed at baseline by computedtomography (CT) (magnetic resonance imaging [MRI] where CT is contraindicated) and issuitable for repeated assessment as per RECIST 1.1.
14. Patients must have normal organ and bone marrow function measured within 28 days priorto randomisation as defined below:
15. Haemoglobin (Hb) ≥10.0 g/dL
16. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
17. Platelet count ≥100 x 109/L
18. Total bilirubin ≤1.5 x institutional upper limit of normal (ULN) unless thepatient has documented Gilbert's Syndrome
19. Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present inwhich case they must be ≤ 5x ULN
20. Patients must have creatinine clearance (CrCl) of ≥51 mL/min estimated ormeasured using standard methodology at the investigating centre (i.e. Cockcroft- Gault, MDRD, CK-EPI, EDTA or 24 hr urine):

Exclusion Criteria:

• Patients should not enter the study if any of the following exclusion criteria arefulfilled:

1. Cytotoxic chemotherapy, hormonal or non hormonal targeted therapy within 21 days ofCycle 1 Day 1 is not permitted. Palliative radiotherapy must have been completed 21 ormore days before Cycle 1 Day 1. The patient can receive a stable dose ofbisphosphonates or denosumab for bone metastases, before and during the study as longas these were started at least 5 days prior to study treatment.
2. More than 2 prior lines of cytotoxic chemotherapy for metastatic disease.
3. Prior treatments with hormonal therapy and non hormonal targeted therapy areallowed and not counted as a prior line of cytotoxic chemotherapy.
4. For the purposes of this protocol, the combination of "an aromatase inhibitor andeverolimus" or "a hormonal therapy and CDK4/6 inhibitor" is not consideredcytotoxic chemotherapy.
5. Treatment with biologics will not be considered as prior line of therapy.
6. Patients receiving any systemic chemotherapy or radiotherapy (except forpalliative reasons) within 3 weeks prior to study treatment
7. Previous treatment with a PARP inhibitor (including olaparib)
8. The minimum washout period for immune checkpoint blockade therapy shall be 21 days.
9. Patients with MDS/AML or with features suggestive of MDS/AML.
10. Patients with second primary cancer, EXCEPTIONS: adequately treated non melanoma skincancer, curatively treated in-situ cancer of the cervix, Ductal Carcinoma in Situ (DCIS), stage 1 grade 1 endometrial carcinoma, or other solid tumours curativelytreated with no evidence of disease for ≥ 5 years prior to study entry (includinglymphomas [without bone marrow involvement]).
11. Mean resting corrected QTc interval using the Fridericia formula (QTcF) >470msec/female patients and >450 msec for male patients (as calculated per institutionalstandards) obtained from 3 ECGs performed 2-5 minutes apart at study entry, orcongenital long QT syndrome.
12. Any of the following cardiac diseases currently or within the last 6 months
13. Unstable angina pectoris
14. Congestive heart failure ≥ Class 2 as defined by the New York Heart Association
15. Acute myocardial infarction
16. Conduction abnormality not controlled with pacemaker or medication (patients witha conduction abnormality controlled with pacemaker or medication at the time ofscreening are eligible)
17. Significant ventricular or supraventricular arrhythmias (patients with chronicrate- controlled atrial fibrillation in the absence of other cardiacabnormalities are eligible)
18. Concomitant use of known strong cytochrome P (CYP) 3A inhibitors (eg. itraconazole,telithromycin, clarithromycin, protease inhibitors boosted with ritonavir orcobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderateCYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washoutperiod prior to starting study treatment is 2 weeks. Patient has had prescription or non-prescription drugs or other products known to besensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, orto be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued 2weeks prior to Day 1 of dosing and withheld throughout the study until 2 weeks afterthe last dose of study drug. Patients should stop using herbal medications 7 daysprior to first dose of study treatment.
19. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) ormoderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washoutperiod prior to starting study treatment is 5 weeks for enzalutamide or phenobarbitaland 3 weeks for other agents.
20. Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy, excludingalopecia.
21. Major surgery within 2 weeks of starting study treatment: patients must have recoveredfrom any effects of any major surgery.
22. Immunocompromised patients, eg, patients who are known to be serologically positivefor human immunodeficiency virus (HIV).
23. Patients considered a poor medical risk due to a serious, uncontrolled medicaldisorder, non-malignant systemic disease or active, uncontrolled infection. a. Examples include, but are not limited to, uncontrolled ventricular arrhythmia,recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder,unstable spinal cord compression, superior vena cava syndrome, extensive interstitialbilateral lung disease on High Resolution CT scan or any psychiatric disorder thatprohibits obtaining informed consent, and any other medical condition that, in theopinion of the Investigator, places the patient at unacceptable risk of toxicity.
24. Patients with symptomatic uncontrolled brain metastases.
25. A scan to confirm the absence of brain metastases is not required. The patientcan receive a stable dose of corticosteroids before and during the study as longas these were started at least 4 weeks prior to treatment. Patients with spinalcord compression unless considered to have received definitive treatment for thisand evidence of clinically stable disease (SD) for 28 days.
26. Patients with a history of treated central nervous system (CNS) metastases areeligible, provided they meet all of the following criteria: Disease outside theCNS is present. No clinical evidence of progression since completion ofCNS-directed therapy. Minimum of 3 weeks between completion of radiotherapy andCycle 1 Day 1 and recovery from significant (Grade ≥3) acute toxicity with noongoing requirement for >10 mg of prednisone per day or an equivalent dose ofother corticosteroid. If on corticosteroids, the patient should be receiving astable dose of corticosteroids, started at least 4 weeks prior to treatment.
27. Patients unable to swallow orally administered medication and patients withgastrointestinal disorders likely to interfere with absorption of the studymedication.
28. Patients with a known hypersensitivity to olaparib or any of the excipients of theproducts.
29. Pregnant or breast feeding women.
30. Patients with HBV infection and uncontrolled hepatitis are not eligible. If patientsare HBV carriers (HBsAg-positive without 2.5x elevation of AST/ALT), these patientscan enter study if they have baseline HBV-DNA level assessed during screening, receiveprophylactic medication and regularly monitored by GI doctor. Patients positive forhepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction isnegative for HCV RNA.
31. Previous allogenic bone marrow transplant or double umbilical cord bloodtransplantation (dUCBT)
32. Whole blood transfusions in the last 120 days prior to entry to the study (packed redblood cells and platelet transfusions are acceptable, for timing refer to inclusioncriteria no.7