To Assess Safety and Efficacy of Agents Targeting DNA Damage Repair With Olaparib Versus Olaparib Monotherapy.

This is a prospective, open label, randomised, multi-centre Phase 2 study that will assess
the efficacy and safety of olaparib monotherapy versus olaparib in combination with an
inhibitor of ATR (AZD6738) and olaparib monotherapy versus olaparib in combination with an
inhibitor of WEE1 (AZD1775) in second or third line setting in patients with TNBC
prospectively stratified by presence/absence of qualifying tumour mutation in genes involved
in the HRR pathway.

Eligible patients will be randomised by a ratio 1:1:1 to treatment Arm 1: olaparib continuous
in a 28-day cycle, Arm 2: AZD6738 Days 1-7 with olaparib continuous in a 28-day cycle or Arm
3: AZD1775 Days 1-3 and 8-10 with olaparib continuous in a 21-day cycle. The study subject
population will be divided into Stratum A (patients with mutations in BRCA1 or BRCA2 (Breast
cancer susceptible gene mutation (BRCAm)), Stratum B (patients with mutations in any of the
other genes involved in the HRR pathway and no mutation in BRCA1 and no mutation in BRCA2),
and Stratum C (patients with no detected tumour mutations in any of the HRR genes). Within
each stratum A, B and C, there will be further stratification by whether the patient received
prior platinum-based therapy.

In the olaparib monotherapy treatment arm as well as in the AZD6738+olaparib treatment arm,
patients will be administered olaparib bd at 300 mg continuously. Two (2) 150 mg olaparib
tablets will be taken at the same time each day, approximately 12 hours apart with one glass
of water (approximately 250 mL). In the AZD1775+olaparib treatment arm, patients will be
given olaparib 200 mg bd (2 x 100 mg tablets twice a day) and AZD1775 150 mg bd from Day 1 to
Day 3 (inclusive) and Day 8 to Day 10 (inclusive) of every 21-day cycle. AZD6738 will be
supplied as 20 mg, 80 mg, or 100 mg film coated tablets. Patients will be administered
AZD6738 od at 160 mg from Day 1 to Day 7 (inclusive) of every 28-day cycle. A total of 160 mg
of AZD6738 tablets will be taken at the same time on each day of dosing with approximately
250 mL of water. AZD1775 will be supplied as capsules containing 25 mg, 50 mg, 75 mg, 100 mg,
or 200 mg of drug substance. AZD1775 will be taken with approximately 250 mL of water
approximately 2 hours before or 2 hours after food. Olaparib, AZD6738 and AZD1775 will be
provided by AstraZeneca.

Primary outcome measures (progression free survival [PFS]) will be analysed for the 3 patient
populations BRCAm, Non BRCAm HRRm (Homologous Recombination Repair gene mutation) and Non
HRRm. Secondary outcome measures will be analysed in 2 patient populations HRRm and All for
PFS, Objective response rate (ORR) and overall survival (OS) will be analysed in all 5
patient populations. DoR, and tumour change will be analysed in BRCAm, Non BRCAm HRRm, and
Non HRRm patient populations. Tumour and germline mutation status will be analysed only in
the all patient population. PK outcome measures will be analysed only in the all patient
population. Blinded Independent Central Review (BICR) of radiological imaging data will be
carried out using RECIST version 1.1 and Investigator assessments will also be analysed for
sensitivity purposes.

Pertinent Inclusion criteria:

1. Informed consent prior to any study specific procedures.

2. Male or female ≥18 years of age.

3. Progressive cancer at the time of study entry.

4. Histologically or cytologically confirmed TNBC with evidence of metastatic disease and
HER2 negative as per ASCO-CAP HER2 guideline recommendations 2013.

5. Patients must have received at least 1 and no more than 2 prior lines of treatment for
metastatic disease with an anthracycline (eg, doxorubicin, epirubicin) and/or a taxane
(eg, paclitaxel, docetaxel) unless contraindicated, in either the neo-adjuvant,
adjuvant or metastatic setting.

6. Confirmed presence of qualifying HRR mutation or absence of any HRR mutation in tumour
tissue by the Lynparza HRR assay.

7. At least one measurable lesion that can be accurately assessed at baseline by computed
tomography (CT) (magnetic resonance imaging [MRI] where CT is contraindicated) and is
suitable for repeated assessment as per RECIST 1.1.

8. Patients must have normal organ and bone marrow function measured within 28 days prior
to randomization (defined in the protocol).

9. ECOG PS 0-1 within 28 days of randomisation.

10. Postmenopausal or evidence of non-childbearing status for women of childbearing
potential (contraception restrictions apply to participants and their partners).

13. Patient is willing to comply with the protocol requirements. 14. Life expectancy of ≥16
weeks.

Pertinent Exclusion criteria:

1. Cytotoxic chemotherapy, hormonal or non hormonal targeted therapy within 21 days of
Cycle 1 Day 1 is not permitted. Palliative radiotherapy must have been completed 21 or
more days before Cycle 1 Day 1. The patient can receive a stable dose of
bisphosphonates or denosumab for bone metastases, before and during the study as long
as these were started at least 5 days prior to study treatment.

2. More than 2 prior lines of cytotoxic chemotherapy for metastatic disease (prior
treatments with hormonal, non-hormonal, biologics or the combination of an aromatase
inhibitor and everolimus are not counted as a prior line of therapy).

3. Previous randomisation in the present study.

4. Previous treatment with a PARP inhibitor (including olaparib) or other DDR inhibitor
(unless less than 3 weeks duration and at least 12 months has elapsed between the last
dose and randomization).

5. Exposure to a small molecule IP within 30 days or 5 half-lives (whichever is longer)
prior to randomisation. The minimum washout period for immunotherapy shall be 42 days.

6. Patients with second primary cancer (exceptions defined in the protocol).

7. Mean resting corrected QTc interval using the Fridericia formula (QTcF) >470
msec/female patients and >450 msec for male patients (as calculated per institutional
standards) or congenital long QT syndrome.

8. Any of the following cardiac diseases currently or within the last 6 months: unstable
angina pectoris, congestive heart failure ≥ Class 2 as defined by the New York Heart
Association, acute myocardial infarction, conduction abnormality not controlled with
pacemaker or medication (patients with a conduction abnormality controlled with
pacemaker or medication at the time of screening are eligible), significant
ventricular or supraventricular arrhythmias (patients with chronic rate-controlled
atrial fibrillation in the absence of other cardiac abnormalities are eligible).

9. Concomitant use of known strong or moderate cytochrome P (CYP) 3A inhibitors, strong
or moderate CYP3A inducers, or sensitive CYP3A4 substrates or CYp3A4 substrates with a
narrow therapeutic index.

10. Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy, excluding
alopecia and CTCAE grade 2 peripheral neuropathy.

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

12. Immunocompromised patients, eg, human immunodeficiency virus (HIV).

13. Patients with known active hepatitis (ie, hepatitis B or C).

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

15. Patients with symptomatic uncontrolled brain metastases.

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

17. Patients with a known hypersensitivity to olaparib, AZD1775, AZD6738, or any of the
excipients of the products.

18. Pregnant or breast feeding women.