Pembrolizumab in Combination With Olaparib in Advanced BRCA-mutated or HDR-defect Breast Cancer

Inclusion Criteria:

• Be willing and able to provide written informed consent/assent for the trial

• Be ≥18 years of age on day of signing informed consent

• Advanced BRCA-mutated and/or HDR-defect breast cancer progressing on or after priortherapy for metastatic disease or locally advanced disease; Prior therapy is definedas follows: for triple negative breast cancer - progressing after at least 1 line ofany prior chemotherapy; for HER2 positive disease must have progressed after atleast two HER2 directed therapies in the metastatic setting includingado-trastuzumab emtansine (T-DM1); for hormone receptor positive disease (ER, PR, orboth) must have progressed after a CDK4/CDK6 inhibitor plus hormonal therapy.Patients with progression within 12 months from previous neoadjuvant or adjuvanttreatment could be enrolled in the study as 1st line therapy in metastatic setting.

• Measurable disease by RECIST 1.1, with at least one lesion, not previouslyirradiated, that can be accurately measured at baseline as ≥ 10 mm in the longestdiameter (except lymph nodes which must have short axis ≥ 15 mm) with computedtomography (CT) or magnetic resonance imaging (MRI) and which is suitable foraccurate repeated measurements. Patients with non-measurable bone metastases inaddition to measurable disease are eligible; however patients with non-measurablebone disease as the only site(s) of disease are not eligible.

• ECOG 0 or 1

• Documented BRCA deleterious germline or somatic mutation and/or HDR-defect.

• FFPE tumor tissue available for analysis

• Adequate organ function

• Female subjects: Postmenopausal or evidence of non-childbearing status for women ofchildbearing potential: negative urine or serum pregnancy test within 28 days ofstudy treatment and confirmed prior to treatment on day 1. Postmenopausal is definedas:

1. Amenorrheic for 1 year or more following cessation of exogenous hormonaltreatments Luteinizing hormone (LH) and Follicle stimulating hormone (FSH)levels in the post menopausal range for women under 50

2. radiation-induced oophorectomy with last menses >1 year ago

3. chemotherapy-induced menopause with >1 year interval since last menses

4. surgical sterilization (bilateral oophorectomy or hysterectomy)

• Women of childbearing potential and their partners, who are sexually active, mustagree to the use of TWO highly effective forms of contraception in combination. Thisshould be started from the signing of the informed consent and continue throughoutthe period of taking study treatment and for at least 1 month after last dose ofstudy drug(s), or they must totally/truly abstain from any form of sexualintercourse.

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

• Patients must have a life expectancy ≥ 16 weeks

Exclusion Criteria:

• Is currently participating or has participated in a study of investigational agentor using an investigational device with 30 days of the first dose of pembrolizumab.

1. Has had prior chemotherapy, targeted small molecule therapy, or radiationtherapy within 3 weeks prior to study Day 1.

2. Subjects must have recovered (i.e., ≤ Grade 1 or at baseline) from any adverseevents due to a previously administered agent. Subjects with ≤ Grade 2neuropathy are an exception to this criterion and may qualify for the study.

3. If subject received major surgery, they must have recovered adequately from thetoxicity and/or complications from the intervention prior to starting therapy.

• Is receiving systemic steroid therapy within three days prior to the first dose ofpembrolizumab or receiving any other form of immunosuppressive medication

• Is expected to require any other form of systemic or localized antineoplastictherapy while on trial.

1. Subjects with ER+/PR+ disease may be given endocrine therapy.

2. Subjects with HER2+ disease will be required to discontinue trastuzumab (Herceptin).

• Has participated in another MK03475 trial. a. Note: Patients with or without prior PARP-inhibitor exposure may be included.

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

• 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 olaparib is 5 weeks for enzalutamide or phenobarbital and 3weeks for other agents.

• Major surgery within 2 weeks of starting study treatment and patients must haverecovered from any effects of any major surgery.

• Has known hypersensitivity to pembrolizumab or any of its excipients

• Has a known additional malignancy that is progressing or requires active treatment.Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of theskin, or in situ cervical cancer that has undergone potentially curative therapy.

• Has known history of prior malignancy except if the patient has undergonepotentially curative therapy with no evidence of that disease recurrence for 5 yearssince initiation of that therapy.

• Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis. Subjects with previously treated brain metastases may participateprovided they are stable (without evidence of progression by MRI for at least fourweeks prior to the first dose of pembrolizumab and any neurologic symptoms havereturned to baseline), have no evidence of new or enlarging brain metastases, andare using no steroids for at least three days prior to study medication.

• Has evidence of interstitial lung disease or active, non-infectious pneumonitis

• Has active tuberculosis

• Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, asjudged by the investigator (eg., unstable ischemia, uncontrolled symptomaticarrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolytedisturbances, etc.), or patients with congenital long QT syndrome.

• Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade

2. caused by previous cancer therapy, excluding alopecia.

• Patients with myelodysplastic syndrome/acute myeloid leukaemia or with featuressuggestive of MDS/AML.

• Patients unable to swallow orally administered medication and patients withgastrointestinal disorders likely to interfere with absorption of the studymedication.

• Patients with a known hypersensitivity to olaparib or any of the excipients of theproduct.

• Has received a live vaccine or live-attenuated vaccine within 30 days prior to thefirst dose of pembrolizumab. Administration of killed vaccines is allowed.

• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

• Has an active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Subjects with vitiligo or resolved childhood asthma/atopywould be exception to this rule. Subjects that require inhaled steroid or localsteroid injections will not be excluded from the study. Subjects with hypothyroidismnot from autoimmune disease and stable on hormone replacement will not be excludedfrom the study. Note: Replacement therapy (eg., thyroxine, insulin, or physiologiccorticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) isnot considered a form of systemic treatment.

• Has had an allogenic tissue / solid organ transplant.

• Previous allogenic bone marrow transplant or double umbilical cord bloodtransplantation (dUCBT).

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thesubject's participation for the full duration of the trial, or is not in the bestinterest of the subject to participate, in the opinion of the treating Investigator.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

• Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the trial, starting with the screening visit (Visit 1) through 120 days after the last dose of study treatment.