A Phase II Randomized, Multi-Center, Double-Blind, Global Study to Determine the Efficacy and Safety of Durvalumab Plus Olaparib Combination Therapy Compared With Durvalumab Monotherapy as Maintenance Therapy in Patients Whose Disease Has Not Progressed Following Standard of Care Platinum-Based Chemotherapy With Durvalumab in First Line Stage IV Non Small Cell Lung Cancer (ORION)
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer NSCLC
Sponsor: AstraZeneca

Document Type:  
Document Dates: 
Study Title: 
Final Protocols 
Protocol Version 4.0 (14 July 2020) 
Phase II Randomized, Multi-Center, Double-Blind, Global 
Study to Determine the Efficacy and Safety of Durvalumab 
plus Olaparib Combination Therapy Compared with 
Durvalumab Monotherapy as Maintenance Therapy in Patients 
whose Disease has not Progressed Following Standard of Care 
Platinum-Based Chemotherapy with Durvalumab in First-Line 
Stage IV Non-Small Cell Lung Cancer (ORION) 
Protocol Reference Number:  D9102C00001 
NCT Number:  
 
NCT03775486 

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Clinical Study Protocol 
Drug Substance 
Olaparib (AZD2281) and 
Durvalumab (MEDI4736) 
Study Code 
D9102C00001 
Version 
4.0 
Date 
14 July 2020 
A Phase II Randomized, Multi-Center, Double-Blind, Global Study 
to Determine the Efficacy and Safety of Durvalumab plus Olaparib 
Combination Therapy Compared with Durvalumab Monotherapy 
as Maintenance Therapy in Patients whose Disease has not 
Progressed Following Standard of Care Platinum-Based 
Chemotherapy with Durvalumab in First-Line Stage IV Non-Small 
Cell Lung Cancer (ORION) 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden 
Local Sponsor in Japan: AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan 
Regulatory Agency Identifying Number(s): IND 140261 

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VERSION HISTORY 
Version 1.0, 12 July 2018 
Initial creation 
Version 2.0: 17 September 2018, Revision based on comments received from US FDA.  
- The term ‘induction phase’ is replaced by ‘Initial therapy’ through-out the document. 
- Figure 1 updated to be consistent with the usage of term ‘Initial therapy’. 
- Section 6.1.3: Addition of ‘No decline in WHO/ECOG PS and addition of following 
statement: In addition to the criteria above, written informed consent will be required to 
continue treatment in the setting of PD. This consent document will specify that treatment 
beyond initial evidence of PD is not the standard-of-care and that alternative treatment options, 
either locally licensed treatments or other clinical trials, are available.  
- Section 6.1.3: Deletion of following statement: accompanied by a decline in WHO/ECOG PS 
to >1. 
- Figure 7: updated to be consistent with the usage of term: Initial therapy 
Version 3.0: 02 December 2019, Revision based on providing a formal alpha-spending plan 
for the key secondary endpoint of OS, update of Hy’s law text and minor corrections and 
clarifications throughout the protocol to improve readability and correct errors.  
- Section 1.1: For standard of care treatment, provided clarification/guidance on delayed or 
missed dose(s). 
- Sections 2.3.2.1 and 8.3.12.1: Based on current Investigator’s Brochure, updated information 
on potential risks and adverse events of interest for durvalumab. 
- Table 1: Clarified that tumor assessments must be performed within 28 days prior to first-dose 
administration. Removed footnote with required infusion times for cisplatin and carboplatin. 
- Table 2, Synopsis, and Section 4.1: Clarified the window for eligibility into maintenance 
phase and that laboratory assessments for eligibility should be taken after the last dose of 
chemotherapy in the initial therapy. 
- Table 2: Clarified footnote e, regarding subsequent labortory assessments. Clarified footnote 
k, regarding use of CrCl measurements to determine olaparib/placebo dose.  
- Table 3: Modified visit window from 3 to 5 days for end of therapy visit.  
- Table 3 and Section 7.1.1: Added text for tumor assessments for patients not randomized into 
maintenance. 

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- Table 5, Synopsis: Clarified study objective for disease-related symptoms and HRQoL to 
assess time to deterioration. 
- Section 2.2: Updated Background section to match current protocol template.  
- Section 5.1, Inclusion criterion 13: Clarified that archival and new tumor samples, if collected, 
must be submitted as separate samples. 
- Section 5.1, Table 14, Synopsis: Clarified that the CrCl is calculated by the investigator or 
designee as this is what will be used for decision making, eg, starting olaparib/placebo 
treatment and dose changes. 
- Section 6.1.1.2: Clarified if a patient meets criteria for randomization before being dosed in 
maintenance but is later found to not meet criteria to start olaparib/placebo before C1D1 
dosing, durvalumab as monotherapy may be started, with olaparib/placebo dosing to commence 
once the patient again meets the hematology/clinical chemistry requirements and conditions 
specified in Section 1.1. 
- Section 6.1.1.3: Removed text regarding duration of standard of care infusions; guidance in 
the prescribing information should be used. 
- Section 6.1.2.2: Added clarification on dosing for patients who meet criteria for 
randomization before maintenance phase treatment who were later found to not meet critera to 
start olaparib/placebo before C1D1 dosing.  
- Sections 6.2.1, 8.8, and 9.4.5: Clarified testing of PD-L1; samples will be collected from all 
enrolled patients, with testing to be carried out for all enrolled patients. 
- Section 6.2.4: Clarified blinded CRO staff will not have access to the randomization. 
- Section 6.4.3: Clarified the administration of rescue medication by a pharmacist. 
- Section 7.1: Added clarification for end of therapy visit for patients who discontinue therapy. 
- Section 8.2.1, Table 14: Updated footnote d to include option for 24-hour urine test to assess 
creatinine and CrCl. 
- Section 8.2.1, Table 15: Updated footnote a to remove reference to calculation of counts by 
Data Management if percentage provided. 
- Section 8.3.4: Updated adverse event data collection text to state all changes in CTCAE grade 
for a calendar day will be recorded, rather than recording only the maximum grade 
- Section 8.4.5.1: Updated language to align with current protocol template. 

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- Section 8.8.1: Clarified that where necessary, EGFR/ALK testing is to be carried out locally at 
sites and in only cases where sites do not have capability to carry out local testing, samples 
should be sent to central laboratory. Removed recommendations for number of slides to refer 
instead to the laboratory manual. 
- Sections 9.2, 9.5.8, 9.6, Synopsis: Updated these sections to provide a formal alpha-spending 
plan for the key secondary endpoint of OS, following the pre-specified hierarchical approach in 
the event the primary analysis of PFS is statistically significant. OS will be analyzed at the time 
of each PFS analysis, in the event that PFS is positive at the same timepoint. Timing of interim 
and final analyses have been updated to reflect most recent randomization information. 
- Section 9.3, Table 17: Removed the separate reference to ADA data in this table. 
- Section 9.3.1: Added new subsection for FAS for the initial therapy phase, separate from FAS 
for the maintenance phase. 
- Section 9.3.2.2: Clarified safety analysis set for maintenance phase consists of patients who 
received at least 1 dose of any study treatment. 
- Table 19: Clarified analysis for HRQoL/function. 
- Section 9.5.1.1, Synopsis: Updated description of modeling and analysis of primary endpoint 
PFS. 
-Section 9.5.1.2: Updated analysis plan for secondary endpoints to clarify Kaplan-Meier plots 
will be presented by treatment arm. 
- Section 9.5.1.4: Clarified subgroup analyses, including adding objective response to intial 
therapy subgroup analysis and clarifying minimum number of events per subgroup for analysis. 
- Section 9.5.1.5: Removed subsection for analysis of OS due to redundancy with the analysis 
of secondary variables subsection. Added pre-specified primary PRO measures and updated 
description of analysis methods for PRO endpoints. 
- Section 9.6.1: Updated to indicate interim analysis and final analysis results are not specific to 
PFS, since OS will be analyzed at those timepoints in the event that PFS is positive at the same 
timepoint. 
- Appendix E: Updated text regarding evaluation of Hy’s law. 
- Updated abbreviation for safety analysis set from SAS to SAF for clarity. 
Version 4.0: 14 July 2020, Revised to remove the first interim analysis for PFS and OS. 
- Section 1.2, Section 4.1: Clarified that follow-up tumor assessments will not be required for 
patients who are not randomized into the maintenance phase. 

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- Table 3: Removed the Day 30 tumor assessments from the schedule of activities for patients 
who have discontinued all study treatment. 
- Section 6.1.3: Updated estimated data cut-off timing and maturity rate. Maturity rate updated 
in other sections as appropriate. 
- Section 9.2, Section 9.5.1.1, Section 9.5.8, Section 9.6, Section 1.2: Removed first interim 
analysis at 104 PFS events, as well as the first interim analysis for OS which was to occur at the 
time of the interim analysis for PFS. 
- Section 9.6.1, Section 1.2: Clarified that the IDMC will review the OS interim analysis 
results. Updated the IDMC meeting frequency to refer to the IDMC Charter for further details. 
- Table 23 in Appendix F: Updated overall response to NED for patients with no new lesions 
and with target/non-target lesions not available. Clarified for the target lesion responses of SD 
or NE, the non-target lesions response may be Non PD or NE or NA. 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 

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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
VERSION HISTORY ............................................................................................................... 2 
TABLE OF CONTENTS .......................................................................................................... 6 
1. 
PROTOCOL SUMMARY.................................................................................... 13 
1.1 
Schedule of activities ............................................................................................ 13 
1.2 
Synopsis ................................................................................................................ 27 
1.3 
Schema .................................................................................................................. 35 
2. 
INTRODUCTION ................................................................................................ 36 
2.1 
Study rationale ...................................................................................................... 36 
2.2 
Background ........................................................................................................... 36 
2.2.1 
Non-small cell lung cancer ................................................................................... 36 
2.2.2 
Immunotherapies .................................................................................................. 37 
2.2.3 
Immunotherapy in non-small cell lung cancer ..................................................... 39 
2.2.4 
Durvalumab .......................................................................................................... 41 
2.2.5 
Olaparib ................................................................................................................ 41 
2.2.6 
Durvalumab in combination with olaparib in the full analysis set ....................... 42 
2.2.6.1 
Rationale for the combination of durvalumab plus olaparib for HRRm tumors .. 43 
2.2.7 
Durvalumab in combination with chemotherapy ................................................. 44 
2.3 
Benefit/risk assessment ......................................................................................... 44 
2.3.1 
Potential benefits .................................................................................................. 44 
2.3.1.1 
Durvalumab .......................................................................................................... 44 
2.3.1.2 
Olaparib ................................................................................................................ 46 
2.3.1.3 
Durvalumab plus olaparib combination therapy................................................... 46 
2.3.1.4 
Durvalumab plus chemotherapy ........................................................................... 46 
2.3.2 
Overall risks .......................................................................................................... 47 
2.3.2.1 
Durvalumab .......................................................................................................... 47 
2.3.2.2 
Olaparib ................................................................................................................ 48 
2.3.2.3 
Durvalumab plus olaparib combination therapy................................................... 48 
2.3.2.4 
Durvalumab plus chemotherapy ........................................................................... 49 
2.3.3 
Overall benefit/risk ............................................................................................... 50 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................... 51 
4. 
STUDY DESIGN ................................................................................................. 52 
4.1 
Overall design ....................................................................................................... 52 
4.2 
Scientific rationale for study design ..................................................................... 54 
4.2.1 
Rationale for efficacy endpoints ........................................................................... 54 
4.2.2 
Rationale for other study endpoints ...................................................................... 55 
4.3 
Justification for dose ............................................................................................. 55 
4.3.1 
Durvalumab monotherapy dose rationale ............................................................. 55 
4.3.2 
Rationale for fixed dosing of durvalumab ............................................................ 56 
4.3.3 
Rationale for proposed study dose and schedule .................................................. 57 

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4.3.4 
Olaparib dose rationale ......................................................................................... 60 
4.4 
End of study definition ......................................................................................... 60 
4.5 
Study termination.................................................................................................. 61 
4.6 
Site closure............................................................................................................ 61 
5. 
STUDY POPULATION ....................................................................................... 61 
5.1 
Inclusion criteria ................................................................................................... 62 
5.2 
Exclusion criteria .................................................................................................. 64 
5.3 
Lifestyle restrictions ............................................................................................. 67 
5.4 
Screen failures ...................................................................................................... 69 
6. 
STUDY TREATMENTS ..................................................................................... 69 
6.1 
Treatments administered ....................................................................................... 69 
6.1.1 
Investigational products ........................................................................................ 69 
6.1.1.1 
Durvalumab (MEDI4736) .................................................................................... 71 
6.1.1.2 
Olaparib (AZD2281) ............................................................................................ 72 
6.1.1.3 
Standard of care .................................................................................................... 73 
6.1.2 
Dose and treatment regimens................................................................................ 73 
6.1.2.1 
Durvalumab (MEDI4736) and platinum-based chemotherapy (initial therapy 
phase) .................................................................................................................... 73 
6.1.2.2 
Durvalumab monotherapy and durvalumab plus olaparib combination therapy 
(maintenance phase) ............................................................................................. 76 
6.1.3 
Duration of treatment and criteria for treatment through progression .................. 77 
6.1.4 
Storage .................................................................................................................. 80 
6.1.4.1 
Durvalumab .......................................................................................................... 80 
6.1.4.2 
Olaparib, placebo, and chemotherapy (SoC) ........................................................ 80 
6.2 
Measures to minimize bias: randomization and blinding ..................................... 80 
6.2.1 
Patient enrollment and randomization .................................................................. 80 
6.2.2 
Procedures for handling incorrectly enrolled or randomized patients .................. 82 
6.2.3 
Methods for assigning treatment arms (maintenance phase) ................................ 83 
6.2.4 
Methods for ensuring blinding (maintenance phase) ........................................... 83 
6.3 
Treatment compliance .......................................................................................... 84 
6.4 
Concomitant therapy ............................................................................................. 85 
6.4.1 
Other concomitant treatment ................................................................................ 89 
6.4.2 
Durvalumab drug-drug interactions ...................................................................... 89 
6.4.3 
Rescue medication ................................................................................................ 89 
6.5 
Dose modification ................................................................................................. 90 
6.6 
Treatment after the end of the study ..................................................................... 91 
7. 
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL .. 91 
7.1 
Discontinuation of study treatment ....................................................................... 91 
7.1.1 
Procedures for discontinuation of study treatment ............................................... 92 
7.2 
Lost to follow-up .................................................................................................. 93 
7.3 
Withdrawal from the study ................................................................................... 93 

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Table 6 
Highly effective methods of contraception (<1% failure rate) ................... 68 
Table 7 
Study treatments .......................................................................................... 70 
Table 8 
Prohibited concomitant medications ........................................................... 85 
Table 9 
Restricted concomitant medications ........................................................... 87 
Table 10 
Supportive medications ............................................................................... 89 
Table 11 
Dose reductions for olaparib/placebo to manage adverse events ................ 90 
Table 12 
Dose reduction for olaparib/placebo if patient develops moderate renal 
impairment .................................................................................................. 90 
Table 13 
Dose reductions for olaparib/placebo if patient has to start taking a 
strong or moderate CYP3A inhibitor .......................................................... 90 
Table 14 
Clinical chemistry ..................................................................................... 100 
Table 15 
Hematology ............................................................................................... 101 
Table 16 
Urinalysis .................................................................................................. 101 
Table 17 
Summary of outcome variables and analysis populations ........................ 125 
Table 18 
Visit responses for symptoms and health-related quality of life ............... 132 
Table 19 
Pre-planned statistical and sensitivity analyses to be conducted .............. 136 
Table 20 
Summary of imaging modalities for tumor assessment ............................ 180 
Table 21 
Evaluation of target lesions ....................................................................... 184 
Table 22 
Evaluation of non-target lesions ................................................................ 184 
Table 23 
Overall visit response ................................................................................ 186 
Table 24 
Management of anemia ............................................................................. 190 
Table 25 
Management of neutropenia, leukopenia, and thrombocytopenia ............ 190 
Table 26 
Dose reductions for study treatment ......................................................... 193 
 
LIST OF FIGURES 
Figure 1 
Study design ................................................................................................ 35 
Figure 2 
Dose and treatment regimen for initial therapy phase (durvalumab with 
nab-paclitaxel plus carboplatin) .................................................................. 74 
Figure 3 
Dose and treatment regimen for initial therapy phase (durvalumab with 
gemcitabine plus carboplatin/cisplatin) ....................................................... 75 
Figure 4 
Dose and treatment regimen for initial therapy phase (durvalumab with 
pemetrexed plus carboplatin/cisplatin) ....................................................... 75 
Figure 5 
Dose and treatment regimen for maintenance phase (durvalumab 
monotherapy) .............................................................................................. 77 
Figure 6 
Dose and treatment regimen for maintenance phase (durvalumab plus 
olaparib combination therapy) .................................................................... 77 
Figure 7 
Tumor assessment schedule for initial therapy and maintenance phases.... 96 
Figure 8 
Multiple testing procedure ........................................................................ 144 
 

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LIST OF APPENDICES 
Appendix A 
Regulatory, ethical and study oversight considerations ............................ 157 
Appendix B 
Adverse event definitions and additional safety information ................... 162 
Appendix C 
Handling of human biological samples ..................................................... 167 
 
 
Appendix E 
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s law .............................................................................. 174 
Appendix F 
Guidelines for evaluation of objective tumor response using RECIST 1.1 
Criteria (Response Evaluation Criteria in Solid Tumors) ......................... 179 
Appendix G 
Olaparib toxicity management instructions .............................................. 190 
Appendix H 
Patient-reported outcomes ......................................................................... 195 
Appendix I 
Abbreviations ............................................................................................ 205 
 
CCI

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1. 
PROTOCOL SUMMARY 
1.1 
Schedule of activities 
The procedures for the initial therapy and maintenance phases in this study are presented in 
Table 1 and Table 2, respectively. The procedures for patients who have discontinued all 
study treatment are shown in Table 3. 
Whenever vital signs and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: vital signs and then blood draws. The timing 
of the vital signs assessments should be such that it allows the blood draw (eg, 
pharmacokinetic [PK] blood sample) to occur at the timepoints indicated in the schedules of 
activities (SoAs). Whenever electrocardiograms (ECGs), vital signs, and blood draws are 
scheduled for the same nominal time, the assessments should occur in the following order: 
ECG, vital signs, and then blood draws. The timing of the first 2 assessments should be such 
that it allows the blood draw (eg, PK blood sample) to occur at the timepoints indicated in the 
SoAs. 
For durvalumab treatment: 
• 
Patients may delay dosing under the following circumstances: 
− 
Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines, due to either an immune or a non-immune-related adverse event (AE). 
− 
If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible. 
− 
Dosing intervals of subsequent cycles may be shortened as clinically feasible in order 
to gradually align treatment cycles with the schedule of tumor efficacy (Response 
Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]) and patient-reported 
outcome (PRO) assessments. Subsequent time between 2 consecutive doses cannot 
be less than 21 days, based on the half-life of durvalumab (see current Investigator 
Brochure [IB] for durvalumab). If there is a dosing delay while on the every 3 weeks 
(q3w) schedule (initial therapy phase), all future dosing days for durvalumab should 
be delayed to ensure that the intervals between dosing study treatment are always at 
least 21 days. 
− 
In the event that standard of care (SoC) is delayed during the initial therapy phase, 
durvalumab administration must also be delayed.  
For standard of care treatment: 
• 
Patients may delay standard of care treatment or miss Day 8 or Day 15 (for gemcitabine 
or nab-paclitaxel dosing) per Investigator judgment and subsequently resume dosing per 
local standard clinical practice. 
− 
If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will occur as soon as feasible. 

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For olaparib/placebo treatment: 
• 
Prior to the start of maintenance treatment with olaparib/placebo and after the last dose of 
chemotherapy in the initial therapy, the patient should have his or her 
hematological/clinical chemistry parameters re-checked. The patient must meet the 
following requirements without blood transfusions in the past 28 days in order to receive 
treatment with olaparib/placebo:  
− 
Hemoglobin (Hb) ≥ 10 g/dL 
− 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
− 
Platelet count ≥ 100 × 109/L 
− 
Serum bilirubin ≤1.5 × the upper limit of normal (ULN); unless due to Gilbert’s 
syndrome, in which case patients will be allowed in consultation with their physician 
and AstraZeneca 
− 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN; 
for patients with hepatic metastases, ALT and AST ≤5 × ULN 
− 
Creatinine clearance (CrCl) ≥51 mL/min calculated by the investigator or designee 
using the Cockcroft-Gault equation (using actual body weight [WT]) or measured by 
24-hour urine collection  
If the patient does not meet these requirements initially, then the hematology and 
clinical chemistry parameters should be checked at the next cycle. However, the 
Investigator may check these laboratory results/parameters earlier (eg, mid cycle) at 
an unscheduled visit. Once olaparib/placebo is administered, these laboratory 
thresholds are not required for continued olaparib administration. However, patients 
must continue to be monitored and assessed (eg, lab parameters and toxicities) per 
Table 2, and dose delays and modifications for olaparib/placebo should be followed 
per Sections 6.5 and 8.4.5.2 and Appendix G. 
• 
Patients may interrupt and subsequently resume dosing per Appendix G. Dose reductions 
may also occur if the study treatment dose is not tolerable. 
− 
If dosing must be interrupted for reasons other than treatment-related toxicity, dosing 
will occur as soon as feasible. 
− 
If a patient meets criteria for randomization before being dosed in maintenance but is 
later found to not meet criteria to start olaparib/placebo before C1D1 dosing, 
durvalumab as monotherapy may be started, with olaparib/placebo dosing to 
commence once the patient again meets the hematology/clinical chemistry 
requirements and conditions specified above. 
One cycle is equal to 28 days (56 doses of olaparib/placebo administered twice daily [BID])

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Screening 
C1 
C2 
C3 
C4 
For 
details, 
see 
Section 
During initial therapy phase, 1 cycle = 21 days, unless SoC dosing is delayed (eg, for 
toxicity reasons) 
Week 
-4 to -1 
0 
1 
3 
4 
6 
7 
9 
10 
Day 
-28 to -1 
1 
8 
22 
29 
43 
50 
64 
71 
Window 
NA 
+3 
±2 
+3 
±2 
+3 
±2 
+3 
±2 
Carboplatin or cisplatin 
 
X 
 
X 
 
X 
 
X 
 
6.1.2.1 
Gemcitabine 
 
X 
X 
X 
X 
X 
X 
X 
X 
6.1.2.1 
Pemetrexed (pemetrexed maintenance 
therapy will not be allowed following the 
initial therapy phase) 
 
X 
 
X 
 
X 
 
X 
 
6.1.2.1 
Other assessments and assays 
Durvalumab immunogenicity assessment 
(ADA sampling to identify ADA 
responses in patient circulation) 
 
Xl 
 
Xl 
 
 
 
Xl 
 
8.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy (newly acquired or 
archival <3 years old or both) 
X 
 
 
 
 
 
 
 
 
8.8 
EGFR and ALK testt 
X 
 
 
 
 
 
 
 
 
6.2.1 
Efficacy evaluations 
Tumor assessments (CT or MRI) 
(RECIST 1.1)u,v 
Xv 
Initial therapy phase on-study tumor assessments occur 14 to 28 days after C2D1 and 
C4D1w of the initial therapy phase. 
8.1 
CCI
CCI
CCI
CCI

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Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated. Every effort should be made to minimize the time 
between screening and starting treatment (ie, within 1 day after enrollment). 
Note: Each cycle during the initial therapy phase is 21 days (unless SoC dosing is delayed). For durvalumab, if there is a dosing delay while on the q3w schedule, 
all future dosing days should be delayed to ensure that the intervals between dosing study treatment are always at least 21 days. For SoC, dosing delays should be 
managed as per local prescribing guidelines. In the event that SoC is delayed, durvalumab administration must also be delayed. 
a 
Written informed consent and any locally required privacy act document authorization must be obtained prior to performing any protocol-specific 
procedures, including screening/baseline evaluations. All patients will be required to provide consent to supply a sample of their tumor (archived or newly 
acquired biopsy) for entry into this study. This consent is included in the main patient ICF. Informed consent of study procedures and tumor biopsy sample 
may be obtained prior to the 28-day screening window, if necessary. Tumor biopsies at progression are optional, and the treating physician will judge the 
feasibility of such a procedure. If laboratory or imaging procedures were performed for alternate reasons prior to signing consent, these can be used for 
screening purposes with consent of the patient. However, all screening laboratory and imaging results must have been obtained within 28 days of 
enrollment. 
b 
Body weight is recorded at each visit along with vital signs. 
c 
Any clinically significant abnormalities detected require triplicate ECG results. 
d 
Individual sites are required to indicate in the unscheduled visit eCRF if an ECG, APTT/INR assessment, or urinalysis was performed during study 
treatment. 
e 
Laboratory assessments should be performed according to local standard clinical practice for SoC; if these items are performed on Day 8 or 15 of each cycle 
per local standard clinical practice, results do not need to be recorded in the clinical database unless abnormal results are associated with AEs and SAEs. 
Criteria for reporting AEs based on laboratory tests are provided in Section 8.3.7.  
f 
Serum or plasma clinical chemistry (including LFT monitoring) and hematology may be performed more frequently if clinically indicated.  
g 
If these screening laboratory assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be repeated at Day 1.  
h 
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1. 
i 
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related to the endocrine system. 
j 
Women of childbearing potential are required to have a pregnancy test within 7 days prior to the first dose of the IP (ie, durvalumab or SoC) and then q3w 
during the initial therapy phase. A urine or serum pregnancy test is acceptable. Pregnancy test may occur on Day 1, but results must be available and 
reviewed by the treating physician or Investigator prior to commencing treatment administration.  
k 
Within 1 hour of the end of infusion.  
l 
Pre-dose (may not exceed 6 hours prior to the start of infusion) same day as infusion. 
m 
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed. 
n 
To be administered in line with local practice for patients with non-squamous tumors who will receive pemetrexed. Folic acid and vitamin B12 should 
commence prior to treatment initiation for up to 7 days, in line with local practice. 
o 
Durvalumab will be infused first, followed by the SoC chemotherapy regimen. 
p 
Results for LFTs, electrolytes, full blood count, and creatinine must be available before commencing IP administration (within 3 days) and reviewed by the 
treating physician or Investigator prior to dosing. 

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Table 2 
Schedule of activities for maintenance phase (durvalumab plus olaparib/placebo) 
 
C1a 
C2 until PDa 
For details, 
see Section 
Week 
0 
q4w ±3 days unless dosing needs to be held for toxicity reasons 
Day 
1 
Every 28 days ±3 days unless dosing needs to be held for toxicity reasons 
Study procedures 
Targeted physical examination 
(based on symptoms) 
X 
X 
8.2.2 
Vital signsb 
X 
X 
8.2.3 
12-lead ECGc,d 
As clinically indicated 
8.2.4 
Concomitant medications 
X 
X 
6.4 
Randomization eligibility criteria 
Xa 
 
5.1, 5.2 
Laboratory assessments 
Clinical chemistrye 
X 
X 
Table 14 
Hematologye 
X 
X 
Table 15 
APTT and INRd 
As clinically indicated 
Table 15 
TSH (reflex free T3 or free T4f) 
X 
X 
Table 14 
Urinalysisd 
X 
As clinically indicated 
Table 16 
Pregnancy testg 
X 
X 
8.2.1 
Pharmacokinetics 
Durvalumab PK sample (serum) 
Xh 
At C2D1 and q12w thereafteri 
8.5 
Safety monitoring 
WHO/ECOG PS 
X 
X 
8.2.6 
AE/SAE assessmentj 
X 
X 
8.3 
Early patient review for safety 
2 weeks ±2 days after receiving the first dose of each of the first 2 cycles of olaparib/placebo 
maintenance therapy; the form of contact and procedures conducted will be at the Investigator’s 
discretion. 
8.2.5 

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C1a 
C2 until PDa 
For details, 
see Section 
Week 
0 
q4w ±3 days unless dosing needs to be held for toxicity reasons 
Day 
1 
Every 28 days ±3 days unless dosing needs to be held for toxicity reasons 
Drug accountability 
X 
X 
6.3 
IP administration 
Durvalumabk 
X 
X 
6.1.1.1, 
6.1.2.2 
Olaparib/placebok,l 
X 
X 
6.1.1.2, 
6.1.2.2 
PRO assessments 
EORTC QLQ-LC13, EORTC 
QLQ-C30, 
, 
m 
X 
X (±7 days) 
8.1.3 
Other assessments and assays 
Durvalumab immunogenicity 
assessment (ADA sampling to 
identify ADA responses in patient 
circulation) 
Xi 
At C2D1 and q12w thereafteri 
8.5 
 
 
 
 
 
 
 
 
 
 
 
 
Optional tumor biopsy (at 
progression) 
 
Xo 
8.8 
Efficacy evaluations 
Tumor assessments (CT or MRI) 
(RECIST 1.1)p,q 
Maintenance phase on-study tumor assessments occur q8w ±1 week relative to the date of 
randomization beginning 8 weeks after randomization for the first 48 weeks and then q12w ±1 week 
thereafter until RECIST 1.1-defined radiological PD plus one or more additional follow-up scans if 
clinically feasible. The schedule of q8w ±1 week for the first 48 weeks and then q12w ±1 week 
thereafter MUST be followed regardless of any delays in dosing. 
8.1 
CCI
CCI
CCI
CCI
CCI

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Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated. 
Note: If there is a dosing delay during the treatment schedule, subsequent time between 2 consecutive doses of durvalumab cannot be less than 21 days 
(olaparib/placebo administration may continue as scheduled if durvalumab is delayed). 
a 
Confirmation of eligibility criteria for randomization (eligibility scan and other specific criteria; see Sections 5.1 and 5.2 for criteria that must be met at 
randomization) will take place 14 to 28 days after C4D1 of the initial therapy phase. Laboratory assessments for eligibility should be taken after the last 
dose of chemotherapy in the initial therapy phase and re-checked prior to receiving maintenance treatment (see footnote e below). If determined eligible, 
patients will be randomized within 5 weeks after C4D1 of the initial therapy phase; every effort should be made to minimize the time between confirmation 
of eligibility, randomization, and starting maintenance treatment. Patients will continue to receive maintenance treatment until clinical disease progression 
(as assessed by the Investigator) or RECIST 1.1-defined radiological PD, unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met. Tumor biopsies at progression are optional, and the treating physician will judge the feasibility of such a procedure. 
b 
Body weight is recorded at each visit along with vital signs. 
c 
Any clinically significant abnormalities detected require triplicate ECG results. 
d 
Individual sites are required to indicate in the unscheduled visit eCRF if an ECG, APTT/INR assessment, or urinalysis was performed during study 
treatment. 
e 
Serum or plasma clinical chemistry (including LFT monitoring) and hematology may be performed more frequently if clinically indicated. Note that CrCl is 
measured at Day 1 of each cycle during the maintenance phase. Please note that if a patient’s creatinine clearance measurement after initial therapy meets 
eligibility criteria for randomization, and the subsequent creatinine clearance measurement prior to C1D1 (of maintenance therapy) do not (eg, CrCl 
<51 mL/min), then although the patient can be randomized and receive durvalumab maintenance, the patient cannot start olaparib/placebo therapy until 
CrCl and other applicable laboratory parameters meet threshold and conditions specified in Section 1.1. 
f 
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related to the endocrine system. 
g 
Women of childbearing potential are required to have a pregnancy test within 7 days prior to the first dose of the IP (ie, durvalumab, olaparib, or placebo) 
and then q4w. A urine or serum pregnancy test is acceptable. Pregnancy test may occur on Day 1, but results must be available and reviewed by the treating 
physician or Investigator prior to commencing treatment administration. 
h 
Within 1 hour of the end of infusion.  
i 
Pre-dose (may not exceed 6 hours prior to the start of infusion) same day as infusion.  
j 
For AEs/SAEs reported during screening, additional information such as medical history and concomitant medications may be needed. 
k 
Results for LFTs, electrolytes, full blood count, and creatinine must be available before commencing IP administration (within 3 days) and reviewed by the 
treating physician or Investigator prior to dosing. The CrCl measured on D1 of each cycle will be used to determine the olaparib/placebo dose. Patients can 
dose reduce olaparib/placebo due to CrCl changes specified in Table 12. However, once olaparib/placebo dose is reduced due to CrCl changes, escalation is 
not permitted. 
l 
Olaparib/placebo is to be administered continually BID; see Section 6.5 for dose modifications for olaparib/placebo. Olaparib/placebo will be administered 
once the patient is able to meet all the hematology/clinical chemistry requirements specified in Section 1.1 without blood transfusions within the past 
28 days. Once olaparib/placebo administration is allowed, olaparib/placebo will be dispensed to patients at each visit until clinical disease progression (as 
assessed by the Investigator) or RECIST 1.1-defined radiological PD, unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion met. All patients must return their bottle(s) of olaparib/placebo at Day 1 of each subsequent cycle. 

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Table 3 
Schedule of activities for patients who have discontinued all study treatment 
 
Time since last dose of IP 
For 
details, 
see 
Section 
Evaluation 
Day (±5) 
Months (±1 week) 
12 months and 
every 2 months 
thereafter 
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Physical examination (full) 
X 
 
 
 
 
 
 
 
8.2.2 
Vital signs (temperature, respiratory 
rate, BP, and pulse) 
X 
X 
X 
 
 
 
 
 
8.2.3 
Weight 
X 
X 
X 
 
X 
 
 
 
8.2.3 
Pregnancy testa,b 
X 
As clinically indicated 
 
8.2.1 
AE/SAE assessmentc 
X 
X 
X 
 
 
 
 
 
8.3 
Concomitant medications 
X 
X 
X 
 
 
 
 
 
6.4 
WHO/ECOG PS 
At timepoints consistent with tumor assessments; at 30, 60, and 90 days; and then at initiation of 
subsequent anticancer therapyd 
8.2.6 
Subsequent anticancer therapye 
X 
X 
X 
X 
X 
X 
X 
X 
8.1.2 
Survival statusf 
 
X 
 
X 
X 
X 
X 
X 
8.1.2 
Hematology 
X 
X 
X 
 
 
 
 
 
Table 15 
Clinical chemistry 
X 
X 
X 
 
 
 
 
 
Table 14 
Urinalysisb 
As clinically indicated 
Table 16 
TSH (reflex free T3 or free T4)g 
X 
X 
X 
 
 
 
 
 
Table 14 
Durvalumab PK sample (serum)h 
 
 
X 
 
 
 
 
 
8.5 
Durvalumab immunogenicity 
assessments (ADA sampling to 
identify ADA responses in patient 
circulation)h 
 
 
X 
 
X 
 
 
 
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1.2 
Synopsis 
International Co-ordinating Investigator 
 
 
 
 
 
 
 
 
Protocol Title: A Phase II Randomized, Multi-Center, Double-Blind, Global Study to 
Determine the Efficacy and Safety of Durvalumab plus Olaparib Combination Therapy 
Compared with Durvalumab Monotherapy as Maintenance Therapy in Patients whose Disease 
has not Progressed Following Standard of Care Platinum-Based Chemotherapy with 
Durvalumab in First-Line Stage IV Non-Small Cell Lung Cancer (ORION) 
Short Title: ORION Study 
Rationale: 
Current SoC therapies for metastatic non-small cell lung cancer (NSCLC) have mixed 
outcomes with responses to systemic chemotherapy in the first-line setting of approximately 
20% to 40% and a median overall survival (OS) of approximately 11 to 14 months (Breslow 
1974, Carbone et al 2017, Paz-Ares et al 2013, Socinski et al 2018, Gandhi et al 2018). 
Treatments are associated with a variety of significant side effects, including neutropenia, 
nausea, vomiting and dehydration, and alopecia (Sandler et al 2006, Scagliotti et al 2008). The 
KEYNOTE-024, KEYNOTE-042, KEYNOTE-189, and KEYNOTE-407 studies, along with 
the IMpower131 and IMpower150 studies, have shown that immunotherapy alone or in 
combination with chemotherapy can be effective first-line treatment for patients with 
metastatic NSCLC (Gandhi et al 2018, Jotte et al 2018, Lopes et al 2018, Paz-Ares et al 2018, 
Reck et al 2016, Socinski et al 2018). 
Results from these studies have been encouraging and represent a substantive advance, but 
further improvement is needed. All of the aforementioned studies yielded a median 
progression-free survival (PFS) of <1 year. Furthermore, there are no approved maintenance 
immunotherapy-based combination regimens for patients with squamous histology. Increased 
DNA damage triggered through polyadenosine 5’diphosphoribose [poly (ADP ribose)] 
polymerase (PARP) inhibition has the potential to not only provide antitumor activity but also 
modify tumor immunogenicity and sensitize tumors to immune checkpoint inhibition, 
promoting a more durable antitumor response. Therefore, in this Phase II study, the 
combination of durvalumab plus olaparib will be investigated to determine if this combination 
PPD

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Confirmation of eligibility criteria for randomization (eligibility scan and other specific 
criteria; see Sections 5.1 and 5.2 for criteria that must be met at randomization) will take place 
14 to 28 days after Cycle 4 Day 1 of the initial therapy phase. Laboratory assessments for 
eligibility should be taken after the last dose of chemotherapy in the initial therapy phase. If 
determined eligible, patients will be randomized within 5 weeks after Cycle 4 Day 1 of the 
initial therapy phase; every effort should be made to minimize the time between confirmation 
of eligibility, randomization, and starting maintenance treatment. Patients will receive 
maintenance treatment until specific discontinuation criteria are met, including clinical disease 
progression (as assessed by the Investigator) or RECIST 1.1-defined radiological PD, 
unacceptable toxicity, and withdrawal of consent. Note that crossover within the study will not 
be permitted. 
Study Period: 
Estimated date of first patient enrolled: Q4 2018 
Estimated date of last patient completed: Q1 2022  
Number of patients: 
Approximately 350 to 400 patients will be enrolled in the initial therapy phase of the study. 
Approximately 250 patients globally who have not progressed will be randomized in a 1:1 
ratio to either the durvalumab plus olaparib treatment arm or the durvalumab plus placebo 
treatment arm, approximately 125 patients per arm. The randomization will be stratified based 
on objective response to durvalumab plus chemotherapy (CR/PR or SD; obtained at the last 
visit prior to randomization [Cycle 4 scan]) and histology (squamous or nonsquamous). 
Treatments and treatment duration: 
Durvalumab (MEDI4736) and platinum-based chemotherapy (initial therapy phase) 
During the initial therapy phase, all patients will receive durvalumab 1500 mg via intravenous 
(IV) infusion q3w for 4 cycles, unless there is unacceptable toxicity, withdrawal of consent, or 
another discontinuation criterion met. If a patient’s WT falls to 30 kg or below, the patient 
should receive WT-based dosing equivalent to 20 mg/kg of durvalumab q3w after 
consultation between Investigator and Study Physician until the WT improves to >30 kg, at 
which point the patient should start receiving the fixed dosing of durvalumab 1500 mg q3w. If 
there is a dosing delay during the treatment schedule for durvalumab, all future dosing days 
for durvalumab should be delayed to ensure that the intervals between dosing study treatment 
are always at least 21 days. The standard infusion time is 60 minutes. In the event that there 
are interruptions during infusion, the total allowed time should not exceed 8 hours at room 
temperature. 

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In addition to durvalumab, patients in the initial therapy phase will also receive 1 of the 
following SoC regimens as part of their treatment regimen (durvalumab will be infused first, 
followed by the SoC chemotherapy regimen):  
• 
Nab-paclitaxel plus carboplatin (squamous and nonsquamous patients): Nab-paclitaxel 
100 mg/m2 via IV infusion on Days 1, 8, and 15 of each 3-week cycle and carboplatin 
area under the concentration-time curve (AUC) 5 or 6 via IV infusion on Day 1 of each 
3-week cycle, for 4 cycles (Figure 2). 
• 
Gemcitabine plus carboplatin (squamous patients only): Gemcitabine 1000 or 
1250 mg/m2 via IV infusion on Days 1 and 8 of each 3-week cycle and carboplatin AUC 
5 or 6 via IV infusion on Day 1 of each 3-week cycle, for 4 cycles (Figure 3). 
• 
Gemcitabine plus cisplatin (squamous patients only): Gemcitabine 1000 or 1250 mg/m2 
via IV infusion on Days 1 and 8 of each 3-week cycle and cisplatin 75 mg/m2 via IV 
infusion on Day 1 of each 3-week cycle, for 4 cycles (Figure 3). 
• 
Pemetrexed plus carboplatin (nonsquamous patients only): Pemetrexed 500 mg/m2 and 
carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 3-week cycle, for 4 cycles 
(Figure 4). Pemetrexed maintenance therapy will not be allowed following the initial 
therapy phase. 
• 
Pemetrexed plus cisplatin (nonsquamous patients only): Pemetrexed 500 mg/m2 and 
cisplatin 75 mg/m2 via IV infusion on Day 1 of each 3-week cycle, for 4 cycles 
(Figure 4). Pemetrexed maintenance therapy will not be allowed following the initial 
therapy phase. 
In the event that SoC is delayed during the initial therapy phase, durvalumab administration 
must also be delayed.  
In the event of unfavorable tolerability, patients can switch between cisplatin and carboplatin 
therapy at any point during the study.  
Durvalumab monotherapy and durvalumab plus olaparib combination therapy (maintenance 
phase) 
During the maintenance phase, all patients will receive durvalumab 1500 mg via IV infusion 
every 4 weeks (q4w). Patients will also receive 300 mg oral olaparib (durvalumab plus 
olaparib treatment arm) or its matching placebo (durvalumab plus placebo treatment arm) BID 
continually until clinical disease progression (as assessed by the Investigator) or 
RECIST 1.1-defined radiological PD (Figure 5 and Figure 6), unless there is unacceptable 
toxicity, withdrawal of consent, or another discontinuation criterion met.  
Before commencing olaparib/placebo treatment, patients must first meet the 
hematology/clinical chemistry requirements specified in Section 1.1 without blood 
transfusions in the past 28 days.  
If a patient’s WT falls to 30 kg or below, the patient should receive WT-based dosing 
equivalent to 20 mg/kg of durvalumab q4w after consultation between Investigator and Study 

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Physician until the WT improves to >30 kg, at which point the patient should start receiving 
the fixed dosing of durvalumab 1500 mg q4w. If there is a dosing delay during the treatment 
schedule for durvalumab, subsequent time between 2 consecutive doses of durvalumab cannot 
be less than 21 days; olaparib/placebo administration may continue as scheduled if 
durvalumab is delayed. The standard infusion time for durvalumab is 60 minutes. In the event 
that there are interruptions during infusion, the total allowed time should not exceed 8 hours at 
room temperature. 
See Section 7.1 for details about discontinuation of either durvalumab or olaparib/placebo in 
the maintenance phase. 
Duration of treatment 
Unless specific treatment discontinuation criteria are met, treatment during the initial therapy 
phase will continue for only 4 cycles of durvalumab plus chemotherapy. There is no 
maximum treatment duration for the maintenance phase; patients will receive maintenance 
treatment until specific discontinuation criteria are met, including clinical disease progression 
(as assessed by the Investigator) or RECIST 1.1-defined radiological PD, unacceptable 
toxicity, and withdrawal of consent. 
Progression during treatment 
Patients with clinical disease progression (as assessed by the Investigator), in the initial 
therapy or maintenance phase of the study, are not eligible for treatment through progression. 
Patients who are clinically stable with RECIST 1.1-defined radiological PD at Cycle 2 of the 
initial therapy phase may continue to receive study treatment at the discretion of the 
Investigator and patient; however, if the patient continues to show a RECIST 1.1-defined 
radiological PD at Cycle 4, the patient will not be eligible for the maintenance phase of the 
study. Patients completing the initial therapy phase who are not randomized cannot continue 
durvalumab. 
During the maintenance phase, patients who are clinically stable at an initial 
RECIST 1.1-defined radiological PD may continue to receive study treatment at the discretion 
of the Investigator and patient. A follow-up scan is to be collected after the initial 
RECIST 1.1-defined radiological PD, preferably at the next (and no later than the next) 
scheduled imaging visit, and no less than 4 weeks after the prior assessment of PD; this 
follow-up scan is evaluated using the Confirmation of Radiological Progression criteria 
outlined in Appendix F. 
Patients with PD in the maintenance phase who continue to receive investigational product 
(IP) at the discretion of the Investigator and patient (following consultation with AstraZeneca) 
will have tumor assessments on their regular imaging schedule for the duration of treatment. 
However, patients will not be permitted to continue immunotherapy or olaparib/placebo if 

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progression occurs after confirmed response (CR or PR as defined by RECIST 1.1) in the 
target lesions (TLs) to either the initial therapy (durvalumab plus chemotherapy) or 
maintenance treatment (durvalumab or olaparib/placebo) of the study regardless of the 
appearance of new lesions. Patients who have discontinued durvalumab will not be permitted 
to be treated with olaparib/placebo monotherapy after progression. 
Follow-up of patients post discontinuation of study drug 
Patients who have discontinued treatment in the maintenance phase for any reason other than 
RECIST 1.1-defined radiological PD will be followed up with tumor assessments until 
RECIST 1.1-defined radiological PD, plus one or more additional follow-up scans if clinically 
feasible. Patients who discontinue treatment due to RECIST 1.1-defined radiological PD will 
have one or more additional follow-up scans, if clinically feasible. All patients will be 
followed for survival. For patients who are not randomized into the maintenance phase for any 
reason, follow-up tumor assessments will not be required. 
Survival 
All patients enrolled in the study should be followed up for survival. Assessments for survival 
must be made every 2 months following treatment discontinuation. See Section 7.3 for further 
details on survival follow-up for patients who choose to withdraw from the study. 
Data Monitoring Committee: 
An Independent Data Monitoring Committee (IDMC) will be established to perform an 
assessment of the safety of durvalumab plus olaparib therapy combinations in this population 
on an ongoing basis. The IDMC will be comprised of independent experts. The committee 
will meet at a frequency outlined in the IDMC Charter.  
IDMC members will be consulted to ensure appropriate frequency. Following each meeting, 
the IDMC will report to AstraZeneca and may recommend changes in the conduct of the 
study. 
Full details of the IDMC procedures, processes, and interim analyses can be found in the 
IDMC Charter.  
Statistical methods 
The primary objective of this study is to assess the efficacy of durvalumab plus olaparib 
combination therapy compared with durvalumab monotherapy during the maintenance phase 
in terms of PFS as determined by Investigator assessment according to RECIST 1.1 in all 
randomized patients. A key secondary objective is to assess the efficacy of durvalumab plus 
olaparib compared with durvalumab monotherapy in terms of OS. In order to provide strong 
control of the type I error rate α=5% (2-sided), the testing procedure for the primary endpoint 
and key secondary endpoint is hierarchical. 

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Additional, secondary efficacy variables include objective response rate (ORR) and duration 
of response (DoR) in the full analysis set (FAS), and PFS as determined by Investigator 
assessment according to RECIST 1.1 in the homologous recombination repair related gene 
mutation (HRRm) subgroup. Sensitivity analyses for the primary endpoint will be performed, 
including analyzing PFS according to blinded independent central review (BICR) in the FAS. 
Approximately 350 to 400 patients will be enrolled in the initial therapy phase of the study. 
Approximately 250 patients globally who have not progressed will be randomized in a 1:1 
ratio to either the durvalumab plus olaparib treatment arm or the durvalumab plus placebo 
treatment arm, approximately 125 patients per arm. The randomization will be stratified based 
on objective response to durvalumab plus chemotherapy (CR/PR or SD; obtained at the last 
visit prior to randomization [Cycle 4 scan]) and histology (squamous or nonsquamous). 
The primary analyses will be based on Investigator-recorded assessment of disease 
progression using RECIST 1.1 criteria. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
The effect of durvalumab + olaparib versus durvalumab + placebo will be estimated by the 
HR together with its 95% CI from a stratified Cox model (an HR less than 1 will favor 
durvalumab in combination with olaparib). The CI will be calculated using a profile likelihood 
approach. 
CCI

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Interactions between treatment and stratification factors will also be tested to rule out any 
qualitative interaction using the approach of Gail and Simon (Gail and Simon 1985). 
1.3 
Schema 
The general study design is summarized in Figure 1. 
Figure 1 
Study design 
 
Note: Crossover within the study will not be permitted. 
1L  First-line; ADA  Anti-drug antibodies; ALK  Anaplastic lymphoma kinase; BICR  Blinded independent 
central review; CR  Complete response; ECOG  Eastern Cooperative Oncology Group; EGFR  Epidermal growth 
factor receptor; DoR  duration of response; FAS  Full analysis set; HRRm  Homologous recombination repair 
related gene mutation; NSCLC  Non-small cell lung cancer; ORR  Objective response rate; OS  Overall survival; 
PFS  Progression-free survival; PK  Pharmacokinetic; PR  Partial response; PRO  Patient-reported outcome; 
PS  Performance status; R  Randomization; RECIST 1.1  Response Evaluation Criteria in Solid Tumors 
version 1.1; SD  Stable disease. 

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2. 
INTRODUCTION 
2.1 
Study rationale 
Current SoC therapies for metastatic NSCLC have mixed outcomes with responses to 
systemic chemotherapy in the first-line setting of approximately 20% to 40% and a median 
OS of approximately 11 to 14 months (Breslow 1974, Carbone et al 2017, Paz-Ares et al 
2013, Socinski et al 2018, Gandhi et al 2018). Treatments are associated with a variety of 
significant side effects, including neutropenia, nausea, vomiting and dehydration, and alopecia 
(Sandler et al 2006, Scagliotti et al 2008). The KEYNOTE-024, KEYNOTE-042, KEYNOTE-
189, and KEYNOTE-407 studies, along with the IMpower131 and IMpower150 studies, have 
shown that immunotherapy alone or in combination with chemotherapy can be effective 
first-line treatment for patients with metastatic NSCLC (Gandhi et al 2018, Jotte et al 2018, 
Lopes et al 2018, Paz-Ares et al 2018, Reck et al 2016, Socinski et al 2018). 
Results from these studies have been encouraging and represent a substantive advance, but 
further improvement is needed. All of the aforementioned studies yielded a median PFS of 
<1 year. Furthermore, there are no approved maintenance immunotherapy-based combination 
regimens for patients with squamous histology. Increased DNA damage triggered through 
PARP inhibition has the potential to not only provide antitumor activity but also modify tumor 
immunogenicity and sensitize tumors to immune checkpoint inhibition, promoting a more 
durable antitumor response. Therefore, in this Phase II study, the combination of durvalumab 
plus olaparib will be investigated to determine if this combination can prolong PFS in the 
maintenance setting in patients whose Stage IV NSCLC has not progressed following SoC 
platinum-based chemotherapy with durvalumab. 
2.2 
Background 
A detailed description of the chemistry, pharmacology, efficacy, and safety of durvalumab and 
olaparib is provided in the respective IB for each compound. 
2.2.1 
Non-small cell lung cancer 
Lung cancer has been the most common cancer in the world for several decades, with an 
estimated 1.8 million new cases in 2012 (12.9% of all new cancers), and was also the most 
common cause of death from cancer in 2012, with 1.6 million deaths (19.4% of cancer deaths; 
GLOBOCAN 2012). NSCLC represents 80% to 85% of all lung cancers. Unfortunately, at the 
time of diagnosis approximately 70% of patients with NSCLC have advanced or metastatic 
disease not amenable to potentially curative surgical resection. Furthermore, approximately 
50% of patients with early-stage NSCLC who have undergone surgery subsequently develop 
distant recurrence and die as a result of NSCLC (Pisters and LeChevalier 2005). 
Despite advances in the diagnosis, imaging, staging, and treatment of NSCLC, the estimated 
5-year OS for patients in Europe and the United States (US) continues to be exceedingly low 

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(11% and 17%, respectively; D’Addario et al 2010, Howlander et al 2017). The 5-year OS for 
patients in the US from the time of diagnosis of metastatic NSCLC is only 4.5% (Howlander 
et al 2017). Patients presenting with metastatic NSCLC without a targetable mutation (ie, 
epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] mutation) 
demonstrate responses to chemotherapy-based systemic treatment of approximately 20% to 
40%, have a median PFS of between approximately 6 to 9 months and a median OS of 11 to 
14 months (Breslow 1974, Carbone et al 2017, Gandhi et al 2018, Paz-Ares et al 2013, 
Socinski et al 2018). The DoRs are also limited, and toxicities can be a major limiting factor.  
Common first-line treatment regimens for metastatic NSCLC without a targetable mutation 
are platinum-based doublets and include carboplatin and paclitaxel (eg, nab-paclitaxel, 
carboplatin and gemcitabine, carboplatin and pemetrexed (nonsquamous only), cisplatin and 
gemcitabine, and cisplatin and pemetrexed (nonsquamous only). Although platinum-based 
doublets are interchangeable in terms of efficacy when used alone, these doublets vary to 
some extent with regard to convenience, associated toxicities, and cost, with the selection of a 
specific regimen often dictated by local practice and individualized on a case-by-case basis. 
Maintenance therapy with either continuation or switch of a component of the patient’s initial 
treatment regimen is an option for patients following initial treatment. Choice of therapy is 
influenced by histologic subtype (squamous or nonsquamous), with choices including single 
agent chemotherapy, bevacizumab, or pemetrexed. There have been multiple studies that have 
illustrated the efficacy of continued maintenance therapy of various agents with improved 
median PFS and median OS compared to observation/best supportive care (Sandler et al 2006, 
Fidias et al 2009, Pérol et al 2012, Ciuleanu et al 2009, Paz-Ares et al 2013). However, upon 
review of the overall data from these studies, the anticipated PFS and OS remain poor and, as 
such, there remains significant room for improvement with many studies currently 
investigating different combinations of these approved agents, immunotherapy, and other 
novel agents in the maintenance setting. 
2.2.2 
Immunotherapies 
It is increasingly understood that cancers are recognized by the immune system, and under 
some circumstances, the immune system may control or even eliminate tumors 
(Dunn et al 2004).  
Programmed cell death ligand-1 (PD-L1) is part of a complex system of receptors and ligands 
that are involved in controlling T-cell activation. The programmed cell death protein-1 (PD-1) 
receptor (cluster of differentiation [CD] 279) is expressed on the surface of activated T cells 
(Keir et al 2008). It has 2 known ligands: PD-L1 (B7-H1; CD274) and programmed cell death 
ligand-2 (PD-L2 [B7-DC; CD273]) (Okazaki and Honjo 2007). PD-1 and PD-L1/PD-L2 
belong to a family of immune checkpoint proteins that act as co-inhibitory factors, which can 
halt or limit the development of T-cell response. When PD-L1 binds to PD-1, an inhibitory 

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signal is transmitted into the T cell, which reduces cytokine production and suppresses T-cell 
proliferation. Tumor cells (TCs) exploit this immune checkpoint pathway as a mechanism to 
evade detection and inhibit immune response. 
PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages (Qin et al 
2016). Importantly, PD-L1 is commonly over-expressed on TCs or on non-transformed cells 
in the tumor microenvironment (Pardoll 2012). PD-L1 expressed on the TCs binds to PD-1 
receptors on the activated T cells, leading to the inhibition of cytotoxic T cells. These 
deactivated T cells remain inhibited in the tumor microenvironment. The PD-1/PD-L1 
pathway represents an adaptive immune resistance mechanism that is exerted by TCs in 
response to endogenous antitumor activity. 
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way 
of evading immune detection and elimination. The binding of an anti-PD-L1 agent to the 
PD-L1 receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed 
on immune cells. This activity overcomes PD-L1-mediated inhibition of antitumor immunity. 
While functional blockade of PD-L1 results in T-cell reactivation, this mechanism of action 
(MOA) is different from direct agonism of a stimulatory receptor such as CD28. 
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 
antibody could be used therapeutically to enhance antitumor immune responses in patients 
with cancer. Results of preclinical and clinical studies of monoclonal antibodies (mAbs) 
targeting the PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable 
safety profile, supporting the hypothesis that an anti-PD-L1 antibody could be used to 
therapeutically enhance antitumor immune response in cancer patients (Brahmer et al 2012, 
Hirano et al 2005, Iwai et al 2002, Okudaira et al 2009, Topalian et al 2012, Zhang et al 2008) 
with responses that tend to be more pronounced in patients with tumors that express PD-L1 
(Powles et al 2014, Rizvi et al 2015a, Segal et al 2015). In addition, high mutational burden 
(eg, in bladder carcinoma; Alexandrov et al 2013) may contribute to the responses seen with 
immune therapy. 
In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively 
expressed by regulatory T cells and upregulated on activated T cells. CTLA-4 delivers a 
negative regulatory signal to T cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on 
antigen-presenting cells (Fife and Bluestone 2008). Blockade of CTLA-4 binding to CD80/86 
by anti-CTLA-4 antibodies results in markedly enhanced T-cell activation and antitumor 
activity in animal models, including killing of established murine solid tumors and initial 
therapy of protective antitumor immunity. Therefore, it is expected that treatment with an 
anti-CTLA-4 antibody will lead to increased activation of the human immune system, 
increasing antitumor activity in patients with solid tumors. 

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Preclinical data has now been added to a wealth of clinical data showing that blockade of 
negative regulatory signals to T cells such as CTLA-4 and PD-L1 has promising clinical 
activity. Ipilimumab was first granted US Food and Drug Administration (FDA) approval for 
the treatment of metastatic melanoma and is currently under investigation for several other 
malignancies. Nivolumab and pembrolizumab, 2 anti-PD-1 agents, along with durvalumab 
and atezolizumab, 2 anti-PD-L1 agents, have been granted approvals by agencies for the 
treatment of a number of malignancies including metastatic melanoma, squamous and 
nonsquamous cell NSCLC, squamous cell carcinoma of the head and neck (SCCHN), and 
urothelial carcinoma. In addition, there are data from agents in the anti-PD-1/PD-L1 class 
showing clinical activity in a wide range of tumor types. 
2.2.3 
Immunotherapy in non-small cell lung cancer 
A plateau has apparently been reached with platinum-based doublet chemotherapy with 
regards to efficacy, in addition to concerns regarding DoR, and tolerability. Therefore, other 
mechanisms and modalities have been explored to improve upon traditional therapies. The 
opportunity to explore immune therapies greatly expanded with the identification of the 
checkpoint inhibitor agents. These agents demonstrated clinically meaningful responses in 
metastatic NSCLC, with some patients exhibiting durable responses even after discontinuing 
therapy (Malhotra et al 2017). As a result, the treatment landscape of NSCLC across different 
lines of therapies has continuously evolved since the introduction of checkpoint inhibitor 
agents.  
For the treatment of NSCLC in the first-line setting, pembrolizumab (a PD-1 inhibitor) 
recently gained FDA approval for the first-line treatment of metastatic NSCLC in patients 
with high PD-L1 expression and without EGFR or ALK genomic tumor aberrations. 
Regulatory approval was based on safety and efficacy data from the KEYNOTE-024 study. 
Results from this study, which included patients with metastatic NSCLC and PD-L1 
expression on at least 50% of TCs and with no activating EGFR mutations or ALK fusions, 
demonstrated that patients treated with pembrolizumab had a longer median PFS (10.3 versus 
6.0 months, HR for disease progression or death, 0.5) and OS (median OS not reached in 
either group, HR for death, 0.60) and higher ORR (44.8% versus 27.8%) compared with 
patients treated with platinum-based therapy (Reck et al 2016). 
Similar results were seen in patients with TCs with ≥50% PD-L1 expression in the 
KEYNOTE-042 study, which included patients of a similar population comparing 
pembrolizumab with platinum-based chemotherapy (Lopes et al 2018). Analysis in this study 
showed that patients with a ≥50% PD-L1 expression derived the greatest benefit from 
pembrolizumab monotherapy in terms of median PFS (7.1 versus 6.4 months, HR for disease 
progression or death 0.81), median OS (20 versus 12.2 months, HR for death 0.69), and ORR 
(39.5% versus 32.0%). An exploratory analysis of patients with a PD-L1 expression of 

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between 1% and 49% showed a modest benefit in this patient population in terms of median 
OS (13.4 versus 12.1 months, HR for death 0.92).  
In addition to the efficacy of monotherapy checkpoint inhibition demonstrated in NSCLC in 
patients with high expression of PD-L1, the KEYNOTE-189 and IMpower150 studies 
demonstrated the efficacy of checkpoint inhibition in combination with chemotherapy. The 
KEYNOTE-189 study is a randomized Phase III study that compared the efficacy and safety 
of pembrolizumab plus a platinum-based agent and pemetrexed to pemetrexed and a 
platinum-based agent alone as first-line therapy for patients with Stage IV nonsquamous 
NSCLC. The IMpower150 study is a Phase III study that compared the efficacy and safety of 
atezolizumab plus bevacizumab, carboplatin, and paclitaxel to bevacizumab, carboplatin, and 
paclitaxel alone in a similar patient population as KEYNOTE-189.  
The KEYNOTE-189 patients who were treated with first-line pembrolizumab in combination 
with pemetrexed and platinum chemotherapy had a longer median PFS (8.8 versus 
4.9 months, HR for disease progression or death 0.52), median OS (OS not reached versus 
11.3 months, HR for death 0.49), and higher ORR (47.6% versus 18.9%) compared with 
pemetrexed plus platinum chemotherapy (Gandhi et al 2018). The IMpower150 patients who 
were treated with first-line atezolizumab in combination with bevacizumab and chemotherapy 
had a longer median PFS (8.3 versus 6.8 months, HR for progression or death 0.62), median 
OS (19.2 versus 14.7 months, HR for death 0.78), and higher ORR (63.5% versus 48%) 
compared with bevacizumab and chemotherapy (Socinski et al 2018). 
Encouraging efficacy results were also demonstrated utilizing checkpoint inhibition in 
combination with chemotherapy for the KEYNOTE-407 and IMpower131 studies in Stage IV 
squamous NSCLC patients. Both KEYNOTE-407 and IMpower131 are Phase III studies, 
comparing pembrolizumab or atezolizumab plus paclitaxel/nab-paclitaxel and carboplatin to 
paclitaxel/nab-paclitaxel and carboplatin as first-line therapy for patients with Stage IV 
squamous NSCLC, respectively. The KEYNOTE-407 patients who were treated with first-line 
pembrolizumab in combination with paclitaxel or nab-paclitaxel had a longer median PFS 
(6.4 versus 4.8 months, HR for disease progression or death 0.56) and median OS (15.9 versus 
11.3 months, HR for death 0.64) compared with paclitaxel/nab-paclitaxel and carboplatin 
(Paz-Ares et al 2018). The IMpower131 patients who were treated with first-line atezolizumab 
in combination with nab-paclitaxel and carboplatin had a longer median PFS (6.3 versus 
5.6 months, HR for disease progression or death 0.71) and greater ORR (49% versus 41%) 
compared with nab-paclitaxel and carboplatin (Jotte et al 2018). However, the OS benefit 
demonstrated by the atezolizumab plus chemotherapy combination was modest (median OS: 
14 versus 13.9 months, HR for death 0.96).  

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All of these aforementioned studies have shown that immunotherapy alone or in combination 
with chemotherapy can be an effective first-line treatment option for patients with metastatic 
NSCLC.  
2.2.4 
Durvalumab 
Durvalumab is a human mAb of the immunoglobulin G 1 kappa subclass that blocks the 
interaction of PD-L1 (but not PD-L2) with PD-1 on T cells and CD80 (B7.1) on immune cells. 
It is being developed by AstraZeneca/MedImmune for use in the treatment of cancer. 
(MedImmune is a wholly owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be 
referred to as AstraZeneca throughout this document.) The proposed MOA for durvalumab is 
interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/ 
PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including 
those that may result in tumor elimination. In vitro studies demonstrate that durvalumab 
antagonizes the inhibitory effect of PD-L1 on primary human T cells resulting in the restored 
proliferation of interferon (IFN)-γ (Stewart et al 2015). In vivo studies have shown that 
durvalumab inhibits tumor growth in xenograft models via a T-cell-dependent mechanism 
(Stewart et al 2015). Based on these data, durvalumab is expected to stimulate the patient’s 
antitumor immune response by binding to PD-L1 and shifting the balance toward an antitumor 
response. Durvalumab has been engineered to reduce antibody-dependent cellular cytotoxicity 
and complement-dependent cytotoxicity.  
To date, durvalumab has been given to more than 6000 patients as part of ongoing studies 
either as monotherapy or in combination with other anticancer agents. Details on the safety 
profile of durvalumab monotherapy are summarized in Section 4.3.1 and Section 8.3.12.1. 
Refer to the current durvalumab IB for a complete summary of preclinical and clinical 
information including safety, efficacy, and PK.  
2.2.5 
Olaparib 
Olaparib (LYNPARZA™) is a potent inhibitor of PARP that received marketing approval 
(tablet formulation) in the US on 17 August 2017 for the following indication: “Lynparza is 
indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, 
fallopian tube or primary peritoneal cancer, who are in a CR or PR to platinum-based 
chemotherapy; and for the treatment of adult patients with deleterious or suspected deleterious 
germline breast cancer susceptibility gene (BRCA)-mutated (gBRCAm) advanced ovarian 
cancer who have been treated with 3 or more prior lines of chemotherapy”. In January 2018, 
olaparib (tablet formulation) also received marketing approval in the US for the following 
indication: “Lynparza is indicated in patients with deleterious or suspected deleterious 
gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast 
cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or 
metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have 
been treated with a prior endocrine therapy or be considered inappropriate for endocrine 

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treatment.” In the European Union (EU), the tablet formulation of olaparib received marketing 
authorization in February 2018 as monotherapy for the maintenance treatment of adult 
patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or 
primary peritoneal cancer who are in response (complete or partial) to platinum-based 
chemotherapy.  
Furthermore, as of 1 March 2017, the capsule formulation of olaparib has received marketing 
approval in more than 50 countries including those in the EU and the US and Switzerland, 
Australia, and Canada. The capsule formulation is indicated for ovarian cancer only. 
Details on the safety profile of olaparib monotherapy are summarized in Section 4.3.4 and 
Section 8.3.12.2. Refer to the current olaparib IB for a complete summary of preclinical and 
clinical information including safety, efficacy, and PK. The tablet formulation will be used for 
this study. 
2.2.6 
Durvalumab in combination with olaparib in the full analysis set 
In this study, the PARP inhibitor olaparib will be combined with the PD-L1 inhibitor 
durvalumab in patients who do not progress following treatment combination of 
platinum-based chemotherapy with durvalumab. Combining durvalumab with olaparib 
therapy may yield additive mechanisms to promote a more robust and durable antitumor 
response. There have been preclinical data to suggest that olaparib may potentiate the efficacy 
of DNA-damaging chemotherapies including platinum-containing agents (Evers et al 2008, 
Rottenberg et al 2008) along with clinical evidence that olaparib can be an effective option in 
platinum-sensitive tumors including ovarian cancer (Oza et al 2015, Ledermann et al 2012). 
There is also preclinical evidence to support olaparib as an effective option for other 
platinum-sensitive tumors such as NSCLC through an analysis that demonstrated the 
correlation of olaparib response with several SoC chemotherapies in a panel of NSCLC cancer 
cell lines. 
 
 
 
This correlation between olaparib and platinum sensitivity is theorized to be due to the 
underlying mechanisms surrounding platinum agents and PARP inhibition, as TCs exhibiting 
DNA repair gene loss of function mutations lack effective, accurate mechanisms for DNA 
repair.  
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Inhibition of PARP in sensitive TCs results in accumulating levels of DNA damage and 
genomic instability, ultimately resulting in cell death (Farmer et al 2005). Furthermore, 
accumulating DNA damage has the potential to modify the immunogenicity of tumors through 
a number of key mechanisms: 
• 
Triggering of intracellular signaling events that result in the activation of nuclear factor 
kappa B and interferon regulatory factor 7. These transcriptional regulators result in the 
increased production of cytokines and chemokines that have the potential to promote 
antitumor immunity, such as type I IFNs (Chatzinikolaou et al 2014). 
• 
Upregulation of surface receptors such as major histocompatibility complex, ligands for 
natural-killer group 2, member D and inducible T-cell costimulatory ligand, which render 
TCs more visible to detection by cytotoxic T cells (Tang et al 2014). 
• 
Increasing the number of CD8(+) T and natural killer cells, boosting production of IFN-γ 
and tumor necrosis factor (TNF)-α, and prolonging survival of mice bearing 
BRCA1-deficient murine ovarian cancer cell line (Huang et al 2015).  
• 
Death of TCs and release of antigen, which may help to promote antigen presentation and 
immune priming (Kroemer et al 2013).  
These effects would be expected to help promote a more robust antitumor immune response 
than that obtained with monotherapy PD-1 or PD-L1 inhibition through improved lung tumor 
immunogenicity. In keeping with this hypothesis, several tumor types with genetic defects 
expected to lead to increased DNA damage show evidence of enhanced immune recognition 
(Mulligan et al 2014) and published data link DNA repair gene mutation frequency, tumor 
mutational burden (TMB), and clinical benefit from checkpoint inhibition in NSCLC (Rizvi et 
al 2015b). 
Details on the safety profile of durvalumab plus olaparib combination therapy are summarized 
in Section 2.3.2.3. Details on the efficacy of durvalumab plus olaparib combination therapy 
are summarized in Section 2.3.1.3. 
2.2.6.1 
Rationale for the combination of durvalumab plus olaparib for HRRm 
tumors 
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair 
mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs). 
Inhibiting PARPs leads to the persistence of SSBs, which are then converted to the more 
serious DNA double strand breaks (DSBs) during the process of DNA replication. During the 
process of cell division, DSBs can be efficiently repaired in normal cells by homologous 
recombination repair (HRR). Tumors with homologous recombination deficiencies cannot 
accurately repair the DNA damage, which may become lethal to cells as it accumulates. The 
MOA for olaparib results from the trapping of inactive PARP onto the SSBs preventing their 
repair (Helleday 2011, Murai et al 2012). Persistence of SSBs during DNA replication results 
in their conversion into the more serious DNA DSBs that would normally be repaired by 
HRR. Therefore, in such tumor types, the addition of olaparib to durvalumab may offer a 

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potentially more robust antitumor response compared with non HRRm tumors with a higher 
amount of accumulating DNA damage to potentially increase lung tumor immunogenicity. 
2.2.7 
Durvalumab in combination with chemotherapy 
The use of combination chemotherapy is a mainstay of oncology therapy. The goal of 
combination chemotherapy is to utilize agents that affect cancer cells by different 
mechanisms, thus reducing the risk of developing resistance. Current studies are now adding 
immunotherapeutics to chemotherapeutics with encouraging activity in Stage IV NSCLC (see 
Section 2.2.3). 
In addition to the PD-1/PD-L1 chemotherapy combination studies mentioned in Section 2.2.3, 
data for durvalumab with or without tremelimumab with standard platinum-based 
chemotherapy in advanced cancers are being generated from 2 ongoing Phase I studies: the 
internal Study D419SC00001 (n=10) and a Phase Ib study (NCT02537418) run by the 
Canadian Cancer Trials Group (CCTG; n=118; Daaboul et al 2017). The combinations tested 
are tolerable and toxicities manageable. Preliminary results from the CCTG study were 
presented for the NSCLC cohorts at the International Association for the Study of Lung 
Cancer (IASLC) 2016 meeting; the overall ORR in NSCLC cohort (n=24) was 52.9% 
(Juergens et al 2017). 
In summary, the efficacy, safety, and tolerability data of immunotherapies in combination 
with chemotherapy support the continued development of these treatments for NSCLC. 
2.3 
Benefit/risk assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of durvalumab and olaparib may be found in the respective IB for each 
compound. 
2.3.1 
Potential benefits 
2.3.1.1 
Durvalumab 
The majority of the safety and efficacy data currently available for durvalumab are based on 
the first-in-human, single-agent study (Study CD-ON-MEDI4736-1108; hereafter referred to 
as Study 1108) in patients with advanced solid tumors and the study of durvalumab 
monotherapy in NSCLC (Study D4191C00003 [ATLANTIC]). In Study 1108, as of 
7 May 2015, 456 of 694 patients treated with durvalumab 10 mg/kg every 2 weeks (q2w) were 
evaluable for response (defined as having ≥24-week follow-up, measurable disease at 
baseline, and ≥1 follow-up scan or discontinued because of disease progression or death 
without any follow-up scan). Data from treatment-naïve patients with NSCLC in this study 
(n=59) showed a favorable disease control rate (DCR) at ≥12 weeks of 56% when durvalumab 
was given 10 mg/kg q2w (Antonia et al 2016). 

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In PD-L1 unselected patients, the ORR, based on Investigator assessment per RECIST 1.1, 
ranged from 0% in uveal melanoma to 20.0% in bladder cancer, and DCR at 24 weeks ranged 
from 4.2% in triple-negative breast cancer to 39.1% in advanced cutaneous melanoma. PD-L1 
status was known for 383 of the 456 response-evaluable patients. Across the PD-L1-positive 
tumors (defined as PD-L1 TC ≥25%), ORR was highest (>10%) for bladder cancer, advanced 
cutaneous melanoma, and hepatocellular carcinoma (33.3% each); NSCLC (26.7%); and 
SCCHN (18.2%). Moreover, in the PD-L1-positive subset, DCR at 24 weeks was highest 
(>10%) in advanced cutaneous melanoma (66.7%), NSCLC (36.0%), hepatocellular 
carcinoma and bladder cancer (33.3% each), and SCCHN (18.2%).  
A total of 444 patients with locally advanced or metastatic NSCLC were treated in the 
ATLANTIC study. As of the data cut-off (DCO) of 3 June 2016, in Cohort 2 (EGFR/ALK 
wild type/unknown, PD-L1 expression on ≥25% of TCs), durvalumab monotherapy showed 
clinically meaningful activity based on ORR in patients with locally advanced or metastatic 
NSCLC who had received at least 2 prior systemic treatment regimens. The responses were 
numerically greater in the PD-L1 TC ≥25% group (16.4%) compared with the PD-L1 
expression on less than 25% of TCs (PD-L1 TC <25%) group (7.5%). The DCR at 6 months 
was 28.8% in the PD-L1 TC ≥25% group and 20.4% in the PD-L1 TC <25% group. The 
median OS was 10.9 months in the PD-L1 TC ≥25% patients and 9.3 months in the PD-L1 TC 
<25% patients. For the PD-L1 TC ≥25% patients, the OS rate at 6 and 12 months were 67.4% 
and 47.7%, respectively. For the PD-L1 TC <25% patients, the OS rate at 6 and 12 months 
were 60.3% and 34.5%, respectively. Observed PFS was numerically longer in the PD-L1 TC 
≥25% group compared with the PD-L1 TC <25% group. In Cohort 3 (EGFR/ALK wild 
type/unknown, PD-L1 expression on ≥90% of TCs [PD-L1 TC ≥90%]), the ORR was 30.9%. 
The DCR at 6 months was 38.2%. Observed PFS and OS were similar to PD-L1 TC ≥25% 
patients in Cohort 2. For patients with PD-L1 ≥90% in the combined Cohorts 2 and 3, the 
ORR was 23.2%. The DCR at 6 months was 34.1%. Observed PFS and OS were similar to 
PD-L1 TC ≥25% patients in Cohort 2. For patients who responded, the response was durable 
across various subgroups (median DoR of 12.3 months in the PD-L1 TC ≥25% group in 
Cohort 2). In Cohort 2, 66.7% of responders in the PD-L1 TC ≥25% group had their first 
response at the time of the first on-treatment tumor assessment (Week 8). The median time to 
response was 1.9 months. In Cohort 1 (EGFR/ALK positive), the ORR was numerically lower 
than in the EGFR/ALK wild type/unknown cohorts. The responses were numerically greater in 
the PD-L1 TC ≥25% group (12.2%) compared with the PD-L1 TC <25% group (3.6%). The 
DCR at ≥6 months was 28.8% in the PD-L1 TC ≥25% group, 20.4% in the PD-L1 TC <25% 
group, and 38.2% in the PD-L1 TC ≥90% group. Observed PFS and OS were numerically 
longer in the PD-L1 TC ≥25% group compared with the PD-L1 TC <25% group (Garassino et 
al 2016; 
). 
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2.3.1.2 
Olaparib 
As of 15 December 2017, approximately 8319 patients were estimated to have received 
olaparib in the clinical program. An estimated 5835 patients with ovarian, breast, pancreatic, 
gastric, and a variety of other solid tumors were estimated to have received treatment with 
olaparib. Since 2012/2013, most new clinical studies have utilized the tablet formulation, 
which was designed to deliver the therapeutic dose of olaparib in fewer dose units than the 
capsule. In the AstraZeneca-sponsored, interventional studies, olaparib was given either as 
monotherapy (3133 patients) or in combination with chemotherapy or other anticancer agents, 
including studies where patients received monotherapy and combination therapy sequentially 
(1442 patients). 
Data from the available nonclinical studies and subsequent clinical development program 
demonstrate that olaparib appears to be active and generally well tolerated in patients with 
solid tumors including those with BRCAm cancers. In ovarian cancer, responses have been 
seen in all patient groups, including platinum-resistant and refractory cancer (refer to the 
current olaparib IB for further details). Furthermore, as described in Section 2.2.6, there is 
nonclinical evidence demonstrating a strong correlation between platinum and olaparib 
responsiveness in multiple tumor types (including NSCLC), as well as evidence showing 
PARP inhibition having the potential to modify the immunogenicity of tumors, leading to 
enhanced susceptibility to immune checkpoint inhibition. These findings suggest that olaparib 
may be a potential maintenance option in combination with durvalumab for patients with 
Stage IV NSCLC. 
2.3.1.3 
Durvalumab plus olaparib combination therapy 
As noted in Section 2.2.6, the hypothesis to be tested in this study is that increased DNA 
damage triggered through PARP inhibition will result in enhanced antitumor immunity that 
can be further enhanced through combination with an immune checkpoint inhibitor in 
NSCLC. Encouraging clinical activity has been seen to date with durvalumab in combination 
with olaparib outside of NSCLC (Lee et al 2017, Karzai et al 2018, Domchek et al 2018). 
2.3.1.4 
Durvalumab plus chemotherapy 
Studies evaluating agents targeting PD-L1/PD-1 in combination with chemotherapy have 
yielded encouraging results (see results of these studies in Section 2.2.3).  
In addition, data on durvalumab ± tremelimumab with standard platinum-based chemotherapy 
in advanced cancers are being generated from an ongoing Phase IB study (NCT02537418) run 
by the CCTG. A total of 118 patients with different tumor types have been dosed with various 
chemotherapy regimens. The overall ORR in the NSCLC cohort (n=24) was 52.9% (95% CI: 
28% to 77%) (Daaboul et al 2017, Juergens et al 2017). 

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2.3.2 
Overall risks 
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-L1 as well as 
those directed against PD-1 or CTLA-4, aim to boost endogenous immune responses directed 
against TCs. By stimulating the immune system, however, there is the potential for adverse 
effects on normal tissues. 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune-mediated mechanism and that may 
require more frequent monitoring and/or unique interventions such as immunosuppressants 
and/or endocrine therapy. These immune-mediated effects can occur in nearly any organ 
system and are most commonly seen as gastrointestinal (GI) AEs such as colitis and diarrhea, 
pneumonitis/interstitial lung disease (ILD), hepatic AEs such as liver enzyme elevations, skin 
events such as rash and dermatitis, and endocrinopathies including hypothyroidism and 
hyperthyroidism.  
2.3.2.1 
Durvalumab 
Risks with durvalumab include, but are not limited to, diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyperthyroidism and hypothyroidism, and type I diabetes mellitus and diabetes insipidus), 
hepatitis/increases in transaminases, nephritis/increases in creatinine, rash/dermatitis, 
myocarditis, myositis/polymyositis, infusion-related reactions, hypersensitivity reactions, 
pancreatitis, serious infections, and other rare or less frequent inflammatory events including 
neuromuscular toxicities (e.g. Guillain Barre syndrome, myasthenia gravis). 
For information on all identified and potential risks with durvalumab, please always refer to 
the current version of the durvalumab IB. 
In monotherapy clinical studies, AEs at an incidence of ≥ 20% include events such as fatigue, 
cough, decreased appetite, dyspnea and nausea. Approximately 10% of patients discontinued 
the drug due to an AE. Please see the current version of the IB for a detailed summary of the 
monotherapy data including AEs, serious adverse events (SAEs), and Common Toxicity 
Criteria Grade 3 to 5 events reported across the durvalumab program. 
The majority of treatment-related AEs were manageable, with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see Section 8.4.5). 
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB. 

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2.3.2.2 
Olaparib 
From the available data to date in patients with advanced cancer, there is no evidence of any 
unexpected toxicity following long-term olaparib (capsule) monotherapy exposure. Adverse 
laboratory findings and/or clinical diagnoses considered to be causally associated with 
administration of olaparib monotherapy include hematological effects (anemia, neutropenia, 
lymphopenia, thrombocytopenia, mean corpuscular volume elevation, and increase in blood 
creatinine), nausea and vomiting, decreased appetite, diarrhea, dyspepsia, stomatitis, upper 
abdominal pain, dysgeusia, fatigue (including asthenia), headache, dizziness, and cough. Most 
of these events were generally mild or moderate in intensity. 
An analysis of data from 13 AstraZeneca-sponsored monotherapy studies in 1006 patients 
with ovarian cancer (634/1006 [63%]) and other non-ovarian solid tumors (372/1006 [37%]) 
who received olaparib capsule at a range of doses estimated that 16.0% (161/1006) of patients 
had been exposed to olaparib (capsule) for >12 months, 8.3% for >18 months, and 4.1% for 
>24 months at the time of database closure for the respective studies. Twenty-one patients 
(2.1%) had received ≥48 months of olaparib exposure. 
In a relatively small number of patients, pneumonitis, myelodysplastic syndrome (MDS)/acute 
myeloid leukemia (AML), and new primary malignancies have been observed. Evidence from 
across the development program for olaparib does not support a conclusion that there is a 
causal relationship between olaparib and these events. 
A detailed summary of olaparib AE data can be found in the current version of the olaparib 
IB.  
2.3.2.3 
Durvalumab plus olaparib combination therapy 
Encouraging clinical activity, combined with acceptable and manageable safety, has been seen 
to date with durvalumab in combination with olaparib. In general, the toxicity profiles of 
durvalumab and olaparib are non-overlapping. Pneumonitis is considered to be the most 
important potential exception. See Section 8.2.7 for the management guidelines for 
pneumonitis that integrate the guidance provided for these 2 agents. 
mAbs are not metabolized through classical hepatic enzymes pathways. Olaparib has 
previously been combined with another mAb (bevacizumab) without significant drug-drug 
interaction. Therefore, no PK interaction is anticipated within this study.  
Clinical data on the tolerability and safety of durvalumab plus olaparib combination therapy 
are emerging. A Phase I, dose escalation study reported that there were no dose-limiting 
toxicities (DLTs) for durvalumab (10 mg/kg q2w or 1500 mg q4w) plus olaparib (200 or 
300 mg BID) combination therapy in 12 female patients with recurrent women’s cancers. The 
most frequent treatment-emergent AEs were hematologic toxicities, including lymphopenia 
and anemia (Lee et al 2017). The combination of durvalumab (1500 mg q4w) plus olaparib 

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(300 mg BID) is also being evaluated in several tumor types in Study NCT02734004 with 
reported safety data in small cell lung cancer. The most frequent Grade 3 and worse AEs in 
this study were anemia (39.5%) and lymphopenia (13.2%). The majority of other AEs could 
be attributed to underlying disease (Krebs et al 2017). Thus far, treatment-related AEs for 
durvalumab plus olaparib combination therapy have been consistent across studies and 
indications, with no evidence of an increase in frequency or severity of immune-mediated 
adverse events (imAEs). 
2.3.2.4 
Durvalumab plus chemotherapy 
Two ongoing studies are evaluating the safety and tolerability of combining durvalumab and 
tremelimumab with different chemotherapy regimens in patients with solid tumors. One study 
is an AstraZeneca internal study (D419SC00001), and the other is CCTG Study 
NCT02537418. 
As of 12 July 2017, a total of 10 patients with advanced solid tumors have been treated with 
durvalumab and tremelimumab in combination with chemotherapy in Study D419SC00001. 
All 10 patients had at least 1 AE (regardless of causality). The AEs (all grades) reported in 
>20% of patients were nausea (80.0%); decreased appetite (70.0%); neutrophil count 
decreased (60%); anemia, cough, insomnia, and pyrexia (50.0% each); constipation, dizziness, 
dyspnea, neutropenia, pruritus, and rash (40.0% each); and abdominal pain, back pain, 
diarrhea, febrile neutropenia, headache, hypokalemia, myalgia, and vomiting (30.0% each). 
SAEs were reported in a total of 5 patients (50.0%). With the exception of diarrhea and 
pyrexia (2 patients each), all the other SAEs were reported in 1 patient each. One patient had a 
fatal AE of lung infection that was considered treatment related. A total of 20.0% of patients 
had AEs that led to permanent discontinuation of treatment. 
In the CCTG study (NCT02537418), 118 patients were exposed to over 700 cycles of 
treatment, which began with chemotherapy combined with durvalumab ± tremelimumab until 
4 to 6 cycles of chemotherapy ended; afterward, patients received further durvalumab ± 
tremelimumab treatment (Daaboul et al 2017). Recent data from the CCTG study show that 
chemotherapy combined with durvalumab ± tremelimumab did not increase immune-related 
adverse events (irAEs), giving support to the combination being tolerable and manageable. 
Overall, 50% of patients had irAEs of any grade and 10% had ≥Grade 3 irAEs. Differences 
between the chemotherapy combination period and the durvalumab ± tremelimumab alone 
period were not significant, with the exception of biochemistry irAEs (chemotherapy 
combination 74% versus durvalumab ± tremelimumab 48%; p=0.003) and ALT/AST changes 
(41% versus 16% and 38% versus 9%, respectively; p=0.005). The irAEs that led to 
discontinuation of treatment in 15 patients were pneumonitis, hepatitis, nephritis, adrenal, 
myocarditis, gastrointestinal, thrombocytopenia, hyperthyroidism, encephalitis, and patient 
decision; pneumonitis and gastrointestinal irAEs were the most common, followed by 

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nephritis. The few significant findings are likely due to the nature of combining numerous 
agents. 
External clinical data also support these findings. In KEYNOTE-189, in patients with NSCLC 
treated with pembrolizumab and chemotherapy or chemotherapy alone, the incidence of 
Grade 3 or worse AEs was 67.2% and 65%, respectively. In the pembrolizumab plus 
chemotherapy group, the most common Grade 3 or worse AEs (AE frequency ≥5%) were 
anemia (16.3%), neutropenia (15.8%), thrombocytopenia (7.9%), asthenia (6.2%), fatigue 
(5.7%), and diarrhea (5.2%). In the chemotherapy-alone group, the most common Grade 3 or 
worse AEs (AE frequency ≥5%) were anemia (15.3%); neutropenia (11.9%); 
thrombocytopenia (6.9%); dyspnea (5.4%); and decreased neutrophil count, pancytopenia, and 
thrombocytopenia (3% each). AEs that led to death occurred in 6.7% of patients in the 
pembrolizumab-combination group and 5.9% of patients in the placebo-combination group. 
Of note, acute kidney injury occurred more frequently in the pembrolizumab-combination 
group than in the placebo-combination group (5.2% vs. 0.5%). In the pembrolizumab-
combination group, acute kidney injury was ≥Grade 3 in 8 patients (2.0%) and led to the 
discontinuation of all trial therapy in 8 patients (2.0%) (Gandhi et al 2018). 
For the IMpower150 study, AEs related to any treatment (as determined by the investigator) 
occurred in 94.4% of patients in the atezolizumab + bevacizumab + chemotherapy group 
(ABCP) and in 95.4% of patients in the bevacizumab + chemotherapy group (BCP). The most 
common Grade 3 or 4 treatment-related AEs were neutropenia, decreased neutrophil count, 
febrile neutropenia, and hypertension. The incidences of rash, stomatitis, febrile neutropenia, 
and hemoptysis were higher by less than 10% among patients in the ABCP group than among 
those in the BCP group. Treatment-related deaths occurred in 11 patients (2.8%) in the ABCP 
group and in 9 patients (2.3%) in the BCP group. The 5 deaths in the ABCP group were due to 
pulmonary hemorrhage or hemoptysis, 4 of which occurred in patients with potential high-risk 
features (eg, tumor infiltration of great vessels or cavitation). Treatment-related SAEs were 
noted in 25.4% of patients in the ABCP group and in 19.3% of those in the BCP group 
(Socinski et al 2018). 
For the KEYNOTE-407 and IMpower131 Stage IV squamous NSCLC studies, the observed 
AEs were consistent with the known safety profiles of pembrolizumab and chemotherapy and 
atezolizumab and chemotherapy, respectively with no new safety signals identified (Jotte et al 
2018, Paz-Ares et al 2018). 
2.3.3 
Overall benefit/risk 
Recent progress in immunotherapy for first-line NSCLC has been a substantive advance, 
although further improvement is needed. Although data from the PD-1/PD-L1 monotherapy 
and chemotherapy combination studies are encouraging, these studies yielded a median PFS 
of <1 year. Furthermore, there are currently no PD-1/PD-L1 combination maintenance 

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regimens in patients with squamous NSCLC. Therefore, additional treatment options with a 
tolerable safety profile are urgently needed to prolong PFS in these patients.  
Treatment with durvalumab and olaparib has shown activity in several tumor types 
(Section 2.3.1.3) with a subset of patients deriving meaningful and durable responses with a 
well-tolerated safety profile. Furthermore, the molecular targeting of olaparib to specific 
subsets of tumors that lack sufficient DNA damage repair mechanisms may provide a further 
opportunity for more effective and tolerable treatment for some patients. 
The study design also aims to minimize potential risks. For example, monitoring is in place 
via an IDMC to assess the safety and tolerability of the durvalumab plus olaparib/placebo 
combination following durvalumab plus SoC-platinum-based chemotherapy. 
Therefore, based upon the available nonclinical and clinical safety data, the strength of 
scientific hypothesis of the complementary effect of the 2 treatment agents, and the 
mitigations designed for this study, the investigation of the potential therapeutic efficacy of 
the combination of durvalumab plus olaparib in the maintenance setting in patients whose 
disease has not progressed following durvalumab plus platinum-based chemotherapy in 
patients with first-line Stage IV NSCLC is acceptable, and the overall benefit/risk assessment 
supports the proposed study design. 
3. 
OBJECTIVES AND ENDPOINTS 
Table 5 
Study objectives 
Primary objective: 
Endpoint/variable: 
To assess the efficacy of durvalumab plus olaparib 
combination therapy compared with durvalumab 
monotherapy in terms of PFS (Investigator-assessed) 
PFS: Time from date of randomization until the date 
of objective radiological disease progression 
according to Investigator assessment using RECIST 
1.1 or death (by any cause in the absence of 
progression) 
Secondary objectives: 
Endpoints/variables: 
To further assess the efficacy of durvalumab plus 
olaparib combination therapy compared with 
durvalumab monotherapy in terms of OS, ORR, and 
DoR 
OS: Time from date of randomization until the date of 
death by any cause 
ORR: Percentage of patients with an 
Investigator-assessed response of CR or PR after 
randomization 
DoR: Time from the date of first documented 
response following randomization until the first date 
of documented progression or death in the absence of 
disease progression 
To further assess the efficacy of durvalumab plus 
olaparib combination therapy compared with 
durvalumab monotherapy in terms of PFS 
(Investigator-assessed) in the HRRm population 
PFS: Time from date of randomization until the date 
of objective radiological disease progression 
according to Investigator assessment in HRRm 
population using RECIST 1.1 or death (by any cause 
in the absence of progression) 

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Stage IV NSCLC. There will be approximately 80 sites in the study. During the initial therapy 
phase, approximately 350 to 400 patients will receive treatment with durvalumab, along with 
the Investigator’s choice of platinum-based doublet therapy for squamous NSCLC 
(nab-paclitaxel plus carboplatin or gemcitabine plus carboplatin/cisplatin) and nonsquamous 
NSCLC (nab-paclitaxel plus carboplatin or pemetrexed plus carboplatin/cisplatin) for 
4 cycles.  
It is estimated that approximately 350 to 400 patients will be enrolled in the initial therapy 
phase in order for approximately 250 patients who have not progressed (ie, maintained CR, 
PR, or SD throughout the initial therapy phase according to Investigator-assessed RECIST 
1.1) to be randomized into the maintenance phase of the study (patients completing the initial 
therapy phase who are not randomized cannot continue durvalumab). Patients will be 
randomized 1:1 to receive either durvalumab plus placebo or durvalumab plus olaparib 
maintenance therapy. Randomization will be stratified by histologic subtype (squamous or 
nonsquamous) and objective response (CR/PR or SD; obtained at the last visit prior to 
randomization [Cycle 4 scan]) during the initial therapy phase.  
Confirmation of eligibility criteria for randomization (eligibility scan and other specific 
criteria; see Sections 5.1 and 5.2 for criteria that must be met at randomization) will take place 
14 to 28 days after Cycle 4 Day 1 of the initial therapy phase. Laboratory assessments for 
eligibility should be taken after the last dose of chemotherapy in the initial therapy phase. If 
determined eligible, patients will be randomized within 5 weeks after Cycle 4 Day 1 of the 
initial therapy phase; every effort should be made to minimize the time between confirmation 
of eligibility, randomization, and starting maintenance treatment. Patients will receive 
maintenance treatment until specific discontinuation criteria are met, including clinical disease 
progression (as assessed by the Investigator) or RECIST 1.1-defined radiological PD, 
unacceptable toxicity, and withdrawal of consent. Note that crossover within the study will not 
be permitted. 
Tumor evaluation using RECIST 1.1 will be conducted at screening (within 28 days prior to 
the first dose of study medication administered during the initial therapy phase), 14 to 28 days 
after Cycle 2 Day 1 and Cycle 4 Day 1 of the initial therapy phase, and every 8 weeks (q8w) 
±1 week during the maintenance phase (for the first 48 weeks, and then q12w ±1 week 
thereafter) until RECIST 1.1-defined radiological PD plus one or more additional follow-up 
scans, if clinically feasible.  
After treatment discontinuation for any reason other than RECIST 1.1-defined radiological 
PD, scanning/tumor assessments will continue until RECIST 1.1-defined radiological PD plus 
one or more additional follow-up scans (if clinically feasible). If treatment is discontinued due 
to RECIST 1.1-defined radiological PD, one or more additional follow-up scans (if clinically 

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feasible) will be performed. For patients who are not randomized into the maintenance phase 
for any reason, follow-up tumor assessments will not be required. 
For an overview of the study design, see Figure 1. For details on treatments given during the 
study, see Section 6.1.  
For details on what is included in the efficacy and safety endpoints, see Section 3.  
4.2 
Scientific rationale for study design 
4.2.1 
Rationale for efficacy endpoints 
The primary objective of this study is to assess the efficacy of durvalumab plus olaparib 
combination therapy compared with durvalumab monotherapy in terms of 
Investigator-assessed PFS. 
This Phase II study will be sized to detect evidence of improved PFS. Conventionally, ORR, 
PFS, and OS are used as validated measures of clinical benefit. However, given that the study 
is designed to evaluate the effect of durvalumab plus olaparib combination therapy in the 
maintenance setting, it is hypothesized that ORR will be modestly improved by the addition of 
olaparib to durvalumab. Therefore, PFS and OS are the 2 measures that will be used as 
validated measures of clinical benefit in the maintenance setting. OS is generally regarded as 
the most reliable cancer endpoint and preferred for studies that can be conducted to adequately 
assess survival. However, PFS may serve as a surrogate endpoint for OS when differences 
between treatment arms are of sufficient magnitude and clinically important (FDA Guidance 
2015, Pazdur 2008). Therefore, the study will be designed to detect significant improvement 
in PFS in patients treated with olaparib plus durvalumab combination therapy versus 
durvalumab monotherapy.  
A PFS primary endpoint also affords an earlier understanding of treatment effect than OS. 
Furthermore, PFS, unlike OS, will not be confounded by cross-over effect of subsequent 
treatments. Although prior studies in various tumor types have demonstrated OS to be a more 
robust measure of clinical benefit than PFS with immune-oncology monotherapy (Balar et al 
2017, Borghaei et al 2015), the prior clinical experience with PARP inhibitors suggests that 
PFS is an appropriate measure of clinical benefit for the addition of olaparib to durvalumab 
(Romero 2017). 
Secondary efficacy endpoints, including ORR, DoR, and OS, will be examined in the FAS to 
further evaluate the antitumor effect of durvalumab plus olaparib combination therapy versus 
durvalumab monotherapy; Investigator-assessed PFS will also be examined in the HRRm 
subgroup.  

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Antitumor activity will be based on Investigator assessment according to RECIST 1.1 
guidelines. 
4.2.2 
Rationale for other study endpoints 
The secondary disease-related symptoms and overall health-related quality of life (HRQoL) 
endpoints, assessed using the European Organisation for Research and Treatment of Cancer 
(EORTC) 30-item Core Quality of Life Questionnaire, version 3 (QLQ-C30 v3) and the 
complementary 13-item Lung Cancer Quality of Life Questionnaire (QLQ-LC13), will show 
the overall influence of the benefits and toxicity of the treatment from the patient’s 
perspective and will aid in understanding the benefit/risk evaluation. These PRO 
questionnaires are well-established instruments that have been previously included in cancer 
clinical studies.  
 
 
 
 
4.3 
Justification for dose 
This study will utilize a fixed dose for durvalumab treatment (1500 mg q3w in initial therapy 
phase and q4w in maintenance phase). Olaparib will be dosed orally at 300 mg BID. 
4.3.1 
Durvalumab monotherapy dose rationale 
A durvalumab dose of 20 mg/kg q4w is supported by in vitro data, preclinical activity, clinical 
PK/pharmacodynamics, biomarkers, safety, and activity data from Study 1108 in patients with 
advanced solid tumors and from a Phase I study performed in Japanese patients with advanced 
solid tumors (Study D4190C00002). 
Pharmacokinetic/Pharmacodynamic data 
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 0.1 to 10 mg/kg q2w or 15 mg/kg q3w, durvalumab exhibited non-linear 
(dose-dependent) PK consistent with target-mediated drug disposition. The PK approached 
linearity at ≥3 mg/kg q2w, suggesting near complete target saturation (membrane-bound and 
soluble programmed death-ligand 1 [sPD-L1]), and further shows that the durvalumab dosing 
frequency can be adapted to a particular regimen given the linearity seen at doses higher than 
3 mg/kg. The expected half-life with doses ≥3 mg/kg q2w is approximately 21 days. A 
dose-dependent suppression in peripheral sPD-L1 was observed over the dose range studied, 
consistent with engagement of durvalumab with PD-L1. A low level of immunogenicity has 
been observed. No patients have experienced immune-complex disease following exposure to 
CCI

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durvalumab. (For further information on immunogenicity, please see the current durvalumab 
IB).  
A population PK model was developed using the data from Study 1108 (doses=0.1 to 
10 mg/kg q2w or 15 mg/kg q3w; Fairman et al 2014). Multiple simulations indicate that a 
similar overall exposure is expected following both 10 mg/kg q2w and 20 mg/kg q4w 
regimens, as represented by AUCss (4 weeks). Median maximum plasma concentration (Cmax) 
at steady state is expected to be higher with 20 mg/kg q4w (~1.5 fold) and median trough 
concentration (Ctrough) at steady state is expected to be higher with 10 mg/kg q2w (~1.25 fold). 
Clinical activity with the 20 mg/kg q4w regimen is anticipated to be consistent with 10 mg/kg 
q2w with the proposed similar dose of 20 mg/kg q4w expected to (a) achieve complete target 
saturation in majority of patients; (b) account for anticipated variability in PK, 
pharmacodynamics, and clinical activity in diverse cancer populations; (c) maintain sufficient 
PK exposure in case of anti-drug antibody (ADA) impact; and (d) achieve PK exposure that 
yielded maximal antitumor activity in animal models. 
Given the similar AUC and modest differences in median peak and trough levels at steady 
state, the observation that both regimens maintain complete sPD-L1 suppression at trough, 
and the available clinical data, the 20 mg/kg q4w and 10 mg/kg q2w regimens are expected to 
have similar efficacy and safety profiles, supporting further development with a dose of 
20 mg/kg q4w.  
Clinical data 
Refer to the current durvalumab IB for a complete summary of clinical information including 
safety, efficacy, and PK at the 20 mg/kg q4w regimen. 
4.3.2 
Rationale for fixed dosing of durvalumab 
A population PK model was developed for durvalumab using monotherapy data from 
Study 1108 (N=292; doses=0.1 to 10 mg/kg q2w or 15 mg/kg q3w; solid tumors). Population 
PK analysis indicated only minor impact of body WT on the PK of durvalumab (coefficient of 
≤0.5). The impact of body WT-based (10 mg/kg q2w) and fixed dosing (750 mg q2w) of 
durvalumab was evaluated by comparing predicted steady-state PK concentrations (5th, 
median, and 95th percentiles) using the population PK model. A fixed dose of 750 mg was 
selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 
1000 patients were simulated using body WT distribution of 40 to 120 kg. Simulation results 
demonstrate that body WT-based and fixed dosing regimens yield similar median steady-state 
PK concentrations with slightly less overall between-patient variability with fixed dosing 
regimen.  
Similar findings have been reported by others (Narwal et al 2013, Ng et al 2006, Wang 
et al 2009, Zhang et al 2012). Wang and colleagues investigated 12 mAbs and found that fixed 

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and body size-based dosing perform similarly, with fixed dosing being better for 7 of 
12 antibodies (Wang et al 2009). In addition, they investigated 18 therapeutic proteins and 
peptides and showed that fixed dosing performed better for 12 of 18 therapeutic proteins and 
peptides in terms of reducing the between-patient variability in PK/pharmacodynamic 
parameters (Zhang et al 2012). 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar PK exposure and variability, it was 
considered it feasible to switch to fixed dosing regimens. Based on median body WT of 
approximately 75 kg, a fixed dose of durvalumab 1500 mg (equivalent to 20 mg/kg) is 
included in the current study. 
4.3.3 
Rationale for proposed study dose and schedule 
The proposed dosing schedule is aligned with the standard fixed dosing of durvalumab 
1500 mg, which is supported by efficacy and safety as well as tolerability data across multiple 
studies in multiple tumor types. To conform with the chemotherapy schedule in the study, 
AstraZeneca proposes to use standard durvalumab combination therapy dose and ratio at a 
q3w dosing schedule for the first 4 cycles rather than the standard q4w schedule.  
The safety of a q3w dosing schedule in combination with chemotherapy has been explored in 
the ongoing Study D419SC00001, where durvalumab 1120 mg q3w plus tremelimumab 
75 mg q3w was given concurrently with carboplatin AUC 5 mg/mL/min and etoposide 
100 mg/m2 q3w, followed by durvalumab monotherapy 1120 mg q3w. The combination has 
been declared tolerable and manageable (see below for more detail). The 1120 mg dose of 
durvalumab is the q3w equivalent of the standard 1500 mg q4w dose. The tremelimumab dose 
was not lowered proportionally to 56 mg because 75 mg is the lowest tested biologically 
effective dose. 
In this study, AstraZeneca proposes to use the Phase III fixed dose of durvalumab 1500 mg 
q3w in combination with chemotherapy. The relative increase in dose density of durvalumab 
(ie, 1500 mg q3w instead of q4w) is supported by the fact that toxicities attributable to 
durvalumab do not appear dose dependent and that PK modeling reveals no meaningful 
differences in drug levels between q3w and q4w dosing, and by the clinical data from the 
D419MC00004 (POSEIDON), CASPIAN (D419QC00001), and NCT02537418 (CCTG) 
studies. During the maintenance phase, the dose and schedule of durvalumab will be 1500 mg 
q4w. 
Supportive clinical data 
The safety of a q3w dosing schedule of durvalumab (with or without tremelimumab) in 
combination with chemotherapy has been explored in 2 ongoing studies, D419SC00001 and 
the CCTG Study NCT02537418. 

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CCTG Study NCT02537418 (Daaboul et al 2017) is an ongoing Phase Ib study of durvalumab 
with or without tremelimumab in combination with multiple standard platinum-based 
chemotherapy regimens in patients with incurable advanced or metastatic cancer. The dose 
escalation and dose regimens in the study initially included a fixed dose cohort of durvalumab 
1125 mg plus tremelimumab 56 mg q3w concurrent with platinum-based doublet 
chemotherapy and then subsequently a cohort of durvalumab 1500 mg plus tremelimumab 
75 mg q3w concurrent with chemotherapy. 
At the DCO of October 2016, a total of 111 patients have been dosed with 7 chemotherapy 
regimens across multiple tumor types and dose levels. Overall, toxicities related to the 
chemotherapy core regimen appeared as expected in severity and frequency. Across all dose 
levels, there was no clear dose dependency in any of the reported AEs and there was no DLT 
reported per protocol-defined criteria (DLT period of 21 days). Toxicities related to 
durvalumab and tremelimumab were also those expected for these agents, although a number 
of potential immuno-oncology (IO)-related toxicities such as diarrhea, skin rash, hepatic 
function changes, or pneumonitis were difficult to differentiate from those reported for 
cytotoxic agents. As expected, there were more IO-related toxicities reported for dose levels 
containing tremelimumab. In general, all regimens were tolerable and manageable at all dose 
levels. The study was presented at the World Conference in Lung Cancer in October 2017 
when 13 patients had been exposed to the fixed durvalumab 1500 mg/tremelimumab 75 mg 
q3w dose. There was no evidence of a dose response including the 1500 mg/75 mg dose 
cohort in terms of the safety data reported. 
Study D419SC00001 is an ongoing study evaluating durvalumab 1120 mg plus tremelimumab 
75 mg q3w given concurrently with carboplatin AUC 5 mg/mL/min and etoposide 100 mg/m2 
q3w, followed by durvalumab 1120 mg monotherapy q3w. At the DCO of 6 December 2016, 
6 patients with SCLC had completed 4 cycles of treatment. No DLT was reported during the 
first cycle of treatment (a 21-day period). One patient developed Grade 4 hepatitis with 
elevation of ALT, AST, and gamma-glutamyl transferase at Cycle 5 Day 1. Although the 
onset of this event was 1 day after the protocol-defined DLT period of 4 cycles, it was 
considered as a DLT following discussion with the Investigator. The liver enzymes were 
normalized within 16 days after steroid use and were confirmed not to be a Hy’s law (HL) 
case. As there was only 1 DLT reported in 6 patients, the safety profile of this combination of 
durvalumab 1120 mg + tremelimumab 75 mg concurrent with platinum-based doublet 
chemotherapy using a q3w schedule was declared tolerable and manageable. 
In general, the overall safety profile from these 2 studies appears to be consistent with 
available safety and tolerability data for durvalumab monotherapy. Taken together with the 
PK data (described further below), the totality of data provided sufficient safety data to 
support the combination of durvalumab 1500 mg combined with chemotherapy on a q3w 
schedule and AstraZeneca has started 2 Phase III studies (CASPIAN and POSEIDON) 

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looking at the combination of fixed dose durvalumab (1500 mg) with or without 
tremelimumab (75 mg) given q3w concurrent with platinum-based doublet chemotherapy.  
Both studies are Phase III randomized studies that are blinded to AstraZeneca. As such, it is 
not possible to provide safety data specific to a fixed dose of durvalumab 1500 mg q3w in 
combination with chemotherapy for these studies as the treatment allocation is currently 
blinded. 
However, AstraZeneca has included in both of these studies the use of an IDMC to review the 
safety data in an unblinded fashion. The IDMC has met and will continue to meet on a regular 
basis to review unblinded data and will make a recommendation on whether recruitment 
should continue, be modified, or be held. In addition, the IDMC for the POSEIDON study was 
convened per protocol to confirm the safety and tolerability of the proposed dose and schedule 
of durvalumab with or without tremelimumab in combination with SoC chemotherapy at 2 
early stages of enrollment. A step-wise approach was adopted. The initial safety review took 
place when the first 30 patients (10 in each arm) completed the first cycle of treatment and had 
21 days of follow-up. A second review utilized an additional 30 patients (10 in each arm) who 
completed the first cycle of treatment and had 21 days of follow-up, making a total of 60 
patients. These 2 reviews were carried out by the IDMC in an unblinded manner. After a 
review of the unblinded data, the IDMC made a recommendation to continue the study as 
planned. 
The IDMC has met and reviewed unblinded safety data for the POSEIDON and CASPIAN 
studies on further occasions and has continued to make the recommendation following the 
safety review meetings for the studies to continue as planned.  
Pharmacokinetic modeling 
PK modeling and simulation have been conducted to evaluate the switch from q4w dosing to 
q3w dosing for durvalumab. Simulated PK profiles based on the study design (q3w dosing 
regimen of durvalumab 1500 mg given at Weeks 0, 3, 6, and 9; durvalumab as a single agent 
in Week 12 followed by q4w durvalumab monotherapy dosing) were compared with 
simulated PK profiles of the q4w dosing regimen (q4w dosing regimen of durvalumab 
1500 mg given as monotherapy).  
Results suggest that for durvalumab, median Cmax following the 5th dose of the q3w dosing 
regimen and the 4th dose of the q4w dosing regimen was 689 and 624 μg/mL, median Ctrough 
at Week 16 was 125 and 94.5 μg/mL, and AUC0-16wk was 28726 and 22772 μg•day/mL for the 
q3w and q4w schedules, respectively.  
Therefore, PK modeling suggests that a q3w schedule does not impose a significant increased 
safety risk based on expected durvalumab and tremelimumab exposures.  

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Taken together, the totality of data provides sufficient safety data to support the combination 
of durvalumab 1500 mg q3w with chemotherapy. There is supportive safety data for the 
combination in a few studies including the CCTG study as well as confirmation from the 
IDMC for POSEIDON and CASPIAN studies to continue the study as planned. This includes 
a safety confirmation phase from POSEIDON study. In addition, PK modeling data suggest 
that there will be a minimal impact on IP exposure if the standard durvalumab dose (1500 mg) 
is given on a q3w dosing regimen. 
4.3.4 
Olaparib dose rationale 
For combination dosing with durvalumab, olaparib dose selection is based on the results from 
the National Cancer Institute (NCI) Study ESR-14-10366 and AstraZeneca Study 
D081KC00001, a Phase I/II study of durvalumab in combination with olaparib in patients 
with advanced solid tumors. In Study ESR-14-10366 (Lee et al 2017), olaparib was 
administered at 200 or 300 mg BID, and durvalumab was studied at a fixed dose of 10 mg/kg 
q2w for the first 2 cohorts. Later in the study, the durvalumab dosing schedule was changed to 
a dose schedule of q4w. Administration of the durvalumab plus olaparib combination was 
well tolerated, with no instances of DLT observed. Data from this study formed the basis for 
the dose selection in Study D081KC00001. Based on these data, the dose of olaparib to be 
used in this study will be the recommended monotherapy dose of 300 mg BID. 
Dose reductions may be required in patients experiencing toxicities related to olaparib 
treatment (Section 6.5). 
4.4 
End of study definition 
The end of study is defined as the last expected visit/contact of the last patient undergoing the 
study (ie, DCO for final OS analysis). 
A patient is considered to have completed the study when he/she has completed his/her last 
scheduled visit or last scheduled procedure shown in the schedule of activities (SoAs). 
Patients may be withdrawn from the study if the study itself is stopped. The study may be 
stopped if, in the judgment of AstraZeneca, study patients are placed at undue risk because of 
clinically significant findings. 
The study may be terminated at individual sites if the study procedures are not being 
performed according to Good Clinical Practice or if recruitment is slow. AstraZeneca may 
also terminate the entire study prematurely if concerns for safety arise within this study or in 
any other study with durvalumab, olaparib, the combination of durvalumab plus olaparib, or 
the combination of durvalumab plus chemotherapy. 

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In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, patients currently receiving treatment may be transitioned to such a 
study, and the current study would reach its end. The roll-over or safety extension study would 
ensure treatment continuation with visit assessments per its protocol. Any patient who would 
be proposed to move to such a study would be given a new informed consent. 
See Appendix A 6 for guidelines for the dissemination of study results. 
4.5 
Study termination 
The study may be stopped if, in the judgement of AstraZeneca, study patients are placed at 
undue risk because of clinically significant findings that are as follows: 
• 
Meet individual stopping criteria or are otherwise considered significant 
• 
Assessed as causally related to study treatment 
• 
Not considered to be consistent with continuation of the study 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the electronic case report form (eCRF). 
All reasons for discontinuation of treatment must be documented. 
4.6 
Site closure 
The Sponsor reserves the right to close the study site at any time for any reason at the sole 
discretion of the Sponsor. Study sites will be closed upon study completion. A study site is 
considered closed when all required documents and study supplies have been collected and a 
study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the 
Institutional Review Board (IRB)/Independent Ethics Committee or local health 
authorities, the Sponsor's procedures, or Good Clinical Practice guidelines 
• 
Inadequate recruitment of participants by the Investigator 
• 
Discontinuation of further study intervention development 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 

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7 
World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) of 0 or 1. 
8 
No prior chemotherapy or any other systemic therapy for Stage IV NSCLC. Patients who 
have received prior platinum-containing adjuvant, neoadjuvant, or definitive 
chemoradiation are eligible, provided that progression has occurred >12 months from end 
of last therapy. 
9 
Life expectancy ≥12 weeks at screening. 
10 Ability to swallow oral medications (capsules and tablets) without chewing, breaking, 
crushing, opening, or otherwise altering the product formulation. Patients should not have 
GI illnesses that would preclude the absorption of olaparib, which is an oral agent. 
11 Patients must also have adequate organ and marrow function without blood transfusions 
in the past 28 days, defined as follows: 
− 
Hb ≥10 g/dL  
− 
ANC ≥1.5 × 109/L 
− 
Platelet count ≥100 × 109/L 
− 
Serum bilirubin ≤1.5 × ULN; unless due to Gilbert’s syndrome, in which case 
patients will be allowed in consultation with their physician and AstraZeneca 
− 
ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × 
ULN 
− 
CrCl ≥51 mL/min calculated by the investigator or designee using the Cockcroft-
Gault equation (using actual body WT) or measured by 24-hour urine collection 
− 
Males: 
− 
CrCl =  WT (kg) × (140 - Age) 
− 
(mL/min)  
72 × Serum creatinine (mg/dL) 
− 
Females: 
− 
CrCl =  WT (kg) × (140 - Age) × 0.85 
− 
(mL/min)  
72 × Serum creatinine (mg/dL) 
12 Patients must have at least 1 lesion, not previously irradiated, that can be accurately 
measured at baseline as ≥10 mm in the longest diameter (except lymph nodes that must 
have a short axis ≥15 mm) with computed tomography (CT) or magnetic resonance 
imaging (MRI) and that is suitable for accurate repeated measurements as per RECIST 
1.1 guidelines. 
13 All patients must provide a formalin-fixed, paraffin embedded (FFPE) tumor sample for 
tissue-based immunohistochemistry (IHC) staining and DNA sequencing to determine 
PD-L1 expression, HRRm status, and other correlatives; either newly acquired or archival 
tumor samples (<3 years old) are acceptable. If available, a newly acquired tumor biopsy, 
collected as part of routine clinical practice, is preferred. If not available, an archival 
sample taken <3 years prior to screening is acceptable. If both an archival sample and a 
fresh tumor biopsy sample are available, both samples should be submitted for analysis 
and must be submitted as different samples using different accession numbers. Slides 
from different blocks cannot be mixed and submitted with the same kit. 

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14 Tumor lesions used for newly acquired biopsies should not be TLs, unless there are no 
other lesions suitable for biopsy. Samples with limited tumor content and fine needle 
aspirate specimens are not acceptable. Specimens from metastatic bone lesions are 
typically unacceptable unless there is a significant soft tissue component and should not 
be decalcified. For additional details on sample requirements, see Section 8.8.1.  
15 Body WT >30 kg. 
Patients must meet the following criteria to be randomized to maintenance treatment: 
16 Patients must have documented radiographic evidence of a timepoint tumor response of 
CR, PR, or SD according to Investigator-assessed RECIST 1.1 guidelines following the 4 
cycles of platinum-based chemotherapy. An objective response does not have to be 
confirmed in order for the patient to be randomized. 
17 CrCl ≥51 mL/min calculated by the investigator or designee using the Cockcroft-Gault 
equation (using actual body WT) or measured by 24-hour urine collection. 
18 Inclusion criterion 10. 
5.2 
Exclusion criteria 
Patients must NOT meet the following criteria at screening prior to receiving treatment: 
1 
Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study. 
2 
Mixed small-cell lung cancer and sarcomatoid variant NSCLC histology. 
3 
No radiation therapy is allowed, unless it is 1) definitive radiation that had been 
administered at least 12 months prior, 2) palliative radiation to brain, with associated 
criteria for stability or lack of symptoms, or 3) palliative radiation to painful bony lesions 
(this must comprise less than 30% of the bone marrow). 
4 
Prior exposure to any chemotherapy agents (with the exception of chemotherapy or 
chemoradiation for non-metastatic disease; see inclusion criterion 8 for full details), 
PARP therapy, or immune-mediated therapy, including, but not limited to, other 
anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic 
anticancer vaccines and other PARP inhibitors. 
5 
Any contraindications to platinum-based doublet chemotherapy. 
6 
Active or prior documented autoimmune or inflammatory disorders (including, but not 
limited to, inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with 
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, 
Wegener syndrome [granulomatosis with polyangiitis], Graves’ disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc). The following are exceptions to this criterion: 
− 
Patients with vitiligo or alopecia 
− 
Any chronic skin condition that does not require systemic therapy 
− 
Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement 
− 
Patients without active disease in the last 5 years may be included but only after 
consultation with AstraZeneca. 

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− 
Patients with celiac disease controlled by diet alone may be included but only after 
consultation with AstraZeneca. 
7 
History of another primary malignancy except for: 
− 
Malignancy treated with curative intent and with no known active disease ≥5 years 
before the first dose of IP and of low potential risk for recurrence 
− 
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease 
− 
Adequately treated carcinoma in situ without evidence of disease 
8 
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. 
Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone 
replacement therapy) is acceptable. 
9 
Current or prior use of immunosuppressive medication within 14 days before the first 
dose of IP. The following are exceptions to this criterion: 
− 
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection) 
− 
Systemic corticosteroids (that are not excluded according to exclusion criterion 10) at 
physiologic doses not to exceed 10 mg/day of prednisone or its equivalent 
− 
Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) 
10 Concomitant use of known strong cytochrome P450 (CYP) 3A (CYP3A) inhibitors (eg, 
itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or 
cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, and telaprevir) or moderate 
CYP3A inhibitors (eg, ciprofloxacin, erythromycin, diltiazem, fluconazole, and 
verapamil). The required washout period prior to starting study treatment is 2 weeks. 
Concomitant use of known strong (eg, phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine, and St. John’s Wort) or 
moderate CYP3A inducers (eg, bosentan, efavirenz, dexamethasone, and modafinil). The 
required washout period prior to starting study treatment is 5 weeks for enzalutamide or 
phenobarbital and 3 weeks for other agents. 
11 Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. 
12 Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged 
by the Investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, QT 
interval corrected for heart rate using Fridericia’s formula [QTcF] value ≥470 ms 
calculated from 3 ECGs [within 15 minutes at 5 minutes apart], electrolyte disturbances, 
etc), or patients with congenital long QT-interval syndrome or congestive heart failure. 
13 Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis 
identified either on the baseline brain imaging (please see Appendix F [RECIST] for 
details on the imaging modality) obtained during the screening period or identified prior 
to signing the ICF. Patients whose brain metastases have been treated may participate 
provided they show radiographic stability (defined as 2 brain images, both of which are 
obtained after treatment to the brain metastases. These imaging scans should both be 
obtained at least 4 weeks apart and show no evidence of intracranial progression). In 
addition, any neurologic symptoms that developed either as a result of the brain 

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metastases or their treatment must have resolved or be stable either, without the use of 
steroids, or are stable on a steroid dose of ≤10 mg/day of prednisone or its equivalent and 
anti-convulsants for at least 14 days prior to the start of treatment. Brain metastases will 
not be recorded as RECIST TLs at baseline. 
14 Uncontrolled intercurrent illness, including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, ILD, or psychiatric illness, or social situations that 
would limit compliance with study requirements, substantially increase the risk of 
incurring AEs from IP, or compromise the ability of the patient to give written informed 
consent. 
15 History of allogenic organ transplantation including umbilical cord blood transplantation. 
16 Patients with MDS/acute myeloid leukaemia or with features suggestive of MDS/AML 
17 History of leptomeningeal carcinomatosis. 
18 History of active primary immunodeficiency. 
19 Active infection including tuberculosis (clinical evaluation that includes clinical 
history, physical examination and radiographic findings, and tuberculosis testing in line 
with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen 
[HBsAg] result), hepatitis C, or human immunodeficiency virus (HIV; positive HIV 
1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of 
hepatitis B core antibody and absence of HBsAg) are eligible. Patients positive for 
hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is 
negative for HCV ribonucleic acid (RNA). 
20 Any unresolved toxicity NCI Common Terminology Criteria for Adverse Event 
(CTCAE) Grade ≥2 from previous anticancer therapy with the exception of alopecia, 
vitiligo, and the laboratory values defined in the inclusion criteria: 
− 
Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician. 
− 
Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab or olaparib may be included only after consultation with 
the Study Physician.  
21 Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients. 
22 Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: 
Patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days 
after the last dose of IP.  
23 Participation in another clinical study with an IP administered in the last 12 months. 
24 Previous IP assignment in the present study. 
25 Prior randomization or treatment in a previous durvalumab (and/or olaparib) clinical 
study regardless of treatment arm assignment. 
26 Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 90 days after the last dose of durvalumab or 30 days after the last dose of 
olaparib/placebo, whichever is later.  

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Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply:  
• 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone levels 
in the post-menopausal range for the institution. 
• 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, and had 
chemotherapy-induced menopause with last menses >1 year ago. 
• 
Women who are surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or 
complete hysterectomy) are eligible.  
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly are described in Table 6. Note 
that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel, which is considered highly effective]; and triphasic combined oral 
contraceptive pills). 
For administration of SoC (initial therapy), follow the local prescribing information relating to 
contraception, the time limits for such precautions, and any additional restrictions for the 
agents administered. 
Table 6 
Highly effective methods of contraception (<1% failure rate) 
Barrier/intrauterine methods 
Hormonal methods 
Copper T intrauterine device 
Levonorgestrel-releasing intrauterine system (eg, 
Mirena®)a 
Implants: Etonogestrel-releasing implants (eg, 
Implanon® or Norplant®) 
Intravaginal devices: Ethinylestradiol/etonogestrel-
releasing intravaginal devices (eg, NuvaRing®)  
Injection: Medroxyprogesterone injection (eg, Depo-
Provera®) 
Combined pill: Normal- and low-dose combined oral 
contraceptive pill 
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®) 
Minipill: Progesterone-based oral contraceptive pill 
using desogestrel: Cerazette® is currently the only 
highly effective progesterone-based pill. 
a 
This is also considered a hormonal method. 
 

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3 
All patients: Patients should not donate blood or blood components while participating in 
this study and through to 90 days after the last dose of durvalumab or 30 days after the 
last dose of olaparib/placebo, whichever is later or until alternate anticancer therapy is 
started.  
4 
Restrictions relating to concomitant medications are described in Section 6.4. 
5 
It is prohibited to consume grapefruit juice while on olaparib/placebo therapy. 
5.4 
Screen failures 
Screen failures are patients who do not fulfill the eligibility criteria for the study and therefore 
must not begin the initial therapy phase. These patients should have the reason for study 
withdrawal recorded as “eligibility criteria not fulfilled” (ie, patient does not meet the required 
inclusion/exclusion criteria). This reason for study withdrawal is only valid for screen failures. 
Patients may be rescreened a single time, but they may not begin the initial therapy phase 
more than once.  
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure patients to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAEs. 
Patients who receive at least 1 dose of study treatment during the initial therapy phase but are 
not randomized for any reason are considered initial therapy failures. 
6. 
STUDY TREATMENTS 
Study treatment is defined as any IP(s) (including marketed product comparator and placebo) 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. Study treatment in this study refers to durvalumab, olaparib, placebo, and 
chemotherapy (SoC). 
6.1 
Treatments administered 
6.1.1 
Investigational products 
AstraZeneca will supply durvalumab, olaparib, and placebo. SoC chemotherapy agents will be 
supplied locally.  

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Table 7 
Study treatments 
 
Durvalumab 
Olaparib 
Placebo 
Chemotherapy (SoC) 
Study treatment 
name 
Durvalumab 
(MEDI4736) 
Olaparib (AZD2281) 
Placebo 
nab-paclitaxel, carboplatin, 
cisplatin, gemcitabine, and 
pemetrexed 
Dosage 
formulation 
500-mg vial 
solution for 
infusion after 
dilution, 
50 mg/mL 
150-mg tablets (2 × 
150-mg tablets for 
300-mg dose) 
100-mg tablet 
available if dose 
reductions are 
required 
Matching tablet  
As sourced locally (under 
certain circumstances 
when local sourcing is not 
feasible, an SoC treatment 
may be supplied centrally 
through AstraZeneca) 
Route of 
administration  
IV 
Oral 
Oral 
IV 
Dosing 
instructions 
1500 mg q3w 
(initial therapy 
phase) and 
1500 mg q4w 
(maintenance 
phase)a,b 
Two × 150-mg 
olaparib tablets 
should be taken at 
the same time each 
day, approximately 
12 hours apart with 
1 glass of water. The 
tablets should be 
swallowed whole 
and not chewed, 
crushed, dissolved, 
or divided. Olaparib 
tablets can be taken 
with or without food. 
Matching placebo 
for oral tablet BID 
Nab-paclitaxel: 100 mg/m2 
on Days 1, 8, and 15 of 
each 3-week cycle 
Carboplatin: AUC 5 or 6 
on Day 1 of each 3-week 
cycle 
Cisplatin: 75 mg/m2 on 
Day 1 of each 3-week 
cycle 
Gemcitabine: 1000 or 
1250 mg/m2 on Days 1 and 
8 of each 3-week cycle 
Pemetrexed: 500 mg/m2 on 
Day 1 of each 3-week 
cycle 
Packaging and 
labeling 
Provided in 500-
mg vials, 
labeled in 
accordance with 
GMP Annex 13 
and per country 
regulatory 
requirements.c 
Study treatment will 
be provided in 
HDPE bottles with 
child-resistant 
closures. Each bottle 
will be labeled in 
accordance with 
GMP Annex 13 and 
per country 
regulatory 
requirement. 
Study treatment 
will be provided in 
HDPE bottles with 
child-resistant 
closures. Each 
bottle will be 
labeled in 
accordance with 
GMP Annex 13 
and per country 
regulatory 
requirement. 
Variable 
Provider 
AstraZeneca 
AstraZeneca 
AstraZeneca 
Sourced locally by site 
(under certain 
circumstances when local 
sourcing is not feasible, an 
SoC treatment may be 
supplied centrally through 
AstraZeneca) 

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a 
Subsequent time between 2 consecutive doses of durvalumab cannot be less than 21 days, based on the 
half-life of durvalumab (see current IB for durvalumab). If there is a dosing delay during the treatment 
schedule for durvalumab, all future dosing days for durvalumab should be delayed to ensure that the 
intervals between dosing study treatment are always at least 21 days. 
b 
If a patient’s WT falls to 30 kg or below, the patient should receive WT-based dosing equivalent to 
20 mg/kg of durvalumab q3w (initial therapy phase) or q4w (maintenance phase) until the WT improves to 
>30 kg, at which point the patient should start receiving the fixed dosing of durvalumab 1500 mg q3w/q4w. 
c 
Label text prepared for durvalumab (MEDI4736) will show the product name as “MEDI4736” or 
“durvalumab (MEDI4736)” depending upon the agreed product name used in the approved study master 
label document. All naming conventions are correct during this transitional period. 
BID  Twice a day; CrCl  Creatinine clearance; GMP  Good Manufacturing Practice; IB  Investigator Brochure; 
IV  Intravenous; q3w  Every 3 weeks; q4w  Every 4 weeks; SoC  Standard of Care. 
 
6.1.1.1 
Durvalumab (MEDI4736) 
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for 
infusion after dilution. The solution contains 50 mg/mL durvalumab (MEDI4736), 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume 
(w/v) polysorbate 80; it has a pH of 6.0. The nominal fill volume is 10.0 mL. IP vials are 
stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product should be kept in 
secondary packaging until use to prevent excessive light exposure. 
Durvalumab will be administered to patients during the initial therapy phase for 4 cycles per 
Table 1, unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion met. Durvalumab will be administered to patients during the 
maintenance phase per Table 2 until clinical disease progression (as assessed by the 
Investigator) or RECIST 1.1-defined radiological PD, unless there is unacceptable toxicity, 
withdrawal of consent, or another discontinuation criterion met. 
Preparation of durvalumab (MEDI4736) doses for administration with an IV bag 
The dose of durvalumab (MEDI4736) for administration must be prepared by the 
Investigator’s or the site’s designated IP manager using aseptic technique. Total time from 
needle puncture of the durvalumab (MEDI4736) vial to the start of administration should not 
exceed:  
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
A dose of 1500 mg (for patients >30 kg in WT) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm in-line filter. Add 30.0 mL of durvalumab (MEDI4736) (ie, 1500 mg 
of durvalumab [MEDI4736]) to the IV bag. The IV bag size should be selected such that the 
final concentration is within 1 to 15 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag.  

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If WT falls to ≤30 kg, WT-based dosing at 20 mg/kg will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm in-line filter. 
Standard infusion time is 60 minutes. In the event that there are interruptions during infusion, 
the total allowed infusion time should not exceed 8 hours at room temperature.  
Do not co-administer other drugs through the same infusion line. 
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed. 
If either preparation time or infusion time exceeds the time limits, a new dose must be 
prepared from new vials. Durvalumab (MEDI4736) does not contain preservatives, and any 
unused portion must be discarded.  
6.1.1.2 
Olaparib (AZD2281) 
Olaparib/placebo tablets will be packed in high-density polyethylene (HDPE) bottles with 
child-resistant closures. Each dosing container will contain sufficient medication for at least 
28 days plus overage. Olaparib/placebo will be dispensed to patients on Day 1 of the 
maintenance phase and at each visit per Table 2 until clinical disease progression (as assessed 
by the Investigator) or RECIST 1.1-defined radiological PD, unless there is unacceptable 
toxicity, withdrawal of consent, or another discontinuation criterion met. 
Study treatment is available as a film-coated tablet containing 100 or 150 mg of olaparib or 
matching placebo. 
Patients will be allowed to receive olaparib/placebo maintenance treatment only after meeting 
the hematology/clinical chemistry requirements specified in Section 1.1 without blood 
transfusions in the past 28 days. If the patient does not meet these requirements initially, then 
the hematology and clinical chemistry parameters should be checked at the next cycle. If a 
patient meets criteria for randomization before being dosed in maintenance but is later found 
to not meet criteria to start olaparib/placebo before C1D1 dosing, durvalumab as monotherapy 
may be started, with olaparib/placebo dosing to commence once the patient again meets the 
hematology/clinical chemistry requirements and conditions specified in Section 1.1. However, 
the Investigator may check these laboratory results/parameters earlier (eg, mid cycle) at an 
unscheduled visit. Once olaparib/placebo is administered, these laboratory thresholds are not 
required for continued olaparib administration. However, patients must continue to be 
monitored and assessed (eg, lab parameters and toxicities) per Table 2, and dose delays and 

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modifications for olaparib/placebo should be followed per Sections 6.5 and 8.4.5.2 and 
Appendix G. 
Patients will be administered olaparib/placebo orally at 300 mg BID continually. 
Olaparib/placebo tablets should be taken at the same time each day, approximately 12 hours 
apart with 1 glass of water. The tablets should be swallowed whole and not chewed, crushed, 
dissolved, or divided. IP tablets can be taken with or without food. 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted. Should any patient enrolled on the 
study miss a scheduled dose for whatever reason (eg, as a result of forgetting to take the 
tablets or vomiting), the patient will be allowed to take the scheduled dose up to a maximum 
of 2 hours after that scheduled dose time. If greater than 2 hours after the scheduled dose time, 
the missed dose is not to be taken and the patient should take their allotted dose at the next 
scheduled time. 
6.1.1.3 
Standard of care 
The SoC agent(s) will either be locally sourced or centrally supplied by AstraZeneca and will 
be administered according to prescribing information or treatment guidance in general use by 
the Investigating site. Under certain circumstances when local sourcing is not feasible, 
AstraZeneca will centrally supply the drug and will be labeled with local language translated 
text in accordance with regulatory guidelines. 
6.1.2 
Dose and treatment regimens 
6.1.2.1 
Durvalumab (MEDI4736) and platinum-based chemotherapy (initial therapy 
phase) 
During the initial therapy phase, all patients will receive durvalumab 1500 mg via IV infusion 
q3w for 4 cycles, unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion met. If a patient’s WT falls to 30 kg or below, the patient should 
receive WT-based dosing equivalent to 20 mg/kg of durvalumab q3w after consultation 
between Investigator and Study Physician until the WT improves to >30 kg, at which point the 
patient should start receiving the fixed dosing of durvalumab 1500 mg q3w. If there is a 
dosing delay during the treatment schedule for durvalumab, all future dosing days for 
durvalumab should be delayed to ensure that the intervals between dosing study treatment are 
always at least 21 days. The standard infusion time is 60 minutes. In the event that there are 
interruptions during infusion, the total allowed time should not exceed 8 hours at room 
temperature. 
In addition to durvalumab, patients in the initial therapy phase will also receive 1 of the 
following SoC regimens as part of their treatment regimen (durvalumab will be infused first, 
followed by the SoC chemotherapy regimen):  

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• 
Nab-paclitaxel plus carboplatin (squamous and nonsquamous patients): Nab-paclitaxel 
100 mg/m2 via IV infusion on Days 1, 8, and 15 of each 3-week cycle and carboplatin 
AUC 5 or 6 via IV infusion on Day 1 of each 3-week cycle, for 4 cycles (Figure 2). 
• 
Gemcitabine plus carboplatin (squamous patients only): Gemcitabine 1000 or 
1250 mg/m2 via IV infusion on Days 1 and 8 of each 3-week cycle and carboplatin 
AUC 5 or 6 via IV infusion on Day 1 of each 3-week cycle, for 4 cycles (Figure 3). 
• 
Gemcitabine plus cisplatin (squamous patients only): Gemcitabine 1000 or 1250 mg/m2 
via IV infusion on Days 1 and 8 of each 3-week cycle and cisplatin 75 mg/m2 via IV 
infusion on Day 1 of each 3-week cycle, for 4 cycles (Figure 3). 
• 
Pemetrexed plus carboplatin (nonsquamous patients only): Pemetrexed 500 mg/m2 and 
carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 3-week cycle, for 4 cycles 
(Figure 4). Pemetrexed maintenance therapy will not be allowed following the initial 
therapy phase. 
• 
Pemetrexed plus cisplatin (nonsquamous patients only): Pemetrexed 500 mg/m2 and 
cisplatin 75 mg/m2 via IV infusion on Day 1 of each 3-week cycle, for 4 cycles 
(Figure 4). Pemetrexed maintenance therapy will not be allowed following the initial 
therapy phase. 
In the event that SoC is delayed during the initial therapy phase, durvalumab administration 
must also be delayed.  
In the event of unfavorable tolerability, patients can switch between cisplatin and carboplatin 
therapy at any point during the study.  
Figure 2 
Dose and treatment regimen for initial therapy phase (durvalumab with 
nab-paclitaxel plus carboplatin) 
 
AUC  Area under the concentration-time curve; IV  Intravenous; Nab  Nanoparticle albumin-bound; q3w  Every 
3 weeks. 

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Figure 3 
Dose and treatment regimen for initial therapy phase (durvalumab with 
gemcitabine plus carboplatin/cisplatin) 
 
AUC  Area under the concentration-time curve; IV  Intravenous; q3w  Every 3 weeks. 
 
Figure 4 
Dose and treatment regimen for initial therapy phase (durvalumab with 
pemetrexed plus carboplatin/cisplatin) 
 
Note: Pemetrexed maintenance therapy will not be allowed following the initial therapy phase. 
AUC  Area under the concentration-time curve; IV  Intravenous; q3w  Every 3 weeks. 

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6.1.2.2 
Durvalumab monotherapy and durvalumab plus olaparib combination 
therapy (maintenance phase) 
During the maintenance phase, all patients will receive durvalumab 1500 mg via IV infusion 
q4w. Patients will also receive 300 mg oral olaparib (durvalumab plus olaparib treatment arm) 
or its matching placebo (durvalumab plus placebo treatment arm) BID continually until 
clinical disease progression (as assessed by the Investigator) or RECIST 1.1-defined 
radiological PD (Figure 5 and Figure 6), unless there is unacceptable toxicity, withdrawal of 
consent, or another discontinuation criterion met. 
Before commencing olaparib/placebo treatment, patients must first meet the 
hematology/clinical chemistry requirements specified in Section 1.1 without blood 
transfusions in the past 28 days. If a patient meets criteria for randomization before being 
dosed in maintenance but is later found to not meet criteria to start olaparib/placebo before 
C1D1 dosing, durvalumab as monotherapy may be started, with olaparib/placebo dosing to 
commence once the patient again meets the hematology/clinical chemistry requirements in 
Section 1.1. 
If a patient’s WT falls to 30 kg or below, the patient should receive WT-based dosing 
equivalent to 20 mg/kg of durvalumab q4w after consultation between Investigator and Study 
Physician until the WT improves to >30 kg, at which point the patient should start receiving 
the fixed dosing of durvalumab 1500 mg q4w. If there is a dosing delay during the treatment 
schedule for durvalumab, subsequent time between 2 consecutive doses of durvalumab cannot 
be less than 21 days; olaparib/placebo administration may continue as scheduled if 
durvalumab is delayed. The standard infusion time for durvalumab is 60 minutes. In the event 
that there are interruptions during infusion, the total allowed time should not exceed 8 hours at 
room temperature. 
See Section 7.1 for details about discontinuation of either durvalumab or olaparib/placebo in 
the maintenance phase. 

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Figure 5 
Dose and treatment regimen for maintenance phase (durvalumab 
monotherapy) 
 
BID  Twice daily; IV  Intravenous; PD  Progressive disease; q4w  Every 4 weeks. 
 
Figure 6 
Dose and treatment regimen for maintenance phase (durvalumab plus 
olaparib combination therapy) 
 
BID  Twice daily; IV  Intravenous; PD  Progressive disease; q4w  Every 4 weeks. 
 
6.1.3 
Duration of treatment and criteria for treatment through progression 
Durvalumab plus chemotherapy will be administered beginning on Day 1 of the initial therapy 
phase for 4 cycles. Durvalumab plus olaparib/placebo will be administered on Day 1 of the 

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maintenance phase until clinical disease progression (as assessed by the Investigator) or 
RECIST 1.1-defined radiological PD, unless there is unacceptable toxicity, withdrawal of 
consent, or another discontinuation criterion met. 
Before commencing olaparib/placebo treatment, patients must first meet the 
hematology/clinical chemistry requirements specified in Section 1.1 without blood 
transfusions in the past 28 days. 
There is no maximum duration of treatment. Patients with clinical disease progression (as 
assessed by the Investigator), in the initial therapy or maintenance phase of the study, are not 
eligible for treatment through progression. Patients who are clinically stable with RECIST 
1.1-defined radiological PD at Cycle 2 of the initial therapy phase may continue to receive 
study treatment at the discretion of the Investigator and patient; however, if the patient 
continues to show a RECIST 1.1-defined radiological PD at Cycle 4, the patient will not be 
eligible for the maintenance phase of the study. Patients completing the initial therapy phase 
who are not randomized cannot continue durvalumab. 
During the maintenance phase, patients who are clinically stable at an initial 
RECIST 1.1-defined radiological PD may continue to receive study treatment at the discretion 
of the Investigator and patient. A follow-up scan is to be collected after the initial 
RECIST 1.1-defined radiological PD, preferably at the next (and no later than the next) 
scheduled imaging visit, and no less than 4 weeks after the prior assessment of PD; this 
follow-up scan is evaluated using the Confirmation of Radiological Progression criteria 
outlined in Appendix F.  
Patients with PD in the maintenance phase who continue to receive IP at the discretion of the 
Investigator and patient (following consultation with AstraZeneca) will have tumor 
assessments on their regular imaging schedule for the duration of treatment. However, patients 
will not be permitted to continue immunotherapy or olaparib/placebo if progression occurs 
after confirmed response (CR or PR as defined by RECIST 1.1) in the TLs to either the initial 
therapy (durvalumab plus chemotherapy) or maintenance treatment (durvalumab or 
olaparib/placebo) of the study regardless of the appearance of new lesions. Patients who have 
discontinued durvalumab will not be permitted to be treated with olaparib/placebo 
monotherapy after progression. 
Patients with rapid tumor progression or with symptomatic progression that require urgent 
medical intervention (eg, CNS metastasis, respiratory failure due to tumor compression, or 
spinal cord compression) must discontinue durvalumab and olaparib/placebo.  
Crossover within the study will not be permitted. 

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For all patients who are treated through progression (ie, durvalumab with or without 
olaparib/placebo), the Investigator should ensure that: 
• 
The patient does not have any significant, unacceptable, or irreversible toxicities related 
to study treatment that indicate continuing treatment will not further benefit the patient. 
The patient may not have experienced a toxicity that required permanent discontinuation 
of study treatment. 
• 
There is absence of clinical symptoms or signs indicating clinically significant disease 
progression. 
• 
No decline in WHO/ECOG PS 
• 
There is absence of rapid disease progression or threat to vital organs or critical 
anatomical sites (eg, CNS metastasis, respiratory failure due to tumor compression or 
spinal cord compression) requiring urgent alternative medical intervention. 
• 
The patient still fulfills the eligibility criteria for screening (for treatment through 
progression in the initial therapy phase) or randomization (treatment through progression 
in the maintenance phase) in this study (see Sections 5.1 and 5.2), with the exception of 
inclusion criteria 8, 13, and 14 and exclusion criteria 4, 9, 24, and 25.  
 
In addition to the criteria above, written informed consent will be required to continue 
treatment in the setting of PD. This consent document will specify that treatment beyond 
initial evidence of PD is not the standard-of-care and that alternative treatment options, either 
locally licensed treatments or other clinical trials, are available. 
Patients who AstraZeneca and the Investigator determine may not continue treatment after 
RECIST 1.1-defined radiological PD will be followed up for survival. Patients who have 
discontinued treatment due to toxicity or symptomatic deterioration, or who have commenced 
subsequent anticancer therapy, will be followed up with tumor assessments until 
RECIST 1.1-defined radiological PD, plus one or more additional follow-up scans if clinically 
feasible and followed for survival. 
Post final data cut-off 
There will be a final DCO defined at the analysis of OS (at approximately 65% maturity; the 
DCO for this analysis is anticipated to occur approximately 38.5 months after the first patient 
has been randomized). This will be considered the end of the study. At this timepoint, the 
clinical study database will close to new data, and after the database lock, all individual 
patients will be informed of their treatment assignments. 
Patients who continue to receive benefit from their assigned treatment at the final DCO and 
database closure may continue to receive their assigned treatment for as long as they and their 
physician consider they are gaining clinical benefit. For patients continuing to receive 
durvalumab and/or olaparib treatment following the final DCO and database closure, it is 
recommended that the patients continue the scheduled site visits and that the Investigators 

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monitor the patients’ safety laboratory results prior to and periodically during treatment in 
order to manage AEs in accordance with the durvalumab and olaparib Dosing Modification 
and Toxicity Management Guidelines (see Section 8.4.5 and Appendix G).  
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, patients currently receiving treatment with durvalumab and/or olaparib 
may be transitioned to such a study, and the current study would reach its end. The roll-over 
or safety extension study would ensure treatment continuation with visit assessments per its 
protocol. Any patient who would be proposed to move to such a study would be given a new 
informed consent. 
6.1.4 
Storage 
6.1.4.1 
Durvalumab 
The Investigator, or an approved representative (eg, pharmacist), will ensure that durvalumab 
is stored in a secured area, in refrigerated temperatures (2°C to 8°C [36°F to 46°F]), and in 
accordance with applicable regulatory requirements. A temperature log will be used to record 
the temperature of the storage area. Temperature excursions outside the permissible range 
listed in the clinical supply packaging are to be reported to the monitor upon detection. A 
calibrated temperature monitoring device will be used to record the temperature conditions in 
the drug storage facility. Storage conditions stated in the IB may be superseded by the label 
storage. 
6.1.4.2 
Olaparib, placebo, and chemotherapy (SoC) 
Olaparib, placebo, and chemotherapy (SoC) IPs should be kept in a secure place under 
appropriate storage conditions. The IP labels specify the appropriate storage. 
6.2 
Measures to minimize bias: randomization and blinding 
6.2.1 
Patient enrollment and randomization 
All patients will be centrally registered and randomized between study arms using an 
interactive voice response system/interactive web response system (IVRS/IWRS). Before the 
study is initiated, the telephone number and call-in directions for the IVRS and/or the log-in 
information and directions for the IWRS will be provided to each site. 
If a patient withdraws from the study, then his/her enrollment/randomization code cannot be 
reused. Withdrawn patients will not be replaced. 
Investigators should keep a record (ie, the patient screening log) of patients who entered 
screening.  
At screening/baseline for initial therapy phase (Days -28 to -1), the Investigators or suitably 
trained delegate will: 

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• 
Define the Investigator’s choice of platinum-based doublet therapy (SoC; based on the 
most appropriate option for the patient) that the patient will receive during the initial 
therapy phase. This must be completed for all patients. The information will be recorded 
in the IVRS/IWRS system. 
• 
Note: For all patients with nonsquamous tumor histology scheduled to receive 
pemetrexed, folic acid and vitamin B12 should commence prior to treatment initiation for 
up to 7 days, in line with local practice. This is to ensure treatment can begin on Day 1. 
Following the initial therapy phase, patients who have not progressed (ie, maintained CR, PR, 
or SD, according to Investigator-assessed RECIST 1.1) may be randomized into the 
maintenance phase of the study after confirming eligibility for the maintenance phase 
(Sections 5.1 and 5.2). If determined eligible, patients will be randomized within 5 weeks after 
Cycle 4 Day 1 of the initial therapy phase. After randomization into the maintenance phase, 
the Investigator or suitably trained delegate will: 
• 
Obtain a unique randomization number via the IVRS/IWRS. Numbers will start at 001 
and will be assigned strictly sequentially by IVRS/IWRS as patients are eligible for entry 
into the study. The system will randomize the eligible patient to 1 of the 2 treatment arms: 
durvalumab plus placebo or durvalumab plus olaparib. Patients will be stratified by 
histologic subtype (squamous or nonsquamous) and objective response (CR/PR or SD; 
obtained at the last visit prior to randomization [Cycle 4 scan]) during the initial therapy 
phase. 
If the patient is ineligible or is not randomized, the IVRS/IWRS should be contacted to 
terminate the patient in the system.  
Patients will begin treatment on Day 1 of the maintenance phase (before commencing 
olaparib/placebo treatment, patients must first meet the hematology/clinical chemistry 
requirements specified in Section 1.1 without blood transfusions in the past 28 days). Every 
effort should be made to minimize the time between confirmation of eligibility, 
randomization, and starting maintenance treatment. Patients must not be randomized and 
treated unless all eligibility criteria specified in Sections 5.1 and 5.2 have been met.  
6.2.2 
Procedures for handling incorrectly enrolled or randomized patients 
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Patients who are 
enrolled, but subsequently found not to meet all the eligibility criteria, must not be 
randomized or initiated on treatment and must be withdrawn from the study. 
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca Study 
Physician immediately, and a discussion should occur between the AstraZeneca Study 
Physician and the Investigator regarding whether to continue or discontinue the patient from 

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treatment. The AstraZeneca Study Physician must ensure all decisions are appropriately 
documented and that the potential benefit/risk profile remains positive for the patient. 
6.2.3 
Methods for assigning treatment arms (maintenance phase) 
The actual treatment given to patients during the maintenance phase will be determined by the 
randomization scheme in the IVRS/IWRS. The randomization scheme will be produced by a 
computer software program that incorporates a standard procedure for generating 
randomization numbers. One randomization list will be produced for each of the 
randomization strata. A blocked randomization will be generated, and all centers will use the 
same list in order to minimize any imbalance in the number of patients assigned to each 
treatment arm.  
Patients will be identified to the IVRS/IWRS per country regulations. Randomization codes 
will be assigned strictly sequentially, within each stratum, as patients become eligible for 
randomization. The IVRS/IWRS will provide the kit identification number to be allocated to 
the patient at randomization and subsequent treatment visits.  
6.2.4 
Methods for ensuring blinding (maintenance phase) 
The maintenance phase of this study will be conducted in a double-blind manner. The olaparib 
and placebo tablets will be identical in color and taste to maintain the double-blind conditions. 
Olaparib/placebo treatment will be blinded to all site staff. The study medication will be 
labeled using a unique kit ID number, which is linked to the randomization scheme. The 
active and placebo tablets will be identical and presented in the same packaging to ensure 
blinding of the study medication. 
No member of the extended study team at AstraZeneca, at the investigational sites, or any 
blinded contract research organization (CRO) handling data will have access to the 
randomization scheme until the time of the primary data analysis. At such time, AstraZeneca 
and any CRO handling data will have access to the randomization scheme. Exceptions are 
relevant persons within the Pharmaceutical Development Supply Chain at AstraZeneca or 
their designee, where the information is needed to package the IP, the drug safety departments 
at AstraZeneca, and personnel providing the analysis of PK samples. 
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the patient requires knowledge of the treatment randomization. 
The Investigator documents and reports the action to AstraZeneca, without revealing the 
treatment given to patient to the AstraZeneca staff. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities. Randomization codes will not be broken for the planned analyses of 

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data until all decisions on the evaluability of the data from each individual patient have been 
made and documented. The IDMC will be provided with unblinded data for their review, but 
AstraZeneca staff and Investigators involved in the study will remain blinded. 
The treatment codes and results will be kept strictly within AstraZeneca to safeguard the 
integrity of the blinding and hence to minimize any possible bias in data handling.  
6.3 
Treatment compliance 
The administration of all IPs should be recorded in the appropriate sections of the eCRF. 
Any change from the dosing schedules, does interruptions, dose reductions, and dose 
discontinuations should be recorded in the eCRF. 
Use of study treatment in doses in excess of that specified in the protocol is considered to be 
an overdose. Refer to Section 8.4.3 for procedures in case of overdose. 
Treatment compliance will be ensured by reconciliation of site drug accountability logs. The 
Investigator or Pharmacist must retain records of all study treatment administered at the site 
(ie, those administered intravenously). The Study Monitor will check these records to confirm 
the compliance with the protocol administration schedule. 
Study site staff will administer chemotherapy (SoC) and durvalumab. Patients will 
self-administer olaparib/placebo and should be given clear written instructions on how and 
when to take their study treatment.  
All patients will be required to complete an olaparib/placebo dosing diary, which must be 
returned to the clinic for review at each visit. The patient should be instructed to record each 
date and time the olaparib/placebo dose(s) is taken on the dosing diary. If a dose is missed, the 
reason must be noted in the diary. A copy of the dosing diary is provided in the study 
reference materials. 
For olaparib and placebo, study site staff will make tablet counts at regular intervals during 
treatment. Compliance will be assessed by the tablet count, and the information will be 
recorded in the appropriate section of the eCRF. After the tablet count has been performed, the 
remaining tablets will not be returned to the patient but will be retained by the study site until 
reconciliation is completed by the Study Monitor. All patients must return their bottle(s) of 
olaparib/placebo at Day 1 of each subsequent cycle, when a new bottle will be dispensed. 
Patients will be instructed to notify study site personnel of missed doses. Dates of missed or 
held doses will be recorded by the patient on their patient diary and by the site staff on the 
eCRF. 

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The IP Storage Manager is responsible for managing the IP from receipt by the study site until 
the destruction or return of all unused IPs. The Investigator(s) is responsible for ensuring that 
the patient has returned all unused IPs. 
6.4 
Concomitant therapy 
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical treatment phase of the study, including the first 
3 months of the post-treatment discontinuation period.  
The use of any natural/herbal products or other traditional remedies should be discouraged. 
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements, that the patient is receiving at the time of enrollment or receives 
during the study must be recorded along with the following: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose, unit, and frequency 
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator. 
Restricted, prohibited, and permitted concomitant medications are described in Table 8, 
Table 9, and Table 10. Refer also to the Dosing Modification and Toxicity Management 
Guidelines (see Section 8.4.5.1 for durvalumab and Section 8.4.5.2 for olaparib). For 
chemotherapy (SoC) agents, refer to the local prescribing information with regards to 
warnings, precautions, and contraindications. 
Table 8 
Prohibited concomitant medications 
Prohibited medication/class of drug 
Usage 
Any investigational anticancer therapy other than 
those under investigation in this study 
Should not be given concomitantly while the patient 
is on study treatment 
mAbs against CTLA-4, PD-1, or PD-L1 other than 
those under investigation in this study 
Should not be given concomitantly while the patient 
is on study treatment 
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal therapy for 
cancer treatment other than those under investigation 
in this study 
Should not be given concomitantly while the patient 
is on study treatment. (Concurrent use of hormones 
for non-cancer-related conditions [eg, insulin for 
diabetes and hormone replacement therapy] is 
acceptable. Local treatment of isolated lesions, 
excluding TLs, for palliative intent is acceptable [eg, 
by local surgery or radiotherapy]). 
Live attenuated vaccines  
Should not be given through 30 days after the last 
dose of IP 

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Prohibited medication/class of drug 
Usage 
Immunosuppressive medications including, but not 
limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumor necrosis 
factor-α blockers 
Should not be given concomitantly or used for 
premedication prior to the IO infusions. The 
following are allowed exceptions: 
Use of immunosuppressive medications for the 
management of IP-related AEs 
Short-term premedication for patients receiving SoC 
(eg, platinum-based chemotherapy), where the 
prescribing information for the agent requires the use 
of steroids for documented hypersensitivity reactions 
Use in patients with contrast allergies  
Use of inhaled, topical, and intranasal corticosteroids 
is permitted 
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of non-immunotherapy related 
events experienced by the patient (eg, chronic 
obstructive pulmonary disease, radiation, nausea, 
etc). 
When treating with steroids, the minimum effective 
dose should be utilized due to the immunosuppressive 
effects of steroids. Baseline steroid use when starting 
PD-L1 blockade may be associated with inferior 
outcomes (Arbour et al 2018) 
EGFR TKIs 
Should not be given concomitantly.  
Should be used with caution in the 90 days post last 
dose of durvalumab.  
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence of 
transaminase increases (with first-generation EGFR 
TKIs) has been reported when durvalumab has been 
given concomitantly. 
Herbal and natural remedies, which may have 
immune-modulating effects 
Should not be given concomitantly unless agreed by 
the Sponsor 
AE  Adverse event; CRT  Chemoradiation therapy; CTLA-4  Cytotoxic T-lymphocyte-associated antigen 4; 
EGFR  Epidermal growth factor receptor; IO  Immuno-oncology; IP  Investigational product; PD-1  Programmed 
cell death 1; PD-L1  Programmed cell death ligand 1; SoC  Standard of care; TKI  Tyrosine kinase inhibitor; 
TL  Target lesion. 
 

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Table 9 
Restricted concomitant medications 
Restricted medication/class of drug 
Concern 
Strong CYP3A inhibitors: Itraconazole, 
telithromycin, clarithromycin, boosted protease 
inhibitors (ie, boosted with ritonavir or cobicistat), 
indinavir, saquinavir, nelfinavir, boceprevir, 
telaprevir 
Moderate CYP3A inhibitors: Ciprofloxacin, 
erythromycin, diltiazem, fluconazole, verapamil 
Strong or moderate CYP3A inhibitors should not be 
taken with olaparib/placebo. If there is no suitable 
alternative concomitant medication, then the dose of 
olaparib/placebo should be reduced for the period of 
concomitant administration. The dose reduction of 
olaparib/placebo should be recorded in the eCRF with 
the reason documented as concomitant CYP3A 
inhibitor use.  
Strong CYP3A inhibitors – reduce the dose of 
olaparib/placebo to 100 mg BID for the duration of 
concomitant therapy with the strong inhibitor and for 
5 half-lives afterwards. 
Moderate CYP3A inhibitors - reduce the dose of 
olaparib/placebo to 150 mg BID for the duration of 
concomitant therapy with the moderate inhibitor and 
for 3 half-lives afterwards. 
After the washout of the inhibitor is complete, the 
olaparib/placebo dose can be re-escalated. 
Strong CYP3A inducers: Phenobarbital, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide, and St. John’s Wort 
Moderate CYP3A inducers: Bosentan, efavirenz, 
dexamethasone, and modafinil 
Strong or moderate CYP3A inducers should not be 
taken with olaparib/placebo.  
If the use of any strong or moderate CYP3A inducers 
is considered necessary for the patient’s safety and 
welfare, this could diminish the clinical efficacy. 
If a patient requires use of a strong or moderate 
CYP3A inducer, then they must be monitored 
carefully for any change in efficacy. 
Effect of olaparib on other drugs 
Based on limited in vitro data, olaparib may increase 
the exposure to substrates of CYP3A4, OATP1B1, 
OCT1, OCT2, OAT3, MATE1, and MATE2K. 
Based on limited in vitro data, olaparib may reduce 
the exposure to substrates of CYP2B6. 
Caution should therefore be observed if substrates of 
these isoenzymes or transporter proteins are 
coadministered. 
Examples of substrates include: 
CYP3A4 – simvastatin, cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, sirolimus, tacrolimus, 
quetiapine 
CYP2B6 – bupropion, efavirenz 
OATP1B1 – bosentan, glibenclamide, repaglinide, 
statins, valsartan 
OCT1, OCT2, MATE1, MATE2K – metformin 
OCT2 – serum creatinine (endogenous substrate) 
OAT3 – furosemide, methotrexate 

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Restricted medication/class of drug 
Concern 
Anticoagulant therapy 
Patients who are taking warfarin may participate in 
this study; however, it is recommended that INR be 
monitored carefully at least once per week for the 
first month, then monthly if the INR is stable. 
Subcutaneous heparin and low-molecular-weight 
heparin are permitted. 
Anti-emetics/anti-diarrheals 
From initiation of maintenance treatment onward, 
should a patient develop nausea, vomiting, and/or 
diarrhea, then these symptoms should be reported as 
AEs (see Section 8.3) and appropriate treatment of 
the event should be given. 
Palliative radiotherapy 
Palliative radiotherapy may be used for the treatment 
of pain at the site of bony metastases or symptomatic 
pelvic soft tissue mass(es) that were present at 
baseline (for initial therapy phase), provided the 
Investigator does not feel that these are indicative of 
clinical disease progression during the study period. 
Study treatment should be discontinued for a 
minimum of 3 days before a patient undergoes 
therapeutic palliative radiation treatment. Study 
treatment should be restarted within 4 weeks as long 
as any bone marrow toxicity has recovered. 
Administration of other anticancer agents 
Patients must not receive any other concurrent 
anticancer therapy, including investigational agents, 
while on study treatment. Patients may continue the 
use of bisphosphonates or denosumab for bone 
disease and corticosteroids (that are not excluded 
according to exclusion criterion 10 [Section 5.2]) for 
the symptomatic control of brain metastases provided 
the dose is stable before and during the study and 
they were started at least 4 weeks prior to beginning 
of study treatment. 
Subsequent therapies for cancer 
Details of first and subsequent therapies for cancer 
and/or details of surgery for the treatment of the 
cancer, after discontinuation of treatment, will be 
collected. Reasons for starting subsequent anticancer 
therapies including access to other PARP inhibitors 
or investigational drugs will be collected and 
included in the exploratory assessments of OS. 
AEs  Adverse events; CYP  Cytochrome P450; eCRF  Electronic case report form; INR  International 
Normalized Ratio; MATE  Multidrug and toxin extrusion protein; OAT  Organic anion transporter; 
OATP  Organic-anion-transporting polypeptide; OCT  Organic cation transporter; OS  Overall survival; 
PARP  Poly (ADP ribose) polymerization. 
 

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Table 10 
Supportive medications 
Supportive medication/class of drug 
Usage 
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications 
identified as “prohibited”, as listed above  
To be administered as prescribed by the Investigator 
Best supportive care (including antibiotics, nutritional 
support, correction of metabolic disorders, optimal 
symptom control, and pain management [including 
palliative radiotherapy to NTLs, etc]) 
Should be used, when necessary, for all patients 
Inactivated viruses, such as those in the influenza 
vaccine 
Permitted 
NTL  Non-target lesion. 
 
6.4.1 
Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF. 
6.4.2 
Durvalumab drug-drug interactions 
There is no information to date on drug-drug interactions with durvalumab either preclinically 
or in patients. As durvalumab is a mAb and therefore a protein, it will be degraded to small 
peptides and amino acids and will be eliminated by renal and reticuloendothelial clearance. It 
is therefore not expected that durvalumab will induce or inhibit the major drug metabolizing 
CYP pathways. As a result, there are no expected PK drug-drug interactions, for example, no 
expected drug-drug interaction with olaparib. The MOA of durvalumab involves binding to 
PD-L1, and therefore significant pharmacodynamic drug interactions with the commonly 
administered concomitant medications are not expected. Despite this, appropriate clinical 
monitoring in all of the planned clinical studies will be conducted to evaluate any potential 
drug-drug interactions. 
6.4.3 
Rescue medication 
As a result of imAEs that could potentially be experienced by patients on durvalumab, steroids 
and other immunosuppressant rescue medication has to be made available to this patient 
population. The 2 products that fall into the category of immunosuppressants are infliximab 
(eg, for colitis) and mycophenolate (eg, for hepatitis). AstraZeneca Supply Chain will only be 
responsible for sourcing these 2 rescue medications to the sites if local regulations prevent the 
use of infliximab and mycophenolate in this indication, as they are considered off-label for 
management of immunotherapy related toxicities. These rescue medications must be 
receipted, controlled, and administered by the pharmacist and stored according to the labeled 
storage conditions, with temperature excursions reported accordingly by the pharmacist. If 

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required for use as a result of an imAE, then the IVRS/ IWRS will provide to the pharmacists 
the kit identification number to be allocated to the patient at the time when the rescue 
medication is centrally supplied by AstraZeneca supply chain. Blinded and unblinded access 
and notifications will be controlled using the IVRS/IWRS. 
6.5 
Dose modification 
In case a dose reduction is necessary, olaparib/placebo treatment will be administered as 
follows: 
Table 11 
Dose reductions for olaparib/placebo to manage adverse events 
Initial dose 
Following re-challenge post 
interruption: Dose reduction 1 
Dose reduction 2 
300 mg BID 
250 mg BID 
200 mg BID 
BID  twice daily. 
 
Table 12 
Dose reduction for olaparib/placebo if patient develops moderate renal 
impairment 
Initial dose 
Moderate renal impairment (calculated CrCl either by Cockcroft-
Gault equation or based on a 24-hour urine test; ≥31 mL/min but 
<51 mL/min): Dose reduction 
300 mg BID 
200 mg BID 
BID  twice daily; CrCl  Creatinine clearance. 
 
Note: No further dose reductions are permitted for patients who receive olaparib/placebo 
treatment at a dose of 200 mg BID due to moderate renal impairment (≥31 mL/min but 
<51 mL/min) and who cannot tolerate this dose. 
Table 13 
Dose reductions for olaparib/placebo if patient has to start taking a 
strong or moderate CYP3A inhibitor 
Initial dose 
Strong CYP3A inhibitor 
Moderate CYP3A inhibitor 
300 mg BID 
100 mg BID 
150 mg BID 
BID  twice daily; CYP  Cytochrome P450. 
 
For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors 
cannot be avoided, see Section 6.4. 
When olaparib/placebo dose reduction is necessary, patients will take one 150-mg tablet and 
one 100-mg tablet BID for the 250 mg BID dose or two 100-mg tablets BID for the 200 mg 
BID dose or one 150-mg tablet BID or one 100-mg tablet BID.  

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For durvalumab, dose reductions are not permitted. Dose delays are permitted for durvalumab 
(see link to Dosing Modification and Toxicity Management Guidelines in Section 8.4.5.1). 
For guidance on dose modifications for management of AEs (including renal impairment) for 
olaparib and durvalumab, refer to Section 8.4.5. 
Investigators should follow local standard clinical practice regarding dose modifications for 
the SoC treatments (chemotherapy). 
6.6 
Treatment after the end of the study 
After the final analysis, AstraZeneca will continue to supply open-label drug to patients 
receiving durvalumab or olaparib monotherapy or durvalumab plus olaparib combination 
therapy up to the time they discontinue treatment for any reason (see Section 6.1.2). 
7. 
DISCONTINUATION OF TREATMENT AND SUBJECT 
WITHDRAWAL 
7.1 
Discontinuation of study treatment  
An individual patient will not receive any further IP (durvalumab, olaparib, placebo, or SoC) 
if any of the following occur in the patient in question: 
• 
Withdrawal of consent from further treatment with IP. The patient is, at any time, free to 
discontinue treatment, without prejudice to further treatment. A patient who discontinues 
treatment is normally expected to continue to participate in the study (eg, for safety and 
survival follow-up), unless they specifically withdraw their consent to all further 
participation in any study procedures and assessments (see Section 7.3).  
• 
An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing 
• 
Any AE that meets criteria for discontinuation as defined in the Dosing Modification and 
Toxicity Management Guidelines (see Section 8.4.5.1 for durvalumab and Section 8.4.5.2 
and Appendix G for olaparib) or as defined in the local prescribing information for the 
SoC agent 
• 
Pregnancy or intent to become pregnant 
• 
Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (eg, refusal to adhere to 
scheduled visits) 
• 
Initiation of alternative anticancer therapy including another investigational agent 
• 
Clinical progression or confirmed radiological progression (refer to Appendix F) and 
Investigator determination that the patient is no longer benefiting from treatment with IP 
A patient who discontinues therapy for any reason will have the end of therapy (EOT) 
recorded as the date of the last dose of IP. The patient should be followed using the schedule 
of activities outlined in Table 3.  

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During the initial therapy phase, if SoC chemotherapy is discontinued due to treatment-related 
toxicity, durvalumab monotherapy may continue at the discretion of the Investigator and 
patient when toxicity resolves to at least Grade 2 or less (however, these patients will not be 
allowed to continue into the maintenance phase [Section 5.2]). Similarly, if durvalumab is 
discontinued due to treatment-related toxicity, SoC may be continued per the study schedule 
and assessments should be continued according to local practice (however, these patients will 
not be allowed to continue into the maintenance phase [Section 5.2]). Patients should be 
monitored per local SoC guidelines and managed using the Dose Modification and Toxicity 
Management Guidelines (see Section 8.4.5.1) for durvalumab; patients should also follow the 
recommended schedule in Table 2 for laboratory assessments, physical examinations, ECGs, 
and AE/SAEs. In these situations, patients cannot be randomized to the maintenance phase of 
the study. 
During the maintenance phase, in the event that durvalumab is discontinued due to 
treatment-related toxicity, olaparib/placebo may still be administered as scheduled at the 
discretion of the Investigator and patient (with the understanding that the patient may be 
receiving placebo, as the study will still be blinded). If olaparib/placebo is discontinued due to 
treatment-related toxicity, durvalumab may continue at the discretion of the Investigator and 
patient when toxicity resolves to Grade 2 or less. Note: If the Investigator feels that a patient is 
ready to restart treatment prior to the toxicity resolving to Grade 2 or less, AstraZeneca should 
be consulted for an exception to this rule. 
7.1.1 
Procedures for discontinuation of study treatment 
Discontinuation of study treatment, for any reason, does not impact the patient’s participation 
in the study. A patient who decides to discontinue IP will always be asked about the reason(s) 
for discontinuation and the presence of any AE. The patient should continue attending 
subsequent study visits, and data collection should continue according to the study protocol. If 
the patient does not agree to continue in-person study visits, a modified follow-up must be 
arranged to ensure the collection of endpoints and safety information. This follow-up could be 
a telephone contact with the patient, a contact with a relative or treating physician, or 
information from medical records. The approach taken should be recorded in the medical 
records. A patient that agrees to modified follow-up is not considered to have withdrawn 
consent or to have withdrawn from the study. 
All patients who are permanently discontinued from further receipt of IP, regardless of the 
reason, will be identified as having permanently discontinued treatment. Patients who are 
permanently discontinued will enter the follow-up period (see the SoA in Table 3).  
Patients who permanently discontinue drug for reasons other than RECIST 1.1-defined 
radiological PD should continue to have RECIST scans performed q8w ±1 week (relative to 
the date of randomization) for the first 48 weeks and then q12w ±1 week thereafter until 

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RECIST 1.1-defined radiological PD plus one or more additional follow-up scans, if clinically 
feasible, as defined the SoAs. Please note, for patients who are not randomized into the 
maintenance phase for any reason, durvalumab will be discontinued and follow-up tumor 
assessments will not be required. 
If a patient is discontinued for RECIST 1.1-defined radiological PD, then the patient should 
have one or more additional follow-up scans performed (if clinically feasible). 
All patients will be followed for survival until the end of the study.  
Patients who decline to return to the site for evaluations should be contacted by telephone as 
indicated in the SoAs as an alternative.  
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IVRS/IWRS. 
7.2 
Lost to follow-up 
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 4.4), such that there is insufficient information to 
determine the patient’s status at that time. Patients who refuse to continue participation in the 
study, including telephone contact, should be documented as “withdrawal of consent” rather 
than “lost to follow-up.” Investigators should document attempts to re-establish contact with 
missing patients throughout the study period. If contact with a missing patient is 
re-established, the patient should not be considered lost to follow-up, and evaluations should 
resume according to the protocol. 
In order to support key end points of PFS and OS analyses, the survival status of all patients in 
the full analysis and the safety analysis sets (SAF) should be re-checked, this includes those 
patients who withdrew consent or are classified as “lost to follow-up.” 
• 
Lost to follow-up – site personnel should check hospital records, the patients’ current 
physician, and a publicly available death registry (if available) to obtain a current survival 
status. (The applicable eCRF modules will be updated.) 
• 
In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient can be obtained by site personnel from 
publicly available death registries (if available), where it is possible to do so under 
applicable local laws to obtain a current survival status. (The applicable eCRF modules 
will be updated.) 
7.3 
Withdrawal from the study 
Patients are free to withdraw from the study at any time (IP and assessments) without 
prejudice to further treatment. 

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Patients who withdraw consent for further participation in the study will not receive any 
further IP or further study observation, with the exception of survival follow-up, which will 
continue until the end of the study unless the patient has expressly withdrawn their consent to 
survival follow-up. The patient may be offered additional tests or tapering of treatment to 
withdraw safely. 
A patient who withdraws consent will be asked about the reason(s) for withdrawal and the 
presence of any AE. The Investigator will follow up AEs outside of the clinical study.  
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent 
to: 
• 
All further participation in the study including any further follow-up (eg, survival contact 
telephone calls) 
• 
Withdrawal to the use of any samples (see Section 8.8.6) 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoAs (Table 1, Table 2, and 
Table 3).  
The Investigator will ensure that data are recorded on the eCRFs. The Web Based Data 
Capture (WBDC) system will be used for data collection and query handling.  
The Investigator will ensure the accuracy, completeness, and timeliness of the data recorded 
and of the provision of answers to data queries according to the Clinical Study Agreement. 
The Investigator will sign the completed eCRFs. A copy of the completed eCRFs will be 
archived at the study site. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
treatment. 
Adherence to the study design requirements, including those specified in the SoAs, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria (patients must also meet added eligibility criteria for the 
maintenance phase prior to randomization). The Investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for screening 
failure, as applicable.  

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Procedures conducted as part of the patient’s routine clinical management (eg, blood count 
and imaging assessments) and obtained before signing of the ICF may be utilized for 
screening or baseline (for initial therapy phase) purposes, provided the procedures met the 
protocol-specified criteria and were performed within the time frame defined in the SoAs. 
8.1 
Efficacy assessments  
This study will evaluate the primary endpoint of PFS (Investigator-assessed). Secondary 
efficacy endpoints include ORR, DoR, and OS in the FAS, and PFS (Investigator-assessed) in 
the HRRm subgroup. Efficacy assessments of PFS (Investigator-assessed), ORR, and DoR 
will be derived using RECIST 1.1 assessments. 
Radiological efficacy will be assessed by RECIST 1.1 on IV contrast-enhanced CT or MRI 
scans of the chest and abdomen (including the entire liver and both adrenal glands). There will 
be 2 baseline assessments, the first for the initial therapy period and the second for the 
maintenance period. A first “Initial Therapy Baseline” scan should be collected during 
screening (Days -28 to -1) for disease staging and for use as a RECIST 1.1 baseline scan for 
the initial therapy phase on-study scans (collected 14 to 28 days after Cycle 2 Day 1 and 
Cycle 4 Day 1 of the initial therapy phase [Table 1]). A patient’s diagnostic scan may be used 
as a baseline scan for the initial therapy phase only if taken within 28 days of first-dose 
administration and in accordance with the scan acquisition requirements (ie, chest and 
abdomen [including the entire liver and both adrenal glands] IV contrast-enhanced CT/MRI) 
outlined in Appendix F. The scan at 14 to 28 days after Cycle 4 Day 1 of the initial therapy 
phase will be compared with the initial therapy baseline scan to determine eligibility for the 
maintenance phase and will also be the “Maintenance Baseline” scan for the assessment of 
response during the maintenance phase (for those patients eligible for randomization into the 
maintenance phase) with new RECIST 1.1 baseline assignment of TLs/NTLs (Table 2). If 
determined eligible, patients will be randomized within 5 weeks after Cycle 4 Day 1 of the 
initial therapy phase; every effort should be made to minimize the time between confirmation 
of eligibility, randomization, and starting maintenance treatment. During the maintenance 
phase, on-study tumor assessments occur q8w ±1 week relative to the date of randomization 
beginning 8 weeks after randomization for the first 48 weeks and then q12w ±1 week 
thereafter until RECIST 1.1-defined radiological PD (plus one or more additional follow-up 
scans if clinically feasible), the end of study, study discontinuation, or Sponsor decision, 
whichever comes first. It is important to follow the tumor assessment schedule as closely as 
possible (refer to the SoAs). If an unscheduled assessment is performed and the patient has not 
progressed, every attempt should be made to resume subsequent assessments according to the 
original imaging visit schedule (relative to the date of randomization). 
For patients who discontinue treatment due to toxicity or other reasons in the absence of 
RECIST 1.1-defined radiological PD, tumor assessments should be continued until 

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RECIST 1.1-defined radiological PD plus one or more additional follow-up scans if clinically 
feasible. 
Figure 7 depicts the tumor assessment schedule for both the initial therapy and maintenance 
phases. 
Figure 7 
Tumor assessment schedule for initial therapy and maintenance phases 
 
 
a 
During the initial therapy phase, 1 cycle is 21 days in duration, unless there are SoC dosing delays (eg, for 
toxicity reasons). If there is a dosing delay during the treatment schedule for durvalumab, all future dosing 
days for durvalumab should be delayed to ensure that the intervals between dosing study treatment are 
always at least 21 days. 
Note: Maintenance phase on-study tumor assessments occur q8w ±1 week relative to the date of randomization 
beginning 8 weeks after randomization for the first 48 weeks and then q12w ±1 week thereafter until 
RECIST 1.1-defined radiological PD plus one or more additional follow-up scans if clinically feasible. 
BL  RECIST 1.1 baseline scan; C  Cycle; D  Day; R  Randomize; RECIST 1.1  Response Evaluation Criteria in 
Solid Tumors version 1.1; S/R  Scan, analyze, randomize; W  Week; X  Scan timepoint. 
 
8.1.1 
Central reading of scans 
All radiological scans, including unscheduled visit scans, will be collected on an ongoing 
basis and sent to an AstraZeneca-appointed CRO for quality control and storage. Guidelines 
for image acquisition, de-identification, storage at the study site as source data, and transfer to 
the imaging CRO for central review will be provided in a separate document. Results of these 
independent reviews will not be communicated to Investigators, and results of Investigator 
RECIST 1.1 assessments will not be shared with the central reviewers. The management of 

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patients will be based upon the results of the RECIST 1.1 assessment conducted by the 
Investigator. Further details of the BICR will be documented in the Independent Review 
Charter (also referred to as ‘Imaging Charter’). 
The BICR of radiological scans will be analyzed as a sensitivity analysis for the primary 
endpoint of PFS (Investigator-assessed). Only Investigator assessments will be captured in the 
RAVE system in RECIST folders. 
8.1.2 
Survival assessments 
Assessments for survival must be made every 2 months following treatment discontinuation. 
Survival information may be obtained via telephone contact with the patient or the patient’s 
family, or by contact with the patient’s current physician. The details of first and subsequent 
therapies for cancer, after discontinuation of treatment, will be collected.  
In addition, patients on treatment or in survival follow-up will be contacted following the 
DCO for the primary analysis and all subsequent survival analyses to provide complete 
survival data. These contacts should generally occur within 7 days of the DCO. 
8.1.3 
Clinical outcome assessments 
A Clinical Outcome Assessment (COA) is any assessment that may be influenced by human 
choices, judgement, or motivation and may support either direct or indirect evidence of 
treatment benefit. PROs are one of the types of COAs. PROs, an umbrella term referring to all 
outcomes and symptoms, are directly reported by the patient. PROs have become a significant 
endpoint when evaluating effectiveness of treatments in clinical studies. The following PROs 
will be administered in this study: EORTC-QLQ-C30; EORTC-QLQ-LC13, 
 
 
see Appendix H). Each is described below. 
The PRO instruments will be completed by the patients using a site-based, electronic 
patient-reported outcome (ePRO) device. All assessments should be completed without 
assistance from anyone according to the assessment schedules (Table 2 and Table 3). 
8.1.3.1 
EORTC QLQ-C30 and QLQ-LC13 
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group 1993. It consists 
of 30 items and measures symptoms, functioning, and global health status/quality of life 
(QoL) (Aaronson et al 1993) for all cancer types. Questions are grouped into 5 multi-item 
functional scales (physical, role, emotional, cognitive, and social); 3 multi-item symptom 
scales (fatigue, pain, and nausea and vomiting); a 2-item global QoL scale; 5 single items 
assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of 
appetite, insomnia, constipation, and diarrhea), and 1 item on the financial impact of the 
CCI

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disease. The EORTC QLQ-C30 is a valid and reliable PRO instrument in this patient 
population (see Appendix H). 
The QLQ-LC13 is a well-validated complementary module measuring lung cancer-associated 
symptoms and side effects from conventional chemotherapy and radiotherapy (Bergman et al 
1994). The QLQ-LC13 includes questions assessing cough, hemoptysis, dyspnea, site-specific 
pain, sore mouth, dysphagia, peripheral neuropathy, alopecia, and pain medication (see 
Appendix H). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.1.3.5 
Administration of the patient-reported outcome questionnaires 
Patients will perform the PRO assessments using an electronic tablet (ePRO) during clinic 
visits. 
Each site must allocate the responsibility for the administration of the PRO instruments to a 
specific individual (eg, a research nurse or study coordinator) and, if possible, assign a 
back-up person to cover if that individual is absent. The PRO questionnaires must be 
administered and completed at the clinic as per the SoAs (Table 2 and Table 3). 
It is important that the site staff explains the value and relevance to hear directly from patients 
how they feel. The following best practice guidelines should be followed: 
• 
PRO questionnaires should be completed prior to any other study procedures and before 
discussion of disease progression to avoid biasing the patient’s responses to the questions. 
• 
PRO questionnaires must be completed in private by the patient. 
• 
Patients should be given sufficient time to complete the PRO questionnaires at their own 
speed. 
• 
The research nurse or appointed site staff should stress that the information is 
confidential. Therefore, if the patient has any medical problems, he/she should discuss 
them with the doctor or research nurse separately from the PRO assessment. 
• 
The research nurse or appointed site staff must train the patient on how to use the ePRO 
device using the materials and training provided in the ePRO device. 
• 
The research nurse or appointed site staff must remind patients that there are no right or 
wrong answers and avoid introducing bias by not clarifying items. The patient should not 
receive help from relatives, friends, or clinic staff in answering the PRO questionnaires. 
A key aspect of study success is to have high PRO compliance. Therefore, it is essential to 
follow the SoAs and that sites make sure the device is charged and fully functional at all times 
in order to minimize missing data. 
8.2 
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoAs (Table 1, Table 2, and 
Table 3). 
8.2.1 
Clinical safety laboratory assessments 
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the times indicated in the assessment schedules and as clinically indicated (see 
the SoAs [Table 1, Table 2, and Table 3]). During the initial therapy phase, laboratory 
assessments should be performed according to local standard clinical practice for SoC; if these 
items are performed on Day 8 or 15 of each cycle per local standard clinical practice, results 
do not need to be recorded in the clinical database unless abnormal results are associated with 
AEs and SAEs.  

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Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a 
licensed clinical laboratory according to local standard procedures. Sample tubes and sample 
sizes may vary depending on the laboratory method used and routine practice at the site. 
Pregnancy tests may be performed at the site using a licensed test (urine or serum pregnancy 
test). Abnormal clinically significant laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours). If pregnancy test results are positive, the patient is 
ineligible for the study/must be discontinued from study treatment immediately. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection, and results (values, units, and reference ranges) will 
be recorded on the appropriate eCRF. 
The laboratory variables to be measured are presented in Table 14 (clinical chemistry), 
Table 15 (hematology), and Table 16 (urinalysis). 
Other safety tests to be performed at screening include assessment for HBsAg, hepatitis C 
antibodies, and HIV antibodies. 
The following laboratory variables will be measured: 
Table 14 
Clinical chemistry 
Albumin 
Lactate dehydrogenase 
Alkaline phosphatasea 
Lipaseb 
ALTa 
Magnesiumc 
Amylaseb 
Potassium 
ASTa 
Sodium 
Bicarbonatec 
Total bilirubina 
Calcium  
Total protein 
Chloridec 
TSHe 
Creatinined  
Free T3f (reflex) 
CrClc,d 
Free T4f (reflex) 
Gamma glutamyltransferasec 
Urea or blood urea nitrogen, depending on local practice 
Glucose 
 
a 
Tests for ALT, AST, alkaline phosphatase, and TBL must be conducted and assessed concurrently. If TBL 
is ≥2 × ULN (and no evidence of Gilbert’s syndrome), then fractionate into direct and indirect bilirubin. 
b 
It is preferable that both amylase and lipase parameters are assessed. For sites where only 1 of these 
parameters is routinely measured, either lipase or amylase is acceptable. 
c 
Bicarbonate (where available), chloride, CrCl, gamma glutamyltransferase, magnesium, testing are to be 
performed at screening, on Day 1 of initial therapy phase (unless all screening laboratory clinical chemistry 
assessments are performed within 3 days prior to Day 1), on Day 1 of maintenance phase, and as clinically 
indicated (except for CrCl, which is also measured at Day 1 of each cycle during the maintenance phase). 

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d 
CrCl will be calculated by the investigator or designee using Cockcroft-Gault equation (using actual body 
WT) or based on a 24-hour urine test. 
e 
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 
1. 
f 
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE 
related to the endocrine system. 
ALT  Alanine aminotransferase; AST  Aspartate aminotransferase, CrCl  Creatinine clearance; 
T3  Triiodothyronine; T4  Thyroxine; TBL  Total bilirubin; TSH  Thyroid-stimulating hormone; ULN  Upper 
limit of normal; WT  Weight. 
 
Table 15 
Hematology 
Absolute neutrophil counta 
Absolute lymphocyte counta 
Hemoglobin 
Platelet count 
Total white cell count 
 
Note: For coagulation parameters, activated partial thromboplastin time and INR are to be assessed at screening 
(initial therapy phase) and as clinically indicated (in both the initial therapy and maintenance phases). Patients 
who are taking warfarin may participate in this study; however, it is recommended that INR be monitored 
carefully at least once per week for the first month, then monthly if the INR is stable. 
a 
Can be recorded as absolute counts or as percentages. Total white cell count therefore has to be provided. 
INR  International Normalized Ratio. 
 
Table 16 
Urinalysis 
Bilirubin 
Ketones 
Blood 
pH 
Color and appearance 
Protein 
Glucose 
Specific gravity 
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high-power field for 
red and white blood cells.  
 
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin (TBL) ≥2 × ULN, 
refer to Appendix E for further instructions on cases of increases in liver biochemistry and 
evaluation of HL. These cases should be reported as SAEs per criteria specified in 
Appendix E.  
All patients should have further chemistry profiles performed at 30 days (±3 days), 2 months 
(±1 week), and 3 months (±1 week) after permanent discontinuation of IP (see Table 3). 
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF. Situations in which laboratory safety results should be 
reported as AEs are described in Section 8.3.7. 

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All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from IP must have further tests performed until the laboratory values have returned to Grade 1 
or 2, unless these values are not likely to improve because of the underlying disease. 
8.2.1.1 
Bone marrow or blood cytogenetic samples 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
hematological toxicities, as defined in Appendix G. 
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic 
analysis and flow cytometry, and a core biopsy for bone marrow cellularity. If it is not 
possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then 
attempts should be made to carry out the tests on a blood sample. Full reports must be 
provided by the Investigator for documentation on the Patient Safety database. These data are 
not required to be entered into eCRF. 
8.2.2 
Physical examinations 
Physical examinations will be performed according to the assessment schedules (see Table 1, 
Table 2, and Table 3). Full physical examinations will include assessments of the head, eyes, 
ears, nose, and throat and the respiratory, cardiovascular, GI, urogenital, musculoskeletal, 
neurological, dermatological, hematologic/lymphatic, and endocrine systems. Height will be 
measured at screening only. Targeted physical examinations are to be utilized by the 
Investigator on the basis of clinical observations and symptomatology. Situations in which 
physical examination results should be reported as AEs are described in Section 8.3.7.  
8.2.3 
Vital signs 
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to Table 1, Table 2, and Table 3. Body WT is also recorded at each visit along with 
vital signs. 
First infusion of durvalumab 
On the first infusion day, patients will be monitored and vital signs collected/recorded in 
eCRF prior to, during, and after infusion of durvalumab as presented in the bulleted list below.  
BP and pulse will be collected from patients before, during, and after each infusion at the 
following times (based on a 60-minute infusion): 
• 
Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [ie, the beginning of the infusion]) 
• 
Approximately 30 minutes during the infusion (halfway through infusion)  
• 
At the end of the infusion (approximately 60 minutes ±5 minutes) 

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If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow 
the principles as described above or be taken more frequently if clinically indicated. A 1-hour 
observation period is recommended after the first infusion of durvalumab.  
Subsequent infusions of durvalumab 
On subsequent infusion days, BP, pulse, and other vital signs should be measured, 
collected/recorded in eCRF prior to the start of the infusion. Patients should be carefully 
monitored, and BP and other vital signs should be measured during and post infusion as per 
institution standard and as clinically indicated. Any clinically significant changes in vital signs 
should be entered onto an unscheduled vital signs eCRF page.  
During the initial therapy phase, on days where SoC is administered without durvalumab, 
patients will be monitored pre-dose and as clinically indicated before every infusion or 
administration. 
Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.7. For any AEs of infusion reactions, the vital signs values should be entered into 
the eCRF. 
8.2.4 
Electrocardiograms 
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study (see the SoAs). ECGs should be obtained after the patient has been in a supine position 
for 5 minutes and recorded while the patient remains in that position. 
In case of clinically significant ECG abnormalities, including a QTcF value ≥470 ms, 
2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm 
the finding.  
Situations in which ECG results should be reported as AEs are described in Section 8.3.7. 
8.2.5 
Early patient review for safety 
During the initial therapy phase, patients will be evaluated 7±2 days after the first dose of each 
cycle of chemotherapy with durvalumab (Day 8 ±2 days) to ensure early identification and 
management of toxicities. It is strongly recommended for any patient experiencing Grade 3 or 
4 neutropenia that granulocyte colony-stimulating factor is administered according to local 
practice. 
Following the initial therapy phase, patients are to be contacted 2 weeks ±2 days after 
receiving the first dose of each of the first 2 cycles of olaparib/placebo maintenance therapy to 
ensure early identification and management of toxicities. For the maintenance phase, the form 
of contact and procedures conducted will be at the Investigator’s discretion. 

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8.2.6 
WHO/ECOG performance status 
WHO/ECOG PS will be assessed at the times specified in the assessment schedules (see 
Table 1, Table 2, and Table 3) based on the following: 
0 
Fully active; able to carry out all usual activities without restrictions 
1 
Restricted in strenuous activity, but ambulatory and able to carry out light work or work 
of a sedentary nature (eg, light housework or office work) 
2 
Ambulatory and capable of self-care, but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; unable to carry out any self-care and totally confined to bed or chair 
5 
Dead  
Any significant change from baseline for the initial therapy or maintenance phases must be 
reported as an AE. 
8.2.7 
Other safety assessments 
If new or worsening pulmonary symptoms (eg, dyspnea or cough) or radiological 
abnormalities occur in the absence of a clear diagnosis, an interruption in study treatment 
dosing is recommended, and further diagnostic workup should be performed to exclude 
pneumonitis. The differential diagnosis should include the possibility of both immune-related 
and non-immune-related processes. AEs of pneumonitis are of interest for AstraZeneca as 
pneumonitis has been observed with use of both anti-PD-1 and anti-PD-L1 mAbs, and 
instances of pneumonitis have been reported in patients undergoing olaparib treatment. 
Initial workup should consider the inclusion of a clinical evaluation, high-resolution CT scan, 
ruling-out infection, pulse oximetry, and other appropriate laboratory workup. Pulmonary 
consultation is highly recommended. Guidelines for the management of patients with 
immune-related AEs including pneumonitis are provided in the Dose Modification and 
Toxicity Management Guidelines (see Section 8.4.5.1). 
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then study treatment can be restarted, if deemed appropriate by the 
Investigator. If significant pulmonary abnormalities are identified, these need to be discussed 
with the Study Physician. 
Pneumonitis (ILD) investigation 
The following assessments, and additional assessments if required, will be performed to 
enhance the investigation and diagnosis of potential cases of pneumonitis. The results of the 
assessment will be collected. 

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• 
Physical examination 
− 
Signs and symptoms (cough, shortness of breath, pyrexia, etc) including auscultation 
for lung field will be assessed. 
• 
SpO2 
− 
Saturation of peripheral oxygen (SpO2) 
• 
Other items 
− 
When pneumonitis (ILD) is suspected during study treatment, the following markers 
should be measured where possible: 
(i) ILD markers (KL-6, SP-D) and β-D-glucan 
(ii) Tumor markers: particular tumor markers that are related to disease progression.  
(iii) Additional Clinical chemistry: CRP, LDH  
8.3 
Collection of adverse events 
The Principal Investigator (PI) is responsible for ensuring that all staff involved in the study 
are familiar with the content of this section 
The definitions of an AE or SAE can be found in Appendix B. 
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorized representative).  
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow up AEs, 
see Section 8.3.3.  
8.3.1 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.  
8.3.2 
Time period and frequency for collecting AE and SAE information  
AEs and SAEs will be collected from the time of signing the informed consent throughout the 
treatment period and including the follow-up period (90 days after the last dose of durvalumab 
or 30 days after the last dose of olaparib/placebo, whichever is later; Table 3). If an event that 
starts after the defined safety follow-up period noted above is considered to be due to a late 
onset toxicity to study drug, then it should be reported as an AE or SAE as applicable. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix B. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. 

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Investigators are not obligated to actively seek AE or SAE in former study patients. However, 
if the Investigator learns of any SAE, including a death, at any time after a patient’s last visit 
and he/she considers the event to be reasonably related to the Study treatment or study 
participation, the Investigator should notify the Sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B. 
8.3.2.1 
Adverse events after the safety follow-up period 
For pharmacovigilance purposes and characterization, any SAE of MDS/AML or new primary 
malignancy occurring after the follow-up period (as defined in Section 8.3.2) should be 
reported to AstraZeneca Patient Safety regardless of Investigator’s assessment of causality or 
knowledge of the treatment arm. Investigators will be asked during the regular follow-up for 
OS if the patient has developed MDS/AML or a new primary malignancy and prompted to 
report any such cases. 
At any time after a patient has completed the study, if an Investigator learns of any SAE 
including sudden death of unknown cause, and he or she considers that there is a reasonable 
possibility that the event is causally related to the IP, the Investigator should notify 
AstraZeneca Patient Safety. 
If patients who are gaining clinical benefit are allowed to continue study treatment after DCO 
and/or after study completion, then all SAEs must continue to be collected and reported to 
Patient Safety within the usual timeframe. 
Otherwise, after study treatment completion (ie, after any scheduled post-treatment follow-up 
period has ended), there is no obligation to actively report information on new AEs or SAEs 
occurring in former study patients. This includes new AEs/SAEs in patients still being 
followed up for survival but who have completed the post-treatment follow-up period. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient 
at subsequent visits/contacts. All SAEs and AEs of special interest (as defined in 
Section 8.3.12), will be followed until resolution, stabilization, the event is otherwise 
explained, or the patient is lost to follow-up  
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated (this may be beyond 90 days after the last dose 
of durvalumab or 30 days after the last dose of olaparib/placebo), but without further 
recording in the eCRF. AstraZeneca retains the right to request additional information for any 
patient with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 

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8.3.4 
Adverse event data collection 
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
Date when the AE started and stopped 
• 
Maximum CTCAE grade reported 
• 
Changes in CTCAE grade (report all changes in CTCAE grade for a calendar day) 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IPs (yes or no) 
• 
Action taken with regard to IPs 
• 
Administration of treatment for the AE 
• 
AE caused patient’s withdrawal from study (yes or no) 
• 
Outcome 
In addition, the following variables will be collected for SAEs where applicable: 
• 
Date the AE met criteria for SAE 
• 
Date the Investigator became aware of the SAE 
• 
Seriousness criteria  
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Whether an autopsy was performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment in relation to other medication, as explained in Section 8.3.5  
• 
Description of the SAE 
The grading scales found in the revised NCI CTCAE version 5.0 will be utilized for all events 
with an assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 
CTCAE grades should be used. A copy of the CTCAE version 5.0can be downloaded from the 
Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
8.3.5 
Causality collection 
The Investigator will assess causal relationship between IP and each AE, and answer “yes” or 
“no” to the question “Do you consider that there is a reasonable possibility that the event may 
have been caused by the IP?”. 

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For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as “yes”. 
A guide to the interpretation of the causality question is found in Appendix B. 
8.3.6 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff: “Have you had any health problems since the previous visit/you were 
last asked?” or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
8.3.7 
Adverse events based on examinations and tests 
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarized in the clinical study report (CSR). Deterioration as compared to baseline 
(ie, initial therapy baseline for the initial therapy phase and maintenance baseline for the 
maintenance phase) protocol-mandated laboratory values and vital signs should therefore only 
be reported as AEs if they fulfill any of the SAE criteria or are the reason for discontinuation 
of treatment with the IP. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low Hb value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline (ie, initial therapy baseline for the initial therapy phase and 
maintenance baseline for the maintenance phase) assessment will be reported as an AE, unless 
unequivocally related to the disease under study, see Section 8.3.9. 
8.3.8 
Hy’s law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with TBL ≥2 × ULN may need to be 

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reported as SAEs. Refer to Appendix E for further instruction on cases of increases in liver 
biochemistry and evaluation of HL. 
8.3.9 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied. It may be an increase in the severity of the 
disease under study and/or increase in any of the symptoms of the disease. The development 
of new or progression of existing metastasis to the primary cancer under study should be 
considered as disease progression and not an AE. Events, which are unequivocally due to 
disease progression should not be reported as an AE during the study. 
8.3.10 
New cancers 
The development of a new cancer should be reported as an AE (see Section 8.3.12.2) and 
would in most cases meet seriousness criteria (with the exception of some non-melanoma skin 
cancers). New primary cancers are those that are not the primary reason for the administration 
of the IP and have been identified after the patient’s inclusion in this study. They do not 
include metastases of the original cancer. Symptoms of metastasis or the metastasis itself 
should not be reported as an AE/SAE, as they are considered to be disease progression. 
8.3.11 
Deaths 
All deaths that occur during the study treatment period or within the protocol-defined 
follow-up period after the administration of the last dose of study drug must be reported as 
follows: 
• 
Death clearly resulting from disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented in the eCRF in 
the Statement of Death page. It should not be reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to the Study Monitor/Physician as an SAE within 
24 hours. It should also be documented in the Statement of Death page in the eCRF. The 
report should contain a comment regarding the co-involvement of PD, if appropriate, and 
should assign main and contributory causes of death. 
• 
Deaths with an unknown cause should always be reported as an SAE. It should also be 
documented in the Statement of Death page in the eCRF. A post mortem may be helpful 
in the assessment of the cause of death, and if performed, a copy of the post-mortem 
results should be forwarded to AstraZeneca Patient Safety or its representative within the 
usual timeframes. 
Deaths occurring after the protocol-defined safety follow-up period after the administration of 
the last dose of study drug should be documented in the Statement of Death page. If the death 
occurred as a result of an event that started post the defined safety follow-up period and the 

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event is considered to be due to a late onset toxicity to study drug then it should also be 
reported as an SAE. 
8.3.12 
Adverse events of special interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the IP and may require close monitoring. An AESI may be serious or 
non-serious. The rapid reporting of AESIs allows ongoing surveillance of these events in 
order to characterize and understand them in association with the use of these IPs. 
8.3.12.1 
Adverse events of special interest for durvalumab 
AESIs for durvalumab include, but are not limited to, events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants, and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy 
and combination therapy. An imAE is defined as an AESI that is associated with drug 
exposure and is consistent with an immune-mediated MOA and where there is no clear 
alternate etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, 
should be used to support an imAE diagnosis. Appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE.  
If the Investigator has any questions in regard to an event being an imAE, the Investigator 
should promptly contact the Study Physician. 
AESIs/imAEs observed with anti PD-L/PD-1 agents such as durvalumab include pneumonitis, 
hepatitis, diarrhea/colitis, intestinal perforation, endocrinopathies (hypo- and 
hyper-thyroidism, adrenal insufficiency, hypophysitis/hypopituitarism and Type 1 diabetes 
mellitus), nephritis, rash/dermatitis, myocarditis,myositis/polymyositis, pancreatitis and 
rare/less frequent imAEs including neuromuscular toxicities such as myasthenia gravis and 
Guillain-Barre syndrome. 
Other inflammatory responses that are rare/less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and other events 
involving the eye, skin, hematological, rheumatological events, vasculitis, non-infectious 
meningitis and non-infectious encephalitis. It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all organs. 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs. 
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the durvalumab IB. More specific guidelines for their evaluation and treatment are 
described in detail in the Dose Modification and Toxicity Management Guidelines (see link in 

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Section 8.4.5.1). These guidelines have been prepared by the Sponsor to assist the Investigator 
in the exercise of his/her clinical judgment in treating these types of toxicities. These 
guidelines apply to AEs considered causally related to the study drug/study regimen by the 
reporting Investigator. 
8.3.12.2 
Adverse events of special interest for olaparib 
AESIs for olaparib are the important potential risks of the following: 
• 
MDS/AML 
• 
New primary malignancy (other than MDS/AML) 
• 
Pneumonitis 
Any event of MDS/AML, new primary malignancy, or pneumonitis should be reported to 
AstraZeneca Patient Safety whether it is considered a non-serious AE (eg, non-melanoma skin 
cancer) or SAE, and regardless of Investigator assessment of causality. These AEs must be 
reported according to the timelines for reporting an SAE (see Section 8.4.1) to allow timely 
safety monitoring. 
A questionnaire will be sent to any Investigator reporting an AESI as an aid to provide further 
detailed information on the event. During the study, there may be other events identified as 
AESIs that require the use of a questionnaire to help characterize the event and gain a better 
understanding regarding the relationship between the event and study treatment. 
8.3.13 
Safety data to be collected following the final DCO of the study 
For patients continuing to receive study treatment after final DCO and database closure, it is 
recommended that the patients continue the scheduled site visits and Investigators monitor the 
patient’s safety laboratory results prior to and periodically during treatment in order to manage 
AEs in accordance with the Dose Modification and Toxicity Management Guidelines (see 
Section 8.4.5 and Appendix G). All data post the final DCO and database closure will be 
recorded in the patient notes but, with the exception of SAEs, will not otherwise be reported 
for the purposes of this study. 
All SAEs that occur in patients still receiving study treatment (or within the follow-up period 
[Section 8.3.2]) after the final DCO and database closure must be reported as detailed in 
Section 8.4.1. 
8.4 
Safety reporting and medical management 
8.4.1 
Reporting of serious adverse events 
All SAEs have to be reported whether or not considered causally related to the IP or to the 
study procedure(s). All SAEs will be recorded in the eCRF. 

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If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day (ie, immediately but no later than 
24 hours of when he/she becomes aware of it). 
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day (ie, immediately but no later than 24 hours of when he/she becomes aware of it). 
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative. 
If the WBDC system is not available, then the Investigator or other study site staff reports a 
SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.  
The PI is responsible for ensuring that procedures and expertise are available to handle 
medical emergencies during the study. A medical emergency usually constitutes an SAE 
and is to be reported as such. 
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study 
Protocol. 
8.4.2 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except if the 
pregnancy is discovered before the study patient has received any study drug. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.4.2.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study, IP should be discontinued 
immediately. 

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Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) occurring from the first dose of study treatment until 90 days 
after the last dose of durvalumab or 30 days after the last dose of olaparib/placebo, whichever 
is later, should be followed up and documented even if the patient was discontinued from the 
study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
inform the appropriate AstraZeneca representatives within 1 day (ie, immediately but no later 
than 24 hours of when he/she becomes aware of it). 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the eCRF is used to report the pregnancy, and the PREGOUT is 
used to report the outcome of the pregnancy. 
8.4.2.2 
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of durvalumab or 30 days after the last dose of olaparib/placebo, 
whichever is later. Please follow the local prescribing information relating to contraception 
and the time limit for such precautions for SoC agents. 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) occurring from the first dose of study treatment until 90 days after 
the last dose of durvalumab or 30 days after the last dose of olaparib/placebo, whichever is 
later, if possible, should be followed up and documented. 
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the patient’s partner. Therefore, the local study 
team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant Ethics Committees (ECs)/IRBs prior to use. 

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Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment and will enter follow-up (see 
Table 3). 
8.4.3 
Overdose 
8.4.3.1 
Durvalumab and olaparib 
Olaparib and durvalumab must only be used in accordance with the dosing recommendations 
in this protocol. Use of durvalumab or olaparib in doses in excess of that specified in the 
protocol is reported as an overdose. There is currently no specific treatment in the event of 
overdose of durvalumab or olaparib, and possible symptoms of overdose are not established.  
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately. 
• 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module. 
• 
An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately or no later than 24 hours of when he/she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
• 
For overdoses associated with a SAE, the standard reporting timelines apply, see 
Section 8.4.1. For other overdoses, reporting must occur within 30 days. 
8.4.3.2 
Standard of care 
For SoC, refer to the local prescribing information for treatment of cases of overdose. If an 
overdose is associated with an AE or SAE, please record the AE/SAE diagnosis or symptoms 
in the relevant AE modules only of the eCRF. 
8.4.4 
Medication error 
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel inform the appropriate AstraZeneca representatives within 1 day (ie, immediately 
but no later than 24 hours of when he/she becomes aware of it). 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (initial fatal/life-threatening or follow-up 
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SAE associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors. 
The definition of a medication error can be found in Appendix B. 
8.4.5 
Management of IP-related toxicities  
The following general guidance should be followed for management of IP-related toxicities: 
• 
Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity if required). 
• 
If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of the assigned IP along with appropriate continuing supportive 
care. If medically appropriate, dose modifications are permitted. 
• 
All dose modifications should be documented with clear reasoning and documentation of 
the approach taken. 
• 
Patients should be thoroughly evaluated to rule out any alternative etiology (eg, disease 
progression, concomitant medications, or infections). This includes SoC-induced toxicity. 
In the event that toxicities are clearly attributed to chemotherapy, both SoC and 
durvalumab should be delayed (note that if SoC is delayed for any reason, durvalumab 
administration must be delayed as well). 
• 
In the event that durvalumab is discontinued or delayed as part of the toxicity 
management guidance, SoC may still be administered as scheduled. 
• 
In the event that SoC chemotherapy is discontinued due to treatment-related toxicity, 
durvalumab monotherapy may continue at the discretion of the Investigator and patient 
when toxicity resolves to at least Grade 2 or less. Note: if the Investigator feels that a 
patient is ready to restart treatment prior to the toxicity resolving to Grade 2 or less, 
AstraZeneca should be consulted for an exception to this rule. 
If unsure how to manage a patient, please contact the Study Physician at AstraZeneca to 
discuss individual cases. All toxicities will be graded according to NCI CTCAE, version 5.0.  
8.4.5.1 
Durvalumab  
Comprehensive toxicity management guidelines (TMGs) have been developed to assist 
investigators with the recognition and management of toxicities associated with the use of the 
immune-checkpoint inhibitors durvalumab [Medi4736] (PD-L1 inhibitor). Given the similar 
underlying mechanisms of toxicities observed with these two compounds, these guidelines are 
applicable to the management of patients receiving either drug as monotherapy or in 
combination. Additionally, these guidelines are applicable when either drug is used alone or in 
combination and is administered concurrently or sequentially with other anti-cancer drugs 
(ie, antineoplastic chemotherapy, targeted agents), as part of a protocol specific treatment 
regimen. The TMGs provide information for the management of immune-mediated reactions, 
infusion-related reactions, and non-immune mediated reactions that may be observed with 
checkpoint inhibitor monotherapy or combination checkpoint inhibitor regimens, with specific 

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instructions for dose modifications (including discontinuations) and treatment interventions. 
Investigators are advised however to use local practice guidelines and consult local references 
for the management of toxicities observed with other cancer treatment. The most current 
version of the TMGs entitled “Dosing Modification and Toxicity Management Guidelines for 
Immune-Mediated, Infusion-Related, and Non-Immune Mediated Reactions (MEDI4736) 
Monotherapy or Combination Therapy with Tremelimumab or Tremelimumab Monotherapy” 
is provided to the investigative site as an Annex document and is maintained within the Site 
Master File. In addition, a version of the current Dosing Modification and Toxicity 
Management Guidelines is available through the following link: https://tmg.azirae.com. Please 
contact the clinical study associate for information on how to gain access to this website. 
Patients should be thoroughly evaluated, and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered 
potentially immune related. 
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued (see Section 7.1 of this protocol and the Dosing Modifications and Toxicity 
Management Guidelines). 
Following the first dose of IP, subsequent administration of durvalumab can be modified 
based on toxicities observed as described in the Dosing Modification and Toxicity 
Management Guidelines. These guidelines have been prepared by the Sponsor to assist the 
Investigator in the exercise of his/her clinical judgment in treating these types of toxicities. 
These guidelines apply to AEs considered causally related to durvalumab by the reporting 
Investigator. 
Dose reductions are not permitted. In case of doubt, the Investigator should consult with the 
Study Physician. 
8.4.5.2 
Olaparib 
Potential olaparib-related toxicities observed during the course of the study could be managed 
by interruption of the dose of study treatment or dose reductions (see Appendix G). Repeat 
dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion. If the 
interruption is any longer, the study team must be informed.  
For patients with CrCl ≥51 mL/min dosed with 300 mg BID, study treatment can be dose 
reduced to 250 mg BID as a first step and to 200 mg BID as a second step. If the reduced dose 
of 200 mg BID is not tolerable, no further dose reduction is allowed and olaparib/placebo 
should be discontinued. 

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Once dose is reduced, escalation is not permitted (except following concomitant treatment 
with CYP3A inhibitors; see Section 6.4). 
No further dose reductions are permitted for patients who receive olaparib treatment at a dose 
of 200 mg BID due to moderate renal impairment (≥31 mL/min but <51 mL/min) and who 
cannot tolerate this dose.  
8.4.5.3 
SoC 
Investigators should follow local standard clinical practice regarding dose modifications for 
SoC. For specific information regarding the individual agent used in this study, refer to the 
local prescribing information for the relevant agent. 
In the event of unfavorable tolerability, patients can switch between cisplatin and carboplatin 
therapy at any point during the study. 
In the event that an AE can reasonably be attributed to SoC, dose adjustment of SoC should be 
attempted before modifying the administration of durvalumab. 
In the event that SoC is delayed, durvalumab administration must also be delayed.  
Every effort should be made to ensure that patients receive 4 cycles of SoC during the initial 
therapy phase, if conditions allow. 
8.5 
Pharmacokinetics 
Drug concentration information that may unblind the study will not be reported to study sites 
or blinded personnel until the study has been unblinded. 
8.5.1 
Collection of samples 
Blood samples for determination of durvalumab concentration in serum will be obtained 
according to Table 1, Table 2, and Table 3.  
Samples for determination of durvalumab concentration in serum will be analyzed by a 
designated third party on behalf of AstraZeneca. Samples will be collected, labeled, stored, 
and shipped as detailed in the Laboratory Manual. Full details of the analytical method used 
will be described in a separate Bioanalytical Validation Report. 
8.5.1.1 
Collection of samples to measure for the presence of ADAs 
The presence of ADA will be assessed in serum samples taken according to Table 1, Table 2, 
and Table 3.  
Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for 
durvalumab using validated assays. Tiered analysis will be performed to include screening, 

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confirmatory, and titer assay components, and positive negative cut points previously 
statistically determined from drug-naïve validation samples will be employed. 
8.5.2 
Storage and destruction of pharmacokinetic/ADA samples 
Durvalumab PK and ADA samples will be destroyed within 5 years of CSR finalization. 
PK and ADA samples may be disposed of or destroyed and anonymized by pooling. 
Additional analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method. Results from such analyses may be reported 
separately from the CSR. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Validation Report. 
Any residual back-up PK samples may be used for future exploratory biomarker research (in 
this case, residual back-up PK samples will be shipped to AstraZeneca-designated biobank; 
see details in the Laboratory Manual). 
8.6 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The FFPE tumor sample provided at baseline will ideally be a sample close to the time of 
study entry; either newly acquired or archival tumor samples (<3 years old) are acceptable. If 
available, a newly acquired tumor biopsy, collected as part of routine clinical practice, is 
preferred. If not available, an archival sample taken <3 years prior to screening is acceptable. 
If both an archival sample and a fresh tumor biopsy sample are available, both samples should 
be submitted for analysis. 
 
 
 
 
 
 
 
 
 
Tumor lesions used for newly acquired biopsies should not be TLs, unless there are no other 
lesions suitable for biopsy. Samples with limited tumor content and fine needle aspirate 
specimens are not acceptable. Specimens from metastatic bone lesions are typically 
unacceptable unless there is a significant soft tissue component and should not be decalcified. 
Patients will be given the option to consent to an optional tumor biopsy (FFPE tumor sample) 
at progression. This should be performed as soon as possible after disease progression is 
confirmed. The treating physician will judge the feasibility of such a procedure. 
8.8.1.1 
HRR mutation testing 
Patient tumor samples will be provided at screening to determine HRR mutation status by a 
central laboratory (details of HRR mutation assessment follow below and in the Laboratory 
Manual). The anticipated prevalence of HRR mutations in the NSCLC patient population is 
approximately 12.5% based on analysis of TCGA data; it is expected to be approximately 
between 15% and 20% in this study population given that patients with platinum-sensitive 
NSCLC may be enriched for HRRm. Sites will be blinded to the result of the central 
assessment. If available, full results from the HRR mutation test will be provided to the 
Investigator upon individual request for randomized patients who received treatment upon 
disease progression and treatment discontinuation.  
The newly acquired or archival tumor sample (<3 years old) provided at baseline 
(Section 8.8.1.1) will be used for tissue-based HRR genes mutation testing. The analysis will 
be performed at a central laboratory testing service using the DNA extracted from FFPE 
tissue.  
The tumor sample will be tested for loss of function and alterations in specific HRR genes that 
have not yet been determined. If the test results indicate that the patient has at least 1 
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qualifying mutation in any of these genes, the patient will be considered HRRm. No local 
testing results are permitted. All tumor samples will be analyzed for a range of cancer-related 
genes to explore correlations between clinical response and DNA alterations. 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.8.3 
Storage, re-use, and destruction of biomarker samples 
Samples will be stored for a maximum of 15 years from the end of study, after which they will 
be destroyed.
 
 
 
 
8.8.4 
Labeling and shipment of biological samples 
The PI will ensure that samples are labeled and shipped in accordance with the Laboratory 
Manual and the Biological Substance, Category B, Regulations (materials containing or 
suspected to contain infectious substances that do not meet Category A criteria); see 
Appendix C IATA 6.2 Guidance Document. 
Any samples identified as Infectious Category A materials will not be shipped, and no further 
samples will be taken from the involved patients unless agreed upon with AstraZeneca and 
appropriate labeling, shipment, and containment provisions are approved. 
8.8.5 
Chain of custody of biological samples 
A full chain of custody will be maintained for all samples throughout their life cycle. 
The PI at each center will keep full traceability of collected biological samples from the 
patients while in storage at the center until shipment or disposal (where appropriate) and will 
keep documentation of sample shipments. 
The sample receiver will keep full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and will keep documentation of receipt of 
arrival. 
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers. 
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks and will 
be registered by the AstraZeneca Biobank Team during the entire life cycle. 
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randomized patients. Secondary efficacy variables include ORR, DoR, and OS in the FAS, 
and PFS as determined by Investigator assessment according to RECIST 1.1 in the HRRm 
subgroup. Sensitivity analyses for the primary endpoint will be performed, including 
analyzing PFS according to BICR in the FAS. 
9.1 
Statistical hypotheses 
The primary objective is to assess the efficacy of durvalumab plus olaparib combination 
therapy compared with durvalumab monotherapy in terms of PFS (Investigator-assessed) for 
patients who are in the FAS. The formal statistical analysis will be performed to test the 
following main hypotheses:  
• 
H01: No difference between durvalumab plus olaparib combination therapy compared 
with durvalumab monotherapy in terms of PFS for the FAS 
• 
H11: There is a difference between durvalumab plus olaparib combination therapy 
compared with durvalumab monotherapy in terms of PFS for the FAS 
If a statistically significant difference is observed in the study, ie, reject the null hypothesis of 
no difference in favor of H11, then the following hypotheses can also be tested:  
• 
H20: No difference between durvalumab plus olaparib combination therapy compared 
with durvalumab monotherapy in terms of OS for the FAS  
• 
H21: There is a difference between durvalumab plus olaparib combination therapy 
compared with durvalumab monotherapy in terms of OS for the FAS 
9.2 
Sample size determination  
The study is sized to characterize the PFS benefit of durvalumab in combination with olaparib 
versus durvalumab monotherapy in patients with Stage IV NSCLC whose disease has not 
progressed after 4 cycles of durvalumab with platinum-based first-line chemotherapy. 
Approximately 350 to 400 patients will be enrolled in the initial therapy phase of the study. 
Approximately 250 patients globally who have not progressed will be randomized in a 1:1 
ratio to either the durvalumab plus olaparib treatment arm or the durvalumab plus placebo 
treatment arm, approximately 125 patients per arm. The randomization will be stratified based 
on objective response to durvalumab plus chemotherapy (CR/PR or SD; obtained at the last 
visit prior to randomization [Cycle 4 scan]) and histology (squamous or nonsquamous). 
The DCO for the primary analysis of PFS will occur when approximately 163 PFS events 
have occurred across the durvalumab plus olaparib treatment arm and durvalumab plus 
placebo treatment arm (approximately 65% maturity). 
 
 
 
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9.3 
Populations for analyses 
Definitions of the analysis sets for each outcome variable are provided in Table 17.  
Table 17 
Summary of outcome variables and analysis populations 
Outcome variables 
Populations 
Efficacy data 
 
PFS (Investigator-assessed) 
FAS (ITT population) and HRRm 
subgroup 
OS, ORR, DoR 
FAS (ITT population)  
PRO 
FAS (ITT population) 
Demography 
FAS (ITT population) 
PK data 
PK analysis set 
Safety data 
 
Exposure 
SAF 
AEs 
SAF 
Laboratory measurements 
SAF 
Vital signs 
SAF 
AE  Adverse event; DoR  Duration of response; FAS  Full analysis set; HRRm  Homologous recombination 
repair related gene mutation; ITT  Intent to treat; ORR  Objective response rate; OS  Overall survival; 
PFS  Progression-free survival.; PK  Pharmacokinetics; PRO  Patient-reported outcome; SAF  Safety analysis 
set. 
 
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9.3.1 
Full analysis sets 
9.3.1.1 
Full analysis set (FAS) for the initial therapy phase 
The FAS for the initial therapy phase will include all patients who received at least 1 dose of 
durvalumab and/or chemotherapy in the study. It will be used to summarize patient disposition 
and demographic characteristics for all patients receiving treatment in the study. It will also be 
used to summarize the tumor response as reported by investigators in the initial therapy phase. 
9.3.1.2 
Full analysis set (FAS) 
The FAS for the maintenance phase will include all randomized patients (ie, intent-to-treat 
population). The FAS will be used for all efficacy analyses (including PROs). Treatment arms 
will be compared based on randomized study treatment, regardless of the treatment actually 
received. Patients who were randomized but did not subsequently proceed to receive study 
treatment are included in the analysis in the treatment arm to which they were randomized. 
9.3.2 
Safety analysis sets 
9.3.2.1 
Safety analysis set for initial therapy phase 
The SAF for the initial therapy phase will consist of all patients who received at least 1 dose 
of durvalumab during the initial therapy phase of the study. Minimal safety data will be 
summarized for the initial therapy phase only (not including post-randomization data for 
randomized patients), unless unexpected safety signals are observed.  
9.3.2.2 
 Safety analysis set for maintenance phase (SAF) 
The SAF for the maintenance phase will consist of all patients who received at least 1 dose of 
any study treatment (durvalumab and/or olaparib/placebo) during the maintenance phase of 
the study. Safety data will not be formally analyzed but summarized using the SAF according 
to the treatment received, that is, erroneously treated patients will be summarized according to 
the treatment they actually received (ie, those randomized to durvalumab plus placebo who 
receive one or more doses of olaparib in error will be reported in the durvalumab plus olaparib 
arm). 
9.3.3 
Pharmacokinetic analysis set 
All patients who receive at least 1 dose of durvalumab for whom any post-dose data are 
available and who do not violate or deviate from the protocol in ways that would significantly 
affect the PK analyses will be included in the PK analysis set. The population will be defined 
by the Study Physician, Pharmacokineticist, and Statistician prior to any analyses being 
performed. 

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9.4 
Outcome measures for analyses 
9.4.1 
Calculation or derivation of efficacy variables 
9.4.1.1 
RECIST 1.1-based endpoints 
The analyses of the primary endpoint (PFS in the FAS) and secondary endpoints (ORR and 
DoR in the FAS, and PFS in the HRRm subgroup) will be based on site Investigator 
assessments using RECIST 1.1. In addition, OS in the FAS will also be evaluated. Sensitivity 
analyses for the primary endpoint will be performed, including analyzing PFS according to 
BICR in the FAS.  
Investigator RECIST 1.1-based assessments 
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy.  
At each visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, 
PR, SD, or PD depending on the Investigator-reported status of their disease compared with 
baseline (Section 9.5) and previous assessments. If a patient has had a tumor assessment that 
cannot be evaluated, then the patient will be assigned a visit response of NE (unless there is 
evidence of progression in which case the response will be assigned as PD). 
Refer to Appendix F for the definitions of CR, PR, SD, PD, and NE. 
Blinded independent central review RECIST 1.1-based assessments 
As described in Section 8.1.1, a BICR of radiological scans will be performed for the 
sensitivity analysis of the primary endpoint in the FAS. The BICR will be performed on all 
radiological scans of all patients. 
All images will be collected centrally. Prior radiotherapy reports will also be provided to the 
BICR to allow the selection of appropriate TLs. The imaging scans will be reviewed by 
2 independent radiologists using RECIST 1.1 and will be adjudicated, if required. For each 
patient, the BICR will define the overall visit response data (CR, PR, SD, PD, or NE) and the 
relevant scan dates for each timepoint (ie, for visits where response or progression is/is not 
identified). If a patient has had a tumor assessment that cannot be evaluated, then the patient 
will be assigned a visit response of NE (unless there is evidence of progression, in which case 
the response will be assigned as PD). PFS according to BICR will be derived from the overall 
visit response date and the scan dates.  
Further details of the BICR will be documented in the Imaging Charter. 

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9.4.1.2 
Progression-free survival 
PFS (per RECIST 1.1 as assessed by the site Investigator and by BICR) will be defined as the 
time from the date of randomization until the date of objective radiological disease 
progression or death (by any cause in the absence of progression) regardless of whether the 
patient withdraws from therapy or receives another anticancer therapy prior to progression (ie, 
date of event or censoring – date of randomization +1). Patients who have not progressed or 
died at the time of analysis will be censored at the time of the latest date of assessment from 
their last evaluable RECIST 1.1 assessment. However, if the patient progresses or dies after 2 
or more missed visits, the patient will be censored at the time of the latest evaluable RECIST 
1.1 assessment prior to the 2 missed visits. If the patient has no post-baseline evaluable visits, 
they will be censored at Day 1 unless they die within 2 visits of baseline, then they will be 
treated as an event with date of death as the event date. 
The PFS time will always be derived based on scan/assessment dates and not visit dates. 
RECIST 1.1 assessments/scans contributing toward a particular visit may be performed on 
different dates. The following rules will be applied: 
• 
For Investigator assessments, the date of progression will be determined based on the 
earliest of the RECIST assessment/scan dates of the component that indicates 
progression. 
• 
For BICR assessments, date of progression will be determined based on the earliest of the 
dates of the component that triggered the progression on the first set of scans that 
indicates progression for the adjudicated reviewer selecting PD, or of either reviewer 
where both reviewers select PD as a timepoint response, and there is no adjudication for 
central review (BICR) data. 
• 
When censoring a patient for PFS, the patient will be censored at the latest of the scan 
dates contributing to a particular overall visit assessment. 
9.4.1.3 
Overall survival 
OS is defined as the time from the date of randomization until death due to any cause. Any 
patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive.  
Note: Survival calls will be made following the date of DCO for the analysis (these contacts 
should generally occur within 7 days of the DCO). If patients are confirmed to be alive or if 
the death date is post the DCO date, these patients will be censored at the date of DCO. Death 
dates may be found by checking publicly available death registries (where possible to do so 
under applicable local laws). 
9.4.1.4 
Objective response rate 
ORR (per RECIST 1.1 using Investigator’s assessments) is defined as the percentage of 
patients with at least 1 visit response of CR or PR after randomization and who have 

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measurable disease at randomization. Data obtained up until progression, or the last evaluable 
assessment in the absence of progression, will be included in the assessment of ORR. Patients 
who go off treatment without progression, receive a subsequent therapy, and then respond will 
not be included as responders in the ORR. 
Categorization of objective tumor response assessment will be based on the RECIST criteria 
of response: CR, PR, SD, PD, and NE. TL progression will be calculated in comparison to 
when the tumor burden was at a minimum (ie, smallest sum of diameters previously recorded 
on study from the time of randomization). In the absence of a best response of progression, 
tumor response (CR, PR, or SD) will be calculated in comparison with the tumor 
measurements used to determine eligibility for the maintenance phase obtained prior to 
randomization. 
A patient will be classified as a responder if the RECIST criteria for a CR or PR are satisfied 
at any time from randomization up to and including the defined analysis cut-off point. For 
each treatment arm, the ORR is the number of CR and PR divided by the number of patients 
in the FAS with measurable disease at time of randomization. 
9.4.1.5 
Duration of response 
DoR (per RECIST 1.1 using Investigator assessment) will be defined as the time from the date 
of first documented response following randomization until the first date of documented 
progression or death in the absence of disease progression (ie, date of PFS event or censoring 
– date of first response +1). The end of response should coincide with the date of progression 
or death from any cause used for the RECIST 1.1 PFS endpoint as assessed by the site 
Investigator.  
DoR will not be defined for those patients who do not have documented response. 
9.4.2 
Calculation or derivation of safety variables 
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, laboratory 
data, vital signs, ECGs, and physical examination findings. These will be collected for all 
patients and summarized separately for the initial therapy and maintenance phases. Data from 
all cycles of treatment will be combined in the presentation of safety data. 
9.4.2.1 
Adverse events 
AEs and SAEs for both treatment arms will be collected throughout the study, from the date of 
signing the informed consent throughout the treatment period and including the follow-up 
period (90 days following discontinuation of durvalumab or 30 days following discontinuation 
of olaparib/placebo, whichever is later). The Medical Dictionary for Regulatory Activities 
(MedDRA) (using the latest or current MedDRA version) will be used to code the AEs. AEs 
will be graded according to the National Cancer Institute CTCAE Version 5.0. 

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Any AE occurring before starting study treatment will be included in the data listings but will 
not be included in the summary tables of AEs. Any AE occurring within the follow-up period 
may be included in the AE summaries, but the majority of the AE summaries will omit the 
AEs observed after a patient has received further therapy for cancer. This will more accurately 
depict AEs attributable to study treatment only as a number of AEs up to the end of the 
follow-up period are likely to be attributable to subsequent therapy. Any AE that occurs after 
a patient has received further therapy for cancer (following discontinuation of study treatment) 
will be flagged in the data listings. 
For the durvalumab plus olaparib arm and the durvalumab plus placebo arm, in the event of 
the components being administered separately, then the date of first dose/last dose will be 
considered as the earliest/latest dosing date of either component. 
The SAF in the initial therapy phase will be used for the reporting of safety data in the initial 
therapy phase, and the SAF in the maintenance phase will be used for the reporting of safety 
data in the maintenance phase. 
A separate data listing of AEs occurring more than 90 days after discontinuation of 
durvalumab and more than 30 days after discontinuation of olaparib/placebo, whichever is 
later, will be produced for both the initial therapy and maintenance phases. These events will 
not be included in AE summaries. 
9.4.2.2 
Safety assessments 
For the change from baseline summaries during the maintenance phase for vital signs, 
laboratory data, and physical examinations, the baseline value will be the latest result obtained 
prior to the start of randomized study treatment.  
QTcF will be derived during creation of the reporting database using the reported ECG values 
(RR and QT) using the following formula: 
QTcF = QT/RR^(1/3), where RR is in seconds. 
Corrected calcium product will be derived during creation of the reporting database using the 
following formula: 
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – albumin (G/L)] × 0.02) 
The denominator used in laboratory summaries will only include evaluable patients, ie, those 
who had sufficient data to have the possibility of an abnormality. 

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For example: 
• 
If a CTCAE criterion involves a change from baseline, evaluable patients would have 
both a pre-dose and at least 1 post-dose value recorded. 
• 
If a CTCAE criterion does not consider changes from baseline to be evaluable, the patient 
need only have 1 post-dose value recorded. 
The denominator in vital signs data should include only those patients with recorded data. 
9.4.3 
Calculation or derivation of patient-reported outcome variables 
Symptoms and overall QoL will be assessed using the EORTC QLQ-C30 and QLQ-LC13 
module (secondary endpoints). Questionnaires will be scored according to published scoring 
guidelines or the developer’s guidelines, if published guidelines are not available. All PRO 
analyses will be based on the FAS. The clinical meaningfulness threshold of the PRO analyses 
described below will be provided in the SAP. 
9.4.3.1 
EORTC QLQ-C30 and EORTC QLQ-LC13 
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional 
scales (physical, role, cognitive, emotional, and social) and 3 symptom scales (fatigue, pain, 
and nausea and vomiting), 5 individual items (dyspnea, insomnia, appetite loss, constipation, 
and diarrhea), and a global measure of health status. The EORTC QLQ-LC13 is a lung 
cancer-specific module from the EORTC for lung cancer comprising 13 items/questions 
(cough, hemoptysis, dyspnea, site-specific pain, sore mouth, dysphagia, peripheral 
neuropathy, alopecia, and pain medication). With the exception of a multi-item scale for 
dyspnea, all are single items. The dyspnea scale will only be used if all 3 items have been 
scored; otherwise, the items are treated as single-item measures. 
An outcome variable consisting of a score from 0 to 100 will be derived for each of the 
symptom scales/symptom items, the functional scales, and the global health status/QoL scale 
according to the EORTC QLQ-C30 Scoring Manual (Fayers et al 2001) and EORTC 
QLQ-LC13 instructions. 
Higher scores on the global health status/QoL and functioning scales indicate better health 
status/function, but higher scores on symptom scales/items represent greater symptom 
severity. 
Changes in score compared with baseline (Section 9.5)will be evaluated. For each subscale, if 
<50% of the subscale items are missing, then the subscale score will be divided by the number 
of non-missing items and multiplied by the total number of items on the subscales (Fayers et 
al 2001). If at least 50% of the items are missing, then that subscale will be treated as missing. 
Missing single items are treated as missing. The reason for any missing questionnaire will be 
identified and recorded. If there is evidence that the missing data are systematic, missing 
values will be handled to ensure that any possible bias is minimized. 

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Evaluability rates for the EORTC QLQ-C30 and EORTC QLQ-LC13 will also be calculated 
separately for each questionnaire: 
Evaluability rate = number of evaluable forms
number of received forms  ×  100 
An expected form = a questionnaire that is expected to be completed at a scheduled 
assessment time, that is, a questionnaire from a patient who has not withdrawn from the study 
at the scheduled assessment time but excluding patients in countries with no available 
translation.  
An evaluable form = a questionnaire with a completion date and at least 1 subscale that is 
non-missing.  
A received form = a questionnaire that has been received and has a completion date and at 
least 1 individual item completed. 
9.4.4 
Calculation or derivation of pharmacokinetic variables 
9.4.4.1 
Population pharmacokinetics and exposure-response/safety analysis 
A population PK model may be developed using a non-linear mixed-effects modeling 
approach. The impact of physiologically relevant patient characteristics (covariates) and 
disease on PK may be evaluated. The relationship between the PK exposure and the effect on 
safety and efficacy endpoints may be evaluated. The results of such an analysis will be 
reported in a separate report. The PK, demographic, safety, and efficacy data collected in this 
study may also be combined with similar data from other studies and explored using 
population PK and/or PK methods. 
9.4.4.2 
Pharmacokinetic analysis 
PK concentration data and summary statistics will be tabulated. Individual and mean blood 
concentration-time profiles will be generated. The following PK parameters will be 
determined after the first and steady-state doses: Cmax and Ctrough (as data allow). Samples 
below the lower limit of quantification will be treated as missing in the analyses. 
9.4.4.3 
Immunogenicity analysis 
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against durvalumab. The 
immunogenicity titer and presence of neutralizing ADAs will be reported for samples 
confirmed positive for the presence of ADAs. The effect of immunogenicity on PK, efficacy, 
and safety may be evaluated, if the data allow. 

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Results of all statistical analyses will be presented using a 95% CI and a 2-sided p-value, 
unless otherwise stated. 
9.5.1 
Efficacy analyses 
Efficacy data will be summarized and analyzed using the FAS. All outputs will be 
summarized by treatment arm and where required for all randomized patients within the 
HRRm subgroup.  
Table 19 details which endpoints are to be subjected to formal statistical analysis, together 
with pre-planned sensitivity analyses, making it clear which analysis is regarded as primary 
for that endpoint. Note that all endpoints compare durvalumab plus olaparib combination 
therapy versus durvalumab monotherapy, unless otherwise indicated. The 2 stratification 
factors are histology (squamous or nonsquamous) and objective response to durvalumab plus 
chemotherapy obtained at the last visit prior to randomization (CR/PR or SD [Cycle 4 scan]; 
response does not have to be confirmed). These factors will be covariates in logistic regression 
and mixed-effect model repeated measure models. 
Table 19 
Pre-planned statistical and sensitivity analyses to be conducted 
Endpoints analyzed 
Notes 
Progression-free survival 
Stratified log-rank tests for: 
Primary analysis using Investigator RECIST 1.1 assessments 
Sensitivity analysis using BICR RECIST 1.1 assessments 
Sensitivity analyses using Investigator RECIST 1.1 assessments 
• 
Interval censored analysis – evaluation time bias 
• 
Analysis using alternative censoring rules – attrition bias 
Secondary analysis using Investigator RECIST 1.1 assessments (HRRm 
subgroup) 
Overall survival 
Stratified log-rank test  
Secondary analysis 
Objective response rate 
Logistic regression for: 
Secondary analysis using Investigator assessments (RECIST 1.1) 
Duration of response 
Summary statistics and KM plot by treatment arm for: 
Secondary analysis using Investigator assessments (RECIST 1.1)  
Time to deterioration (EORTC 
QLQ-C30 and QLQ-LC13 
endpoints) 
Stratified log-rank test 
Change from baseline in 
symptoms (EORTC QLQ-C30 
and QLQ-LC13 endpoints) 
MMRM analysis 
HRQoL/Function and symptom 
improvement rate (EORTC QLQ-
C30 and QLQ-LC13 endpoints) 
Logistic regression 

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BICR  Blinded independent central review; EORTC  European Organisation for Research and Treatment of 
Cancer; HRRm  Homologous recombination repair related gene mutation; MMRM  Mixed-effect model repeated 
measure; PFS  Progression-free survival; QLQ-C30  30-item Core Quality of Life Questionnaire; 
QLQ-LC13  13-item Lung Cancer Quality of Life Questionnaire; RECIST 1.1  Response Evaluation Criteria in 
Solid Tumors version 1.1. 
 
9.5.1.1 
Primary endpoint: progression-free survival 
The primary analysis of PFS will occur when it is expected that approximately 163 PFS events 
have occurred (approximately 65% maturity) in the FAS. The analysis will be performed for 
patients in the FAS using a stratified log-rank test adjusting for objective response to 
durvalumab plus chemotherapy (CR/PR or SD; obtained at the last visit prior to randomization 
[Cycle 4 scan]) and histology (squamous or nonsquamous) for generation of the p-value, and 
using a method that corresponds to the Breslow approach for handling ties (Breslow 1974).  
The effect of durvalumab + olaparib versus durvalumab + placebo will be estimated by the 
HR together with its 95% CI from a stratified Cox model (an HR less than 1 will favor 
durvalumab in combination with olaparib). The CI will be calculated using a profile likelihood 
approach. The stratified Cox model will be fitted using PROC PHREG (in SAS) with the 
EFRON method to control for ties and the strata variables included in the strata statement.  
Interactions between treatment and stratification factors will also be tested to rule out any 
qualitative interaction using the approach of Gail and Simon (Gail and Simon 1985). 
The primary analyses will be based on Investigator-recorded assessment of disease 
progression using RECIST 1.1 criteria.  
Stratification variables will be defined according to data from the IVRS/IWRS. If there are 
any patients who are mis-stratified, a sensitivity analysis will be carried out using the baseline 
data collected in the eCRF.  
KM plots of PFS will be presented by treatment arm. Summaries of the number and 
percentage of patients experiencing a PFS event, and the type of event (RECIST or death) will 
be provided along with a median PFS for each treatment arm.  
The primary analysis will be based on programmatically derived PFS based on Investigator 
assessments and using all scans regardless of whether they were scheduled or not.  
The number of patients prematurely censored will be summarized by treatment arm together 
with baseline prognostic factors of the prematurely censored patients. A patient is defined as 
prematurely censored if they had not progressed and the latest scan prior to DCO was more 
than 1 scheduled tumor assessment interval (+2 weeks) prior to the DCO date.  

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9.5.1.2 
Analysis of the secondary variables 
The analyses of OS in the FAS, and of PFS as assessed by the site Investigator in the HRRm 
subgroup, will use the same methodology as specified for PFS as assessed by the site 
Investigator in the FAS (see Section 9.5.1.1).  
For OS, summaries of the number and percentage of patients who have died, those still in 
survival follow-up, those lost to follow-up, and those who have withdrawn consent will be 
provided along with the median OS for each treatment. KM plots will be presented by 
treatment arm.  
ORR in the FAS will be analyzed using logistic regression models adjusting for the same 
factors as the primary endpoint (histology and objective response to durvalumab plus 
chemotherapy). The results of the analysis will be presented in terms of an odds ratio together 
with its associated profile likelihood CI and p-value (based on twice the change in 
log-likelihood resulting from the addition of a treatment factor to the model).  
KM estimates (ie, median DoR and 95% CIs) will be provided for the DoR in responding 
patients in the FAS, including the associated KM curves (without any formal comparison of 
treatment arms or p-value attached).  
9.5.1.3 
Sensitivity analysis 
Summary statistics for the number of weeks between the time of progression and the last 
evaluable RECIST assessment prior to progression will be presented for each treatment arm.  
BICR 
The analysis of PFS as assessed by BICR in the FAS will use the same methodology as 
specified for PFS as assessed by the site Investigator in the FAS (see Section 9.5.1.1).  
Evaluation time bias 
Sensitivity analyses will be performed to assess possible evaluation-time bias that may be 
introduced if scans are not performed at the protocol-scheduled timepoints. The midpoint 
between the time of progression and the previous evaluable RECIST assessment will be 
analyzed using a stratified log-rank test. For patients whose death was treated as PFS event, 
the date of death will be used to derive the PFS time used in the analysis. This approach has 
been shown to be robust even in highly asymmetric assessment schedules (Sun and Chen 
2010). This approach will use the Investigator RECIST assessments.  
Attrition bias 
Attrition bias will be assessed by repeating the PFS analysis except that the actual PFS event 
times, rather than the censored times, of patients who progressed or died in the absence of 

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progression immediately following 2 or more non-evaluable tumor assessments will be 
included. In addition, patients who take subsequent therapy prior to progression or death will 
be censored at their last evaluable assessment prior to taking the subsequent therapy. This 
analysis will be supported by a KM plot of the time to censoring where the censoring indicator 
of the PFS analysis is reversed. This approach will use the Investigator RECIST 1.1 
assessments. 
9.5.1.4 
Subgroup analyses 
Subgroup analyses will be conducted comparing PFS (per RECIST 1.1 using Investigator 
assessments) between durvalumab plus olaparib combination therapy versus durvalumab 
monotherapy in the following subgroups of the FAS (but not limited to): 
• 
Sex (male or female) 
• 
Age at randomization (<65 or ≥65 years of age) 
• 
PD-L1 status (<1%, 1% to 49%, ≥50%) 
• 
Histology (squamous or nonsquamous) 
• 
Objective response to initial therapy (CR/PR or SD)  
• 
Smoking (smoker or non-smoker [never smoker]) 
• 
Race (Asian or non-Asian) 
• 
HRRm status (yes, no, unknown) 
• 
Investigator’s choice of chemotherapy (cisplatin doublet versus carboplatin doublet; 
nab-paclitaxel doublet versus pemetrexed doublet versus gemcitabine doublet) 
Other baseline variables may also be assessed if there is a clinical justification or an imbalance 
is observed between the treatment arms. The purpose of the subgroup analyses is to assess the 
consistency of treatment effect across expected prognostic and/or predictive factors.  
No adjustment to the significance level for testing of the subgroup and sensitivity analyses 
will be made since all these analyses will be considered supportive of the analysis of PFS. 
Interactions between treatment and stratification factors will also be tested to rule out any 
qualitative interaction using the approach of Gail and Simon (Gail and Simon 1985). 
Additionally, for each subgroup, the HR (durvalumab plus olaparib combination 
therapy:durvalumab monotherapy) and 95% CI will be calculated from a Cox proportional 
hazards model with treatment as the only covariate. These will be presented on a forest plot 
including the HR and 95% CI from the FAS.  
If there are too few events available for a meaningful analysis of a particular subgroup (it is 
not considered appropriate to present analyses where there are less than 20 events across both 
treatment groups in a subgroup), the relationship between that subgroup and PFS will not be 
formally analyzed. In this case, only descriptive summaries will be provided. 

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9.5.1.5 
Patient-reported outcomes 
EORTC QLQ-C30 and QLQ-LC13 
The primary PRO measures will be subject-reported lung cancer symptoms assessed using the 
EORTC QLQ-LC13 and EORTC QLQ-C30, namely: 
• 
QLQ-LC13: Dyspnea (multi-item scale based on three questions: “Were you short of 
breath when you rested; walked; climbed stairs?”) 
• 
QLQ-LC13: Cough: one item (“How much did you cough?”) 
• 
QLQ-LC13: Chest pain: one item (“Have you had pain in your chest?”) 
• 
QLQ-C30: Fatigue (multi-item scale based on three questions: “Did you need rest; Have 
you felt weak; Were you tired?”) 
• 
QLQ-C30: Appetite loss: one item (“Have you lacked appetite?”) 
 
In addition, physical and role functioning and overall global health status/QoL domains of the 
EORTC-CT30 are furthermore pre-specified endpoints of interest. 
Summaries of original and change from baseline values of each symptom scale/item, the 
global HRQoL score, and each functional domain will be reported by assessment timepoint 
for each treatment group. Graphical presentations may also be produced as appropriate. 
Summaries of the number and percentage of patients in each response category at each 
assessment timepoint for each ordinal item (in terms of the proportion of patients in the 
categories of improved, stable, and worsened as defined in Table 18) will also be produced for 
each treatment group. 
Changes from baseline will analyzed using a linear mixed model for repeated measures 
analysis for each assessment time point (for primary PRO measures only). 
Time to deterioration will be analyzed for each of the symptom scales/items, function scales, 
and global health status/QoL using a stratified log-rank test as described for the primary 
analysis of PFS. The HR and 95% CI for each scale/item will be presented graphically on a 
forest plot. 
For each of the symptom scales/items, functional scales, and global health status/QoL, time to 
deterioration will be presented using a Kaplan-Meier plot. Summaries of the number and 
percentage of patients experiencing a clinically relevant deterioration as well as who are 
censored will also be provided along with the medians for each treatment group. 
Additional analyses and data visualizations may be considered. Further details will be 
provided in the SAP. 

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9.5.2 
Safety analyses 
Safety and tolerability will be presented overall for the initial therapy phase and by treatment 
arm for the maintenance phase.  
A brief overview of safety data during the initial therapy period will be summarized using the 
initial therapy phase SAF; details of these summaries will be provided in the SAP. 
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For the maintenance phase SAF, data from all cycles will be combined in the presentation of 
safety data. AEs (both in terms of MedDRA preferred terms and CTCAE grade) will be listed 
individually by patient. The number and percentage of patients experiencing each AE will be 
summarized by treatment arm and CTCAE grade. Additionally, data presentations of the rate 
of AEs per person-years at risk may be produced. Any safety summaries examining 
retreatment with durvalumab will be produced separately as described in the SAP. 
Other safety data will be assessed in terms of physical examination, serum chemistry, 
hematology, urinalysis, vital signs, and ECGs. Exposure to each study treatment, time on 
study, dose delays, and dose reductions will also be summarized. At the end of the study, 
appropriate summaries of all safety data will be produced, as defined in the SAP. 
9.5.3 
Pharmacokinetic data 
PK concentration data for durvalumab will be listed for each patient and each PK sampling 
timepoint, and a summary will be provided for all evaluable patients. 
9.5.4 
Immunogenicity data 
Immunogenicity results will be listed by patient, and a summary will be provided by the 
number and percentage of patients who develop detectable anti-durvalumab antibodies. The 
immunogenicity titer and neutralizing ADA data will be listed for samples confirmed positive 
for the presence of anti-durvalumab antibodies. 
The effect of immunogenicity as well as the effect of its neutralizing properties on PK, 
efficacy, and safety may be evaluated, if the data allow. 
 
 
 
  
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI

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The primary endpoint of PFS (FAS) will be tested at 1 primary analysis of PFS. The key 
secondary endpoint, OS (FAS), will be tested at 2 timepoints: 1 interim analysis and 1 final 
analysis. The test at the primary analysis of PFS (FAS) (ie, shown in Box 1 in Figure 8) will 
be considered as 1 test family, as will the tests for the interim analysis and final analysis of 
OS. As long as 1 test in the family can be rejected, the family is rejected. Thus, the assigned 
total alpha to the family will be recycled to the next MTP level. Details of the interim analyses 
are provided in Section 9.6. 
Figure 8 shows the multiple testing framework. The details of the multiple testing procedure 
will be provided in the SAP. 
Figure 8 
Multiple testing procedure 
 
FAS  Full analysis set; OS  Overall survival; PFS  Progression-free survival. 
 
9.6 
Interim analyses  
A primary analysis for PFS will occur at approximately 163 events. If the PFS analysis occurs 
at exactly 163 events, a significant result will be declared if the OS HR is 0.74. Assuming 
non-uniform randomization, a median PFS of 8 months for the durvalumab monotherapy arm 
and an exponential distribution, randomization of 250 patients in 15 months would be 
expected to yield 163 PFS events approximately 25 months after the first patient is 
randomized.  
There will be 1 interim analysis performed for OS. The OS interim will occur at the time of 
the primary analysis for PFS. It is anticipated that approximately 67% of the OS events will be 
available for this OS IA (approximately 109 of 163 OS events). With an alpha level of 5% and 

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if 67% of the OS events required at the time of the final OS analysis are available at the time 
of the interim (109/163 OS events have occurred) and the final analysis occurs once 163 OS 
events are reached, then the 2-sided significance levels of 0.012 and 0.046 will be applied to 
the interim and final analysis for OS, respectively. If the interim analysis occurs at exactly 
109/163 OS events and the final analysis for OS occurs once 163 OS events are reached, a 
significant result will be declared if the OS HR is 0.62 at the interim or 0.73 at the final 
analysis.  
The recommendations from the IDMC will not reveal the results of the analysis but will take 
the form of “Continue/Modify/Stop”. 
The SAP will describe the planned interim analyses in greater detail. 
9.6.1 
Data monitoring committee 
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators. 
An IDMC will be established to perform an assessment of the safety of durvalumab plus 
olaparib therapy combinations in this population on an ongoing basis. The IDMC will be 
comprised of independent experts. The committee will meet at a frequency outlined in the 
IDMC Charter.  
IDMC members will be consulted to ensure appropriate frequency. Following each meeting, 
the IDMC will report to AstraZeneca and may recommend changes in the conduct of the 
study. 
Full details of the IDMC procedures, processes, and interim analyses can be found in the 
IDMC Charter.  

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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 

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Appendix A Regulatory, ethical and study oversight considerations 
A 1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
• 
Applicable laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), Investigator Brochure, and 
other relevant documents (eg, advertisements) must be submitted to an Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.  
The Investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• 
Notifying the IRB/IEC of serious adverse events or other significant safety findings as 
required by IRB/IEC procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples. 
A 2 
Financial disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 

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A 3 
Informed consent process 
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study.  
Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center.  
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative.  
 
 
If a patient’s partner becomes pregnant during the study or within 90 days after the last dose 
of durvalumab or 30 days after the last dose of olaparib/placebo (whichever is later), the 
partner is asked to sign the “Adult Study Informed Consent Form for Pregnant Partners of 
Study Patients”, and provide information about the pregnancy accordingly. 
 
 
 
 
 
 
 
 
 
 
CCI
CCI

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A 4 
Data protection 
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation. In some cases, such wording will be in a separate accompanying document. 
AstraZeneca will not provide individual genotype results to patients, their family members, 
their general physician, any insurance company, any employer, or any other third party, unless 
required to do so by law. 
Precautions are taken to preserve confidentiality and prevent genetic data from being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and might also have access to his or her genetic data. Also, regulatory authorities may 
require access to the relevant files. Even so, the patient’s medical information and the genetic 
files would remain physically separate. 
Each patient will be assigned a unique identifier by the Sponsor. Any patient records or data 
sets transferred to the Sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred.  
The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient.  
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
A 5 
Committees structure 
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and 
letters to Investigators. 
A 6 
Dissemination of clinical study data 
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical study and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the main study is 
conducted. 

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A 7 
Data quality assurance 
All patient data relating to the study will be recorded on printed or electronic case report form 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by physically 
or electronically signing the case report form (CRF).  
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor.  
A 8 
Source documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and 
evaluation of the study are defined as source documents. Source data are contained in source 
documents (original records or certified copies). 

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A 9 
Publication policy 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments.  
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multi-center studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 

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Appendix B Adverse event definitions and additional safety information 
B 1 
Definition of adverse events 
An adverse event (AE) is the development of any untoward medical occurrence (other than 
progression of the malignancy under evaluation) in a patient or clinical study patient 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, an 
abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
B 2 
Definitions of serious adverse event 
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, 
treatment, washout, follow-up), that fulfils 1 or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity.  
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardize the patient or may require medical 
treatment to prevent 1 of the outcomes listed above. 
Regulatory reporting requirements for serious adverse event 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both local authority and other regulatory 
agencies about the safety of a study intervention under clinical investigation. The Sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, institutional review boards (IRBs)/independent ethics committees (IECs), 
and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 

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An Investigator who receives a safety report describing an SAE or other safety information 
(eg, summary of listing of SAEs) from the Sponsor will review and then file it along with the 
Investigator’s Brochure and will notify the IRB/IEC if appropriate according to local 
requirements. 
B 3 
Life threatening 
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure). 
B 4 
Hospitalization 
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the patient was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study. 
B 5 
Important medical event or medical treatment 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the patient or may require 
medical treatment to prevent 1 or more outcomes listed in the definition of serious. These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used. 
• 
Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse 
B 6 
CTCAE grade 
The grading scales found in the revised National Cancer Institute Common Terminology 
Criteria for Adverse Event (CTCAE) latest version will be utilized for all events with an 

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assigned CTCAE grading. For those events without assigned CTCAE grades, the criteria 
recommended in the CTCAE manual that converts severity levels into CTCAE grades should 
be used. A copy of the CTCAE can be downloaded from the Cancer Therapy Evaluation 
Program website (http://ctep.cancer.gov). The applicable version of CTCAE should be 
described clearly. 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Appendix B 2. 
B 7 
A guide to interpreting the causality question 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
• 
Time Course. Exposure to suspect drug. Has the patient actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
• 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
• 
No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors. 
• 
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge. 
• 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognized feature of overdose of the drug? 
• 
Is there a known mechanism? 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 

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‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 
B 8 
Medication error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error.  
• 
occurred 
• 
was identified and intercepted before the participant received the drug 
• 
did not occur, but circumstances were recognized that could have led to an error 
Examples of events to be reported in clinical studies as medication errors: 
• 
Drug name confusion 
• 
Dispensing error (eg, medication prepared incorrectly, even if it was not actually given to 
the participant) 
• 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
• 
Drug not taken as indicated (eg, tablet dissolved in water when it should be taken as a 
solid tablet)  
• 
Drug not stored as instructed (eg, kept in the fridge when it should be at room 
temperature)  
• 
Wrong participant received the medication (excluding interactive voice response system 
[IVRS]/interactive web response system [IWRS] errors) 
• 
Wrong drug administered to participant (excluding IVRS/IWRS errors) 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting from IVRS/IWRS - including those which lead to 1 of the 
above listed events that would otherwise have been a medication error  

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• 
Participant accidentally missed drug dose(s) (eg, forgot to take medication) 
• 
Accidental overdose (will be captured as an overdose) 
• 
Participant failed to return unused medication or empty packaging 
• 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product  
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 

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Appendix C Handling of human biological samples 
C 1 
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Investigator at each center keeps full traceability of collected biological samples from the 
patients while in storage at the center until shipment or disposal (where appropriate). 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers. 
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks and will 
be registered by the AstraZeneca Biobank Team during the entire life cycle. 
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner. 
C 2 
Withdrawal of informed consent for donated biological samples  
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent. 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed, 
AstraZeneca is not obliged to destroy the results of this research. 
As collection of the biological sample(s) is an integral part of the study, then the patient is 
withdrawn from further study participation. 
The Investigator: 
• 
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca 
• 
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action documented 
• 
Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented, 
and the study site informed 
• 
Ensures that the patient and AstraZeneca are informed about the sample disposal 

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AstraZeneca ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action is 
documented and the study site is informed. 
C 3 
International Airline Transportation Association 6.2 guidance 
document 
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories (http://www.iata.org/whatwedo/cargo/dgr/pages/index.aspx). For transport 
purposes the classification of infectious substances according to risk groups was removed 
from the Dangerous Goods Regulations in the 46th edition (2005). Infectious substances are 
now classified either as Category A, Category B, or Exempt. There is no direct relationship 
between Risk Groups and Categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are eg, Ebola, Lassa fever virus: 
• 
are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses and 
human immunodeficiency virus types 1 and 2. They are assigned the following UN number 
and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
are to be packed in accordance with UN 3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
• 
Clinical study samples will fall into Category B or exempt under IATA regulations 
• 
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dgr/pages/index.aspx) 
• 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
• 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable 
• 
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 

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containment standards are encouraged wherever possible when road or rail transport is 
used. 

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CCI

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CCI

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CCI

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CCI

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Appendix E Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s law 
E 1 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law (HL). It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries. Specific guidance on managing liver 
abnormalities can be found in the Dosing Modification and Toxicity Management Guidelines 
(see Section 8.4.5). 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory.   
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than drug-induced liver injury (DILI) caused by the investigational product (IP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes. 
E 2 
Definitions 
Potential Hy’s law (PHL) 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 × upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in alkaline phosphatase 
(ALP).  

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Hy’s law (HL) 
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
IP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame within which the 
elevations in transaminases and TBL must occur. 
E 3 
Identification of potential Hy’s law cases 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT ≥3 × ULN 
• 
AST ≥3 × ULN 
• 
TBL ≥2 × ULN 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• 
Determine whether the patient meets PHL criteria (see Appendix E 2 for definition) by 
reviewing laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory case report form (CRF) 
E 4 
Follow-up 
E 4.1 
Potential Hy’s law criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol. 
E 4.2 
Potential Hy’s law criteria met 
If the patient does meet PHL criteria the Investigator will: 
• 
Notify the AstraZeneca representative who will then inform the central Study Team  
• 
Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting. 
• 
For subjects that met PHL criteria prior to starting IMP, the investigator is not required to 
submit a PHL SAE unless there is a significant change# in the subject’s condition 

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• 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data. 
• 
Subsequent to this contact the Investigator will: 
• 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated  
• 
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. 
• 
Complete the 3 Liver CRF Modules as information becomes available  
# A ‘significant’ change in the subject’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or total 
bilirubin) in isolation or in combination, or a clinically relevant change in associated 
symptoms.  The determination of whether there has been a significant change will be 
at the discretion of the Investigator, this may be in consultation with the Study 
Physician if there is any uncertainty. 
E 5 
Review and assessment of potential Hy’s law cases 
The instructions in this section should be followed for all cases where PHL criteria are met. 
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the IP, 
to ensure timely analysis and reporting to health authorities within 15 calendar days from date 
PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and Global Safety 
Physician will also be involved in this review together with other patient matter experts as 
appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
• 
If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AstraZeneca standard processes. 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP: 

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• 
Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  
− 
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made: 
• 
Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term ‘Potential Hy’s Law’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting. 
• 
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the previously submitted PHL SAE report following 
CSP process for SAE reporting, according to the outcome of the review amending the 
reported term if an alternative explanation for the liver biochemistry elevations is 
determined. 
E 6 
Actions required for repeat episodes of potential Hy’s law 
This section is applicable when a patient meets PHL criteria on study treatment, and has 
already met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study (eg, chronic or progressing malignant disease, severe infection or liver 
disease)? 
If No: Follow the process described in Appendix E 4.1 for reporting PHL as an SAE. 
If Yes: Determine if there has been a significant change in the patient’s condition# compared 
with when PHL criteria were previously met 
• 
If there is no significant change, no action is required. 
• 
If there is a significant change, follow the process described in Appendix E 4. 

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#A ‘significant’ change in the patient’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination 
of whether there has been a significant change will be at the discretion of the Investigator; 
this may be in consultation with the Study Physician if there is any uncertainty. 

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Appendix F Guidelines for evaluation of objective tumor response using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid 
Tumors) 
Introduction 
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 guidelines (Eisenhauer et al 2009) for this study with regard to Investigator 
assessment of tumor burden including protocol-specific requirements for this study. 
Additional special guidance is provided for determination of confirmation of radiological 
progression. 
Definitions of measurable, non-measurable, target and non-target lesions 
Measurable: 
A lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
(except lymph nodes which must have short axis1diameter of ≥15 mm) with computed 
tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate 
repeated measurements. 
Non-measurable: 
• 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis diameter at baseline2). 
• 
Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, and abdominal masses/abdominal organomegaly identified 
by physical examination (manual palpation) that is not measurable by CT or MRI. 
• 
Previously irradiated lesions3  
• 
Brain metastasis 
Special cases: 
• 
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, 
can be considered measurable if the soft tissue component meets the definition of 
measurability. Blastic lesions are considered non-measurable. 
• 
Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in the 
same patient, these should be selected over cystic lesions as target lesions (TLs). 
                                                 
1 The short axis is defined as the longest axis perpendicular to long axis 
2 Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as non-target lesions (NTLs). 
3 Localised post-radiation changes which affect lesion sizes may occur. Therefore, lesions that have been 
previously irradiated are typically considered non-measurable and as NTL at baseline and followed up as part of 
the NTL assessment. 

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Target Lesions (TLs): 
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as TLs 
at baseline. Lymph nodes, in any location (local/regional and distant), are collectively 
considered as a single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, 
adrenal glands), a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each 
considered as a single organ. 
Only patients with measurable target disease at baseline should be included in the study.  
Tumor lesions selected for fresh screening biopsy should not be selected as target lesions, 
unless imaging occurred at least ~2 weeks after biopsy, allowing time for healing. 
Non-Target Lesions (NTLs): 
Additional measurable lesions not recorded as TLs and non-measurable lesions (or sites of 
disease) should be identified as NTLs at baseline. 
Imaging Modalities 
A summary of the imaging modalities to be used for RECIST 1.1 assessment of target lesions, 
non-target lesions, and new lesions is provided in Table 20. 
Table 20 
Summary of imaging modalities for tumor assessment 
Target lesions  
Non-target lesions 
New lesions 
CT (preferred) 
MRI 
CT (preferred) 
MRI 
Plain X-ray 
Chest X-ray 
CT (preferred) 
MRI 
Plain X-ray 
Chest X-ray 
Bone scan 
FDG-PET/CT 
CT  Computed tomography; FDG-PET/CT  18F-Fluoro-deoxyglucose positron emission tomography/CT; 
MRI  Magnetic resonance imaging.  
 
CT and MRI  
CT and MRI, each preferably with IV contrast, are generally considered to generate the best 
currently available and reproducible anatomical images for measurement of TL, assessment of 
NTL, and identification of any new lesions.  
It is recommended that IV contrast-enhanced CT examinations of the chest and abdomen 
(including the entire liver and both adrenal glands) will be used to assess tumor burden at 
baseline and follow-up visits. Any other areas of disease involvement (eg, pelvis, brain) 

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should be additionally imaged based on the signs and symptoms of individual patients. In 
patients who are sensitive to intravenous CT contrast, a non-contrast CT examination of the 
chest and an MRI with intravenous MRI contrast of the abdomen is appropriate. In patients 
with severely compromised renal function a non-contrast CT examination of the chest and 
abdomen is appropriate. For brain lesion assessment, MRI with IV contrast is the preferred 
method over IV contrast-enhanced CT. It is strongly recommended to maintain use of the 
same imaging modality (CT or MRI), acquisition protocol, facility and scanner across all 
imaging time points per patient. 
Clinical examination  
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST assessments. Tumors identified by clinical examination will need to 
be assessed by correlative CT or MRI anatomical scans. 
Chest X-ray 
Chest X-ray assessment will not be used for assessment of TL. Chest X-ray can, however, be 
used to assess NTL and to identify the presence of new lesions. 
Plain X-ray  
Plain X-ray may be used as a method of assessment for bone NTL and to identify the presence 
of new bone lesions.  
Ultrasound  
Ultrasound examination will not be used for RECIST assessment of tumors as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation and may 
not provide an accurate assessment of true tumor size. Tumors identified by ultrasound will 
need to be assessed by correlative CT or MRI anatomical scan. 
Endoscopy and laparoscopy  
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated 
in the context of tumor assessment. 
Tumor markers  
Tumor markers on cytological or histological (biopsy) samples will not be used for tumor 
response assessments as per RECIST 1.1. 
Histology and Cytology 
Histology on tumor biopsy samples will not be used as part of the tumor response assessment 
as per RECIST 1.1.  

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Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, pleural effusion) that appears or worsens during the study will not be 
used as part of the tumor response assessment in this study. An effusion that appears or 
significantly worsens (from trace to large) radiologically by CT/MRI anatomical scans will be 
considered to be disease progression due to new lesions or progression of NTLs, respectively. 
Isotopic bone scan  
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment.  
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. New lesions may be recorded in case positive hot-spots 
appear on a bone scan that were not present on a previous bone scan; however, a newly 
observed equivocal hot-spot on a bone scan which cannot be verified with correlative imaging 
(CT, MRI, X-ray) of the same anatomical region shall not be the only trigger for a PD 
assessment at that timepoint.  
FDG-PET/CT 
18F-Fluoro-deoxyglucose positron emission tomography/computed tomography/CT 
(FDG-PET/CT) scans may be used as a method for identifying new lesions, according to the 
following algorithm: New lesions will be recorded where there is positive 
18F-Fluoro-deoxyglucose uptake4 not present on baseline or prior FDG-PET scan or in a 
location corresponding to a new lesion on CT/MRI at the same follow-up visit. If there is no 
baseline or prior FDG-PET scan available, and no evidence of new lesions on CT/MRI scans 
then follow-up CT/MRI assessments should be continued, scheduled as per protocol or 
clinical indicated, in order to verify new lesions. 
At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT scan 
are of limited use in anatomically-based efficacy assessments, and it is therefore suggested 
that they should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumor 
measurements by RECIST 1.1. In exceptional situations, if a site can document that the CT 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with 
intravenous contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT 
can be used for RECIST 1.1 tumor assessments. Caution that this is not recommended because 
the PET portion of the CT introduces additional (PET) data that may bias an Investigator if it 
is not routinely or serially performed. 
                                                 
4 A positive FDG-PET scan lesion should be reported only when an uptake (eg, SUV) greater than twice that of 
the surrounding tissue or liver is observed. 

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Tumor response evaluation  
Target lesions 
Documentation of target lesions 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TL at baseline. Target lesions should be selected on the basis of their 
size (longest diameter for non-nodal lesions or short axis diameter for nodal lesions), but in 
addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion, which can be measured 
reproducibly, should be selected. 
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes). All measurements should be recorded in 
millimeters. At baseline the sum of the diameters for all TL will be calculated and reported as 
the baseline sum of diameters. At follow-up visits the sum of diameters for all TL will be 
calculated and reported as the follow-up sum of diameters. 
Special cases: 
• 
For TL measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter.  
• 
If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan. 
• 
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as a new 
lesion. 
• 
If a TL splits into two or more parts, then record the sum of the diameters of those parts.  
• 
If two or more TLs merge then the sum of the diameters of the combined lesion should be 
recorded for one of the lesions and 0 mm recorded for the other lesion(s).  
• 
If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm. 
• 
If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion.  
• 
When a TL has had any intervention eg, definitive radiotherapy, embolization, surgery, 
etc. during the study, the size of the TL should still be provided where possible and the 
intervention recorded in the RECIST case report form. If a TL has been completely 
removed (surgery), the longest diameter should be recorded as 0 mm. 

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Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL (see Table 21). 
Table 21 
Evaluation of target lesions 
Complete response (CR) 
Disappearance of all TLs since baseline. Any pathological lymph nodes 
selected as TLs must have a reduction in short axis diameter to <10 mm. 
Partial response (PR) 
At least a 30% decrease in the sum of the diameters of TL, taking as 
reference the baseline sum of diameters 
Stable disease (SD) 
Neither sufficient decrease in sum of diameters to qualify for PR nor 
sufficient increase to qualify for PD 
Progression of disease (PD) 
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest previous sum of diameters (nadir) – this includes 
the baseline sum if that is the smallest on study. In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm from nadir. 
Not evaluable (NE) 
Only relevant if any of the TLs at follow-up were not assessed or not 
evaluable (eg missing anatomy) or had a lesion intervention at this visit. 
Note: if the sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a TL response 
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; SD  Stable disease; 
TL  Target lesion. 
 
Non-target lesions 
Evaluation of non-target lesions 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline. Measurements are not required for these lesions, but their status should be followed 
at subsequent visits. At each visit an overall assessment of the NTL response should be 
recorded by the Investigator. This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit (see 
Table 22). 
Table 22 
Evaluation of non-target lesions 
Complete response (CR) 
Disappearance of all NTLs since baseline. All lymph nodes must be non-
pathological in size (<10 mm short axis). 
Non CR/non PD 
Persistence of one or more NTL. 
Progression (PD) 
Unequivocal progression of existing NTLs. Unequivocal progression 
may be due to an important progression in one lesion only or in several 
lesions. In all cases the progression MUST be clinically significant for 
the physician to consider changing (or stopping) therapy. 

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Table 22 
Evaluation of non-target lesions 
Not evaluable (NE) 
Only relevant when one or some of the NTLs were not assessed and, in 
the Investigator’s opinion, they are not able to provide an evaluable 
overall NTL assessment at this visit. 
Note: for patients without TLs at baseline, this is relevant if any of the 
NTLs were not assessed at this visit and the progression criteria have not 
been met. 
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; NTL  Non-target 
lesion; TL  Target lesion. 
 
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of stable disease or 
partial response in TLs, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more NTLs is usually not 
sufficient to qualify for unequivocal progression status. 
New lesions 
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression. The finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor. If a new lesion is 
equivocal, for example because of its small size, the treatment and tumor assessments should 
be continued until the previously new lesion has been assessed as unequivocal and then the 
progression date should be declared using the date of the initial scan when the new lesion first 
appeared. 
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
Symptomatic deterioration 
Symptomatic (clinical) deterioration is not a descriptor of an objective response: it is a reason 
for stopping study therapy. 
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective radiologic evidence of disease progression at that time should continue to undergo 
tumor assessments where clinically feasible. 
Evaluation of overall visit response 
The overall visit response will be derived using the algorithm shown in Table 23. 

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Table 23 
Overall visit response 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
NA 
CR 
No 
CR 
CR 
Non CR/Non PD  
No 
PR 
CR 
NE 
No  
PR 
PR 
Non PD or NE 
No 
PR 
SD  
Non PD or NE or NA 
No 
SD 
NA 
Non-CR/Non-PD 
No 
SD (Non-CR/non-PD) 
NE 
Non PD or NE or NA 
No 
NE 
NA 
NE 
No 
NE 
NA 
NA 
No 
NED 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR  Complete response; NA  Not applicable (only relevant if there were no target and/or non-target lesions at 
baseline); NE  Not evaluable; NED  No evidence of disease; PD  Progression of disease; PR  Partial response; 
SD  Stable disease.  
 
Confirmation of Radiological Progression 
A follow-up scan is collected after the initial RECIST 1.1-defined PD, preferably at the next 
(and no later than the next) scheduled imaging visit, and no less than 4 weeks after the prior 
assessment of PD, and the Confirmation of Radiological Progression criteria described below 
are applied for tumor assessments of this follow-up scan. Patients with confirmed radiological 
PD who continue to receive study treatment at the discretion of the Investigator and patient 
(following consultation with AstraZeneca) can receive treatment until no longer having 
clinical benefit, and will continue to have tumor assessments on their regular imaging 
schedule for the duration of treatment. 
Confirmation of radiological progression guidelines are set for the following reasons:  
• 
For patient management and treatment decisions 
• 
In the absence of significant clinical deterioration, to promote the collection of additional 
scans after the first radiologic RECIST 1.1 assessment of progressive disease (PD) in 
order to distinguish pseudoprogression from true radiologic progression. 
• 
When scans are evaluated by Investigator and by blinded independent central review 
(BICR), additional scans can reduce informative censoring by Investigator assessments (if 
the Investigator assesses PD but collects no follow-up scans, and the BICR reviewer does 
not identify RECIST PD among the available scans, then this patient would be censored 
for PFS by BICR). 

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Confirmation of Radiological Progression Criteria: 
An immediate prior RECIST 1.1-defined radiologic PD would be considered confirmed if any 
of the following criteria are met in the subsequent follow-up scan (acquired preferably at the 
next regularly scheduled imaging visit but no sooner than 4 weeks after the RECIST 1.1-
defined PD scan): 
• 
≥20% increase in the sum diameters of TLs compared with the nadir at 2 consecutive 
visits, each with an absolute increase of at least 5 mm in sum of diameters compared to 
nadir (as per RECIST 1.1 definition) 
• 
and/or significant progression (worsening) of NTLs at the follow-up scan timepoint 
compared with the immediate prior timepoint (as per RECIST 1.1 definition) 
• 
and/or significant progression (worsening) of pre-existing new lesions at the follow-up 
scan timepoint compared with the immediate prior timepoint (unique definition) 
• 
and/or additional (brand) new unequivocal lesions at the follow-up scan timepoint (as per 
RECIST 1.1 definition) 
NOTE: In order to have confirmed radiological progression, there should be two consecutive 
assessments meeting the PD definition: the first PD by RECIST 1.1 and the second PD using 
the Confirmation of Radiological Progression criteria (above). If the first assessment fulfilling 
the PD definition by RECIST 1.1 is not confirmed, in the absence of significant clinical 
deterioration, then the patient may continue with assessments until the next PD by RECIST 
1.1, which will also require a follow-up scan evaluated using the Confirmation of Radiological 
Progression criteria. If the first PD (by RECIST 1.1) is not confirmed by the immediate 
next scan, then the Investigator should not change the PD assessment of the first scan. 
Central Review 
All radiological scans, including unscheduled visit scans, will be collected on an ongoing 
basis and sent to an AstraZeneca-appointed contract research organization (CRO) for quality 
control and storage. Guidelines for image acquisition, de-identification, storage at the study 
site as source data, and transfer to the imaging CRO for central review will be provided in a 
separate document. Results of these independent reviews will not be communicated to 
Investigators, and results of Investigator RECIST 1.1 assessments will not be shared with the 
central reviewers. The management of patients will be based upon the results of the RECIST 
1.1 assessment conducted by the Investigator. Further details of the BICR will be documented 
in the Independent Review Charter (also referred to as ‘Imaging Charter’). 
Specifications for anatomical imaging 
These notes are recommendations for use in clinical studies. The use of standardized protocols 
for CT and MRI allows comparability both within and between different studies, irrespective 
of where the examination has been undertaken. 

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CT and MRI 
CT and MRI, each preferably with IV contrast, are generally considered to generate the best 
currently available and reproducible anatomical images for measurement of TL, assessment of 
NTL, and identification of new lesions.  
For standard RECIST 1.1 assessments, it is recommended that IV contrast-enhanced CT 
examinations of the chest, abdomen (including the entire liver and both adrenal glands), and 
pelvis will be used to assess tumor burden at baseline and follow-up visits. It is strongly 
encouraged to acquire follow-up scans using the same modality (CT/MRI) and acquisition 
parameters that were used at baseline. In patients who are sensitive to IV CT contrast, a 
non-contrast CT examination of the chest and an MRI with IV MRI contrast of the abdomen 
and pelvis is appropriate. In patients who develop sensitivity to both CT and MRI IV contrast 
or severely compromised renal function, a non-contrast CT examination of the chest, 
abdomen, and pelvis is appropriate. Any other areas of disease involvement (eg, brain) should 
be additionally imaged based on the signs and symptoms of individual patients. For brain 
lesion assessment, MRI with IV contrast is the preferred method over IV contrast-enhanced 
CT. 
CT and MRI scans – General Guidance 
CT scans of the chest, abdomen, and pelvis should be contiguous throughout all the anatomic 
region of interest. The most critical CT and MRI image acquisition parameters for optimal 
tumor evaluation using RECIST 1.1 are anatomic coverage, contrast administration, slice 
thickness, and reconstruction interval. 
MRI has excellent contrast, spatial and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, 
and measurement. Furthermore, the availability of MRI is variable globally. The modality 
used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. Generally, axial imaging of the abdomen and 
pelvis (and other anatomies, eg, neck) with T1 and T2 weighted imaging preferably with fat 
suppression along with T1 weighted imaging with fat suppression following IV injection of 
gadolinium-based contrast agent is performed. The field of view, matrix, number of 
excitations, phase encoding steps, use of fat suppression and fast sequences should be 
optimized for the specific body part being imaged as well as the scanner utilized. CT of the 
chest is typically recommended over MRI due to significant motion artifacts (heart, major 
blood vessels, breathing) associated with MRI. It is beyond the scope of this appendix to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. 
Ideally, the same scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans for each patient. Body scans should be 
performed with breath-hold scanning techniques if possible. For these reasons, CT is the 
imaging modality of choice. 

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a. Anatomic coverage: Optimal anatomic coverage for most solid tumors is the chest, 
abdomen, and pelvis. Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual patients. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, careful consideration should be given to the extent of 
imaging coverage at baseline and at subsequent follow-up time points. This will enable better 
consistency not only of tumor measurements but also identification of new disease. 
b. IV contrast administration: Optimal visualization and measurement of metastases in solid 
tumors requires consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. An adequate volume of a suitable contrast agent should be given so that the tumor 
lesions are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given patient. Oral contrast is recommended to help visualize and 
differentiate structures in the abdomen and pelvis.  
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) with ≤5 mm slice thickness for optimal lesion 
measurements. Exceptionally, particular institutions may perform medically acceptable scans 
at slice thicknesses greater than 5 mm. If this occurs, the minimum size of measurable lesions 
at baseline should be twice the slice thickness of the baseline scans. 
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study. 
References 
Eisenhauer et al 2009 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47. 

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Appendix G Olaparib toxicity management instructions 
Management of hematological toxicity 
Management of anemia 
Table 24 
Management of anemia 
Hemoglobin 
Action to be taken 
Hb <10 g/dL but ≥8 g/dL 
(CTCAE Grade 2) 
First occurrence (after patient has initiated olaparib/placebo treatment): 
Give appropriate supportive treatment, and investigate causality. 
Investigator judgment to continue olaparib with supportive treatment (eg, 
transfusion) or interrupt dose for a maximum of 4 weeks. Study treatment can be 
restarted if Hb has recovered to >9 g/dL. 
Subsequent occurrences: 
If Hb <10 g/dL but ≥9 g/dL, Investigator judgment to continue olaparib with 
supportive treatment (eg, transfusion) or interrupt dose (for a maximum of 4 
weeks), and upon recovery dose reduction may be considered (to 250 mg BID as a 
first step and to 200 mg BID as a second step). 
If Hb <9 g/dL but ≥8 g/dL, interrupt dose (for a maximum of 4 weeks) until Hb ≥9 
g/dL and upon recovery dose reduction may be considered (to 250 mg BID as a 
first step and to 200 mg BID as a second step). 
Hb <8 g/dL (CTCAE 
Grade 3) 
Give appropriate supportive treatment (eg, transfusion), and investigate causality. 
Interrupt olaparib for a maximum of 4 weeks, until improved to Hb ≥9 g/dL. 
Upon recovery reduce dose to 250 mg BID as a first step and to 200 mg BID as a 
second step in the case of repeat Hb decrease. 
BID  Twice daily; CTCAE  Common Terminology Criteria for Adverse Events; Hb  Hemoglobin. 
 
Common treatable causes of anemia (eg, iron, vitamin B12 or folate deficiencies, and 
hypothyroidism) should be investigated and appropriately managed. In some cases, 
management of anemia may require blood transfusions. For cases where patients develop 
prolonged hematological toxicity (≥2 week interruption/delay in study treatment due to 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or worse anemia and/or 
development of blood transfusion dependence), refer to guidance later in this section for 
management. 
Management of neutropenia, leukopenia, and thrombocytopenia 
Table 25 
Management of neutropenia, leukopenia, and thrombocytopenia 
Toxicity 
Study treatment dose adjustment 
CTCAE Grades 1-2 
Investigator judgment to continue treatment or if dose 
interruption, this should be for a maximum of 4 weeks; 
appropriate supportive treatment and causality 
investigation. 

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Toxicity 
Study treatment dose adjustment 
CTCAE Grades 3-4 
Dose interruption until recovered to CTCAE Grade 1 
or better for a maximum of 4 weeks. 
If repeat CTCAE Grades 3-4 occurrence, reduce 
olaparib to 250 mg BID as a first step and 200 mg BID 
as a second step. 
BID  Twice daily; CTCAE  Common Terminology Criteria for Adverse Events. 
 
Adverse events (AEs) of neutropenia and leukopenia should be managed as deemed 
appropriate by the Investigator with close follow-up and interruption of study drug if 
neutropenia CTCAE Grade 3 or worse occurs. 
Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is not 
recommended. However, if a patient develops febrile neutropenia, study treatment should be 
stopped and appropriate management including G-CSF should be given according to local 
hospital guidelines. Please note that G-CSF should not be used within at least 24 hours (7 days 
for pegylated G-CSF) of the last dose of study treatment unless absolutely necessary. 
Platelet transfusions, if indicated, should be done according to local hospital guidelines. 
For cases where patients develop prolonged hematological toxicity (≥2 week 
interruption/delay in study treatment due to CTCAE Grade 3 or worse), refer to guidance later 
in this section for management. 
Management of prolonged hematological toxicities while on study treatment 
If a patient develops prolonged hematological toxicity such as the following: 
• 
≥2-week interruption/delay in study treatment due to CTCAE Grade 3 or worse anemia 
and/or development of blood transfusion dependence 
• 
≥2-week interruption/delay in study treatment due to CTCAE Grade 3 or worse 
neutropenia (absolute neutrophil count <1 × 109/L) 
• 
≥2-week interruption/delay in study treatment due to CTCAE Grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (platelets 
<50 × 109/L) 
Check weekly differential blood counts including reticulocytes and peripheral blood smear. If 
any blood parameters remain clinically abnormal after 4 weeks of dose interruption, the 
patient should be referred to hematologist for further investigations. Bone marrow analysis 
and/or blood cytogenetic analysis should be considered at this stage according to standard 
hematological practice. Study treatment should be discontinued if blood counts do not recover 
to at least CTCAE Grade 1 within 4 weeks of dose interruption. 

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Development of a confirmed myelodysplastic syndrome (MDS) or other clonal blood disorder 
should be reported as a serious AE and full reports must be provided by the Investigator to 
AstraZeneca Patient Safety. Olaparib treatment should be discontinued if patient’s diagnosis 
of MDS and/or acute myeloid leukemia is confirmed. 
Management of non-hematological toxicity 
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each 
occasion. If the interruption is any longer than this, the Study Monitor must be informed. 
Where toxicity reoccurs following re-challenge with study treatment, and where further dose 
interruptions are considered inadequate for management of toxicity, the patient should be 
considered for dose reduction or must permanently discontinue study treatment. 
Study treatment dose can be reduced to 250 mg twice daily (BID) as a first step and to 200 mg 
BID as a second step. Treatment must be interrupted if any National Cancer Institute CTCAE 
Grade 3 or 4 AE occurs that the Investigator considers to be related to administration of study 
treatment. 
Management of new or worsening pulmonary symptom 
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormalities occur 
in the absence of a clear diagnosis, an interruption in study treatment dosing is recommended 
and further diagnostic workup (including a high-resolution computed tomography [CT] scan) 
should be performed to exclude pneumonitis. Please also refer to the durvalumab toxicity 
management guidelines below. 
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then study treatment can be restarted, if deemed appropriate by the 
Investigator. If significant pulmonary abnormalities are identified, these need to be discussed 
with the Study Physician. 
Management of nausea and vomiting 
Events of nausea and vomiting are known to be associated with olaparib treatment. These 
events are generally mild to moderate (CTCAE Grade 1 or 2) in severity, intermittent, and 
manageable on continued treatment. The first onset generally occurs in the first month of 
treatment for nausea and within the first 6 months of treatment for vomiting. For nausea, the 
incidence generally plateaus at around 9 months, and for vomiting at around 6 to 7 months. 
No routine prophylactic anti-emetic treatment is required at the start of study treatment; 
however, patients should receive appropriate anti-emetic treatment at the first onset of nausea 
or vomiting and as required thereafter, in accordance with local treatment practice guidelines. 
Alternatively, olaparib tablets can be taken with a light meal/snack (ie, 2 pieces of toast or a 
couple of biscuits). 

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As per international guidance on anti-emetic use in cancer patients (European Society for 
Medical Oncology and National Comprehensive Cancer Network), generally a single-agent 
anti-emetic should be considered (eg, dopamine receptor antagonist, antihistamines, or 
dexamethasone). 
Interruptions for intercurrent non-toxicity related events 
Study treatment dose interruption for conditions other than toxicity resolution should be kept 
as short as possible. If a patient cannot restart study treatment within 4 weeks for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with AstraZeneca Study Physician. 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the electronic case report form. 
Olaparib treatment should be stopped at least 3 days prior to planned surgery. After surgery 
study treatment can be restarted when the wound has healed. No stoppage of olaparib 
treatment is required for any needle biopsy procedure. 
Olaparib treatment should be discontinued for a minimum of 3 days before a patient 
undergoes radiation treatment. Olaparib treatment should be restarted within 4 weeks as long 
as any bone marrow toxicity has recovered. 
Because the AEs related to olaparib may include asthenia, fatigue, and dizziness, patients 
should be advised to use caution while driving or using machinery if these symptoms occur. 
Table 26 
Dose reductions for study treatment 
Initial dose 
Following re-challenge post 
interruption: Dose reduction 1 
Dose reduction 2 
300 mg BID 
250 mg BID 
200 mg BID 
BID - Twice daily. 
 
Renal impairment 
If subsequent to study entry and while still on study therapy, a patient’s estimated creatine 
clearance (CrCl) falls below the threshold for study inclusion (≥51 mL/min), retesting should 
be performed promptly. 
A dose reduction is recommended for patients who develop moderate renal impairment 
(calculated CrCl either by Cockcroft-Gault equation or based on a 24-hour urine test) of 
≥31 mL/min but <51 mL/min for any reason during the course of the study: the dose of 
olaparib should be reduced to 200 mg BID. 

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Because the CrCl determination is only an estimate of renal function, in instances where the 
CrCl falls to ≥31 mL/min but <51 mL/min, the Investigator should use his or her discretion in 
determining whether a dose change or discontinuation of therapy is warranted. 
Olaparib has not been studied in patients with severe renal impairment (≤30 mL/minute) or 
end-stage renal disease; if patients develop severe impairment or end-stage disease it is 
recommended that olaparib be discontinued. 

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Appendix H Patient-reported outcomes 
This appendix includes example copies of the following patient-reported outcome (PRO) 
questionnaires: 
• 
European Organisation for Research and Treatment of Cancer (EORTC) 30-item Core 
Quality of Life Questionnaire 
• 
EORTC 13-item Lung Cancer Quality of Life Questionnaire 
 
t 
 
 
 
 
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Appendix I 
Abbreviations 
Abbreviation or special 
term 
Explanation 
1L 
first line 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BICR 
blinded independent central review 
BID 
twice daily 
BP 
blood pressure 
BRCA 
breast cancer susceptibility gene 
BRCAm 
BRCA gene mutation 
C 
cycle 
CCTG 
Canadian Cancer Trials Group 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
COA 
Clinical Outcome Assessment 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form 
CRO 
contract research organization 
CRT 
chemoradiation therapy 
CSR 
clinical study report 
CT 
computed tomography 

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Abbreviation or special 
term 
Explanation 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Event 
 
 
CTLA-4 
cytotoxic T lymphocyte-associated antigen-4 
Ctrough 
trough concentration 
CYP 
cytochrome P450 
D 
day 
DCO 
data cut-off 
DCR 
disease control rate 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DoR 
duration of response 
DSB 
double strand break 
EC 
ethics committee, synonymous to institutional review board (IRB) and 
independent ethics committee (IEC) 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDoR 
expected duration of response 
EGFR 
epidermal growth factor receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
end of therapy 
ePRO 
electronic patient-reported outcome 
 
 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin embedded 
gBRCAm 
germline BRCA mutation 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GI 
gastrointestinal 
GMP 
Good Manufacturing Practice 
H0 
null hypothesis 
H1 
alternative hypothesis 
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Abbreviation or special 
term 
Explanation 
Hb 
hemoglobin 
HBsAg 
HBV surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HL 
Hy’s Law 
 
 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
HRR 
homologous recombination repair 
HRRm 
homologous recombination repair related gene mutation 
IASLC 
International Association for the Study of Lung Cancer 
IATA 
International Airline Transportation Association 
IB 
Investigator Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
 
 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IM 
intramuscular 
imAE 
immune-mediated adverse event 
INR 
International Normalized Ratio 
International Co-ordinating 
Investigator 
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the Investigators and/or activities 
internationally.  
IO 
immuno-oncology 
IP 
investigational product 
IRB 
Institutional Review Board 
ITT 
intent to treat 
IV 
intravenous 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
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Abbreviation or special 
term 
Explanation 
KM 
Kaplan-Meier 
LFT 
liver function test 
LIMS 
laboratory information management system 
mAb 
monoclonal antibody 
MATE 
multidrug and toxin extrusion protein 
MDS 
myelodysplastic syndrome 
MEDI4736 
durvalumab 
MMRM 
mixed-effect model repeated measure 
MOA 
mechanism of action 
MRI 
magnetic resonance imaging 
 
 
NA 
Not applicable 
Nab 
Nanoparticle albumin-bound 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
not evaluable 
NED   
no evidence of disease 
NSCLC 
non-small cell lung cancer 
NTL 
Non-target lesion 
OAT 
organic anion transporter 
OATP 
organic-anion-transporting polypeptide 
OCT 
organic cation transporter 
ORR 
objective response rate 
OS 
overall survival 
PARP 
polyadenosine 5’diphosphoribose [poly (ADP ribose)] polymerase 
 
 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death-ligand 1 
PD-L2 
programmed cell death-ligand 2 
PFS 
progression-free survival 
 
 
PHL 
potential Hy’s Law 
PI 
Principal Investigator  
PK 
pharmacokinetic(s) 
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Abbreviation or special 
term 
Explanation 
PR 
partial response 
PRO 
patient-reported outcome 
PS 
performance status 
q12w 
every 12 weeks 
q2w 
every 2 weeks 
q3w 
every 3 weeks 
q4w 
every 4 weeks 
q8w 
every 8 weeks 
QLQ-C30 
30-item Core Quality of Life Questionnaire 
QLQ-LC13 
13-item Lung Cancer Quality of Life Questionnaire 
QoL 
quality of life 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
R 
Randomization 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
 
 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SAF 
safety analysis set 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SoAs 
schedule(s) of activities 
SoC 
standard of care 
sPD-L1 
soluble programmed death-ligand 1 
S/R 
scan, analyze, randomize 
SSB 
single strand break 
T3 
triiodothyronine 
T4 
thyroxine 
TBL 
total bilirubin 
TC 
tumor cells 
TKI 
tyrosine kinase inhibitor 
TL 
target lesion 
 
 
TMG 
toxicity management guideline 
TNF 
tumor necrosis factor 
TSH 
thyroid stimulating hormone 
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Abbreviation or special 
term 
Explanation 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 
w 
week 
WBDC 
Web Based Data Capture 
WHO 
World Health Organization 
WT 
weight 
w/v 
weight/volume