To Study Clinical Effectiveness and Safety of Olaparib Monotherapy in Metastatic Breast Cancer Patients.

A Phase IIIb, Single-arm, Open-label Multicentre Study of Olaparib Monotherapy in the Treatment of HER2-ve Metastatic Breast Cancer Patients With Germline or Somatic BRCA1/2 Mutations.

This open-label, multi-centre phase IIIb study will assess the effectiveness, benefits and potential harms in the use of olaparib monotherapy treatment for patients with HER2-ve metastatic breast cancer associated with germline or somatic breast cancer susceptibility gene (gBRCA1/2 or sBRCA1/2) mutations.

The study is a phase IIIb, multicenter, single-arm, open-label study designed to evaluate the clinical effectiveness in a real-world setting of olaparib monotherapy in patients with confirmed germline or somatic breast cancer susceptibility gene (gBRCA1/2 or sBRCA1/2) mutations. This study will generate additional data to support other olaparib studies, which may help inform and guide clinical practice. Physician defined the progression-free survival (PFS) for gBRCAm patients is the primary outcome measure. Based on the prevalence of gBRCA1/2 mutations, it is estimated that up to 1400 patients may require screening in order to identify 250 gBRCA mutated patients and 20 sBRCA mutated patients. Patients will be administered two olaparib 150mg tablets in morning and evening of every day after a light meal. Dose reductions may be required for olaparib treatment related toxicities. Patients should continue to receive study treatment until documented physician-defined disease progression as assessed by the investigator (gBRCA mutated patients), RECIST1.1 disease progression (sBRCA mutated patients) or unacceptable toxicity, or for as long as they do not meet any other discontinuation criteria. A positive benefit/risk profile is expected and no ethical issues are identified from exposing patients to olaparib within the planned clinical study.

Inclusion criteria:

1. Provision of informed consent prior to any study specific procedures. For patients aged <20 years and screened in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.

2. Patients must be ≥18 years of age.

3. Histologically or cytologically confirmed HER2-ve breast cancer with evidence of metastatic disease. Patients can have either TNBC (defined as oestrogen receptor and progesterone receptor negative [immunohistochemistry nuclear staining <1%] and HER2-ve [immunohistochemistry 0, 1+ or 2+ and/or in situ hybridization nonamplified with ratio less than 2.0]) or oestrogen receptor / progesterone receptor positive breast cancer as long as they are HER2-ve.

4. Documented BRCA1/2 status

   • To be regarded as BRCA1/2 (+ve), the patient must have a mutation that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental / lead to loss of function). Mutations that are not clearly pathogenic may be assessed by a committee of genetic specialists to adjudicate if the patient is eligible.
   • Patients with tBRCA mutations: must be confirmed by a validated method (e.g. results from a CLIA-certified laboratory or CE-IVD device)

5. Prior treatment with a taxane or an anthracycline in either an adjuvant (may include neoadjuvant) or metastatic breast cancer treatment setting.

6. Patients should have received no more than two prior cytotoxic chemotherapy regimens in the metastatic setting. If a patient has oestrogen receptor and/or progesterone receptor positive HER2 negative metastatic breast cancer and has completed a prior line of hormonal treatment, then if the current or currently planned choice of treatment for the patient does not include a hormonal treatment then they would be a suitable patient to enter the study. Previous endocrine therapy could be in either an adjuvant or a metastatic setting and include endocrine therapy in combination with a targeted agent such as a CDK4/6 or mTOR inhibitor.

7. Be considered suitable, by the Investigator, for further treatment with single-agent chemotherapy for the metastatic disease

8. Patients must have normal organ and bone marrow function measured within 14 days prior to administration of study treatment as defined below:

   • Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days
   • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
   • Platelet count ≥ 100 x 109/L
   • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) unless the patient has documented Gilbert's Syndrome
   • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT)) / alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase (SGPT)) ≤ 2.5 x institutional ULN unless liver metastases are present in which case they must be ≤ 5x ULN
   • Patients must have creatinine clearance (CrCl) estimated using the Cockcroft- Gault equation of ≥ 51 mL/min or 24 hour urine test may be done if standard of care:

   Estimated CrCl = (140-age [years]) x weight (kg) (x F)a serum creatinine (mg/dL) x 72

   a- where F=0.85 for females and F=1 for males

9. Patients must have a life expectancy ≥ 16 weeks

10. Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on Day 1

    Postmenopausal is defined as (at least one criterion met):

    • amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments
    • luteinizing hormone and follicle stimulating hormone levels in the postmenopausal range for women under 50
    • radiation-induced oophorectomy with last menses >1 year ago
    • chemotherapy-induced menopause with >1 year interval since last menses
    • surgical sterilisation (bilateral oophorectomy or hysterectomy).

11. Women of childbearing potential, who are sexually active, must agree to the use of one highly effective form of contraception and their male partners must use a condom from the signing of the informed consent, throughout the period of taking study treatment and for at least 1 month after last dose of study drug, or they must totally/truly abstain from any form of sexual intercourse.

12. Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use one highly effective form of contraception if they are of childbearing potential.

13. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations for greater than 6 months.

Exclusion criteria:

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)

2. Previous enrolment in the present study

3. Exposure to an investigational product (IP) during the last 1 month or 5 half-lives (whichever is longer) prior to enrolment

4. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment

5. Any previous treatment with a PARP inhibitor, including olaparib

6. Other malignancy unless curatively treated with no evidence of disease for ≥5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma.

7. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.

8. Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.

9. Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.

10. Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia.

11. Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML

12. Patients with symptomatic uncontrolled brain metastases.

    - Exception: Patients with adequately treated brain metastases documented by baseline CT or MRI scan that has not progressed since previous scans and that does not require corticosteroids (except ≤10 mg/day prednisone or equivalent for at least 14 continuous days prior to dosing) for management of CNS symptoms are eligible, provided that a repeat CT or MRI following the identification of CNS metastases (obtained at least 2 weeks after definitive therapy) must document adequately treated brain metastases.

13. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.

14. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.

    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 interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.

15. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication

16. Breastfeeding women

17. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV)

18. Patients with a known hypersensitivity to olaparib or any of the excipients of the product

19. Patients with known active hepatitis (i.e., hepatitis B or C)

20. Whole blood transfusions in the last 28 days prior to entry to the study.