Conditions: Prostate Adenocarcinoma Without Neuroendocrine Differentiation Stage I Prostate Cancer AJCC v8 Stage II Prostate Cancer AJCC v8 Stage IIA Prostate Cancer AJCC v8 Stage IIB Prostate Cancer AJCC v8 Stage IIC Prostate Cancer AJCC v8
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
This phase II trial studies how well olaparib works in treating participants with prostate cancer that has not spread to other parts of the body (localized). Olaparib may stop the growth of tumor cells by interfering with the activity of a substance called PARP, which is inside cells. Giving olaparib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed description:
PRIMARY OBJECTIVE:

I. To assess the pathological complete response rate following olaparib when administered as neoadjuvant therapy prior to prostatectomy in patients with localized prostate cancer containing homozygous or complementary deoxyribonucleic acid \[DNA\] repair deficiency.

SECONDARY OBJECTIVE:

I. To determine the rate of positive surgical margins, extracapsular extension, positive seminal vesicles and lymph nodes at the time of prostatectomy.

OUTLINE:

Participants receive olaparib orally twice daily for 90 days in the absence of unacceptable toxicity. Beginning 1 day after last olaparib dose, participants undergo radical prostatectomy.

After completion of study treatment, participants are followed up for 30 days.

Arms:
arm 1: Participants receive olaparib orally twice daily for 90 days in the absence of unacceptable toxicity. Beginning 1 day after last olaparib dose, participants undergo radical prostatectomy.

Interventions: intervention 1: Olaparib intervention 2: Radical Prostatectomy
Intervention descriptions: intervention 1: Given orally intervention 2: Undergo surgery

Protocol document:
Prot_SAP_001.pdf: 
1(61) 
Drug Substance 
Olaparib (AZD2281, KU-0059436) 
Study Number:                      
Consortium Study Number:  
ESR-16-11851 
9985 
Version Number 
4.0 
Date 
04/12/2020 
Open-Label, Pilot Study of Olaparib as a Neoadjuvant Therapy for Patients 
Undergoing Prostatectomy for Localized Prostate Cancer 
Sponsor-Investigator:  Robert Bruce Montgomery, M.D. 
 
 
IRB received 04/15/20
FHCRC IRB Approval  
APR 23 2020 
Document Released Date


Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Consortium Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
 
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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ........................................................................................................... 1 
TABLE OF CONTENTS ......................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................ 7 
1. 
INTRODUCTION ................................................................................................... 8 
1.1 
Background .............................................................................................................. 8 
1.2 
Olaparib .................................................................................................................. 10 
1.2.1 
Pre-clinical experience ........................................................................................... 11 
1.2.2 
Toxicology and safety pharmacology summary .................................................... 11 
1.2.3 
Clinical experience ................................................................................................. 11 
1.3 
Research hypothesis ............................................................................................... 14 
1.4 
Rationale for conducting this study ....................................................................... 14 
1.5 
Benefit/risk and ethical assessment ........................................................................ 15 
2. 
STUDY OBJECTIVES .......................................................................................... 16 
2.1 
Primary objective ................................................................................................... 16 
2.2 
Secondary objective ............................................................................................... 16 
2.3 
Exploratory objectives ........................................................................................... 16 
3. 
STUDY PLAN AND PROCEDURES .................................................................. 17 
3.1 
Overall study design and flow chart ...................................................................... 17 
3.2 
Rationale for study design, doses and control groups ............................................ 18 
4. 
PATIENT SELECTION CRITERIA ..................................................................... 20 
4.1 
Inclusion criteria .................................................................................................... 20 
4.2 
Exclusion criteria ................................................................................................... 21 
5. 
STUDY CONDUCT .............................................................................................. 23 
5.1 
Restrictions during the study.................................................................................. 23 
5.1.1 
Grapefruit juice ...................................................................................................... 23 
5.1.2 
Contraception ......................................................................................................... 23 
5.1.3 
Androgen deprivation ............................................................................................ 23 
5.2 
Subject enrollment and initiation of investigational product ................................. 23 
5.3 
Procedures for handling subjects incorrectly enrolled or initiated on 
investigational product ........................................................................................... 23 


Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Consortium Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
 
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5.4 
Treatments .............................................................................................................. 23 
5.4.1 
Enrollment procedure ............................................................................................. 23 
5.4.2 
Study Evaluations .................................................................................................. 24 
5.4.3 
Day 30 (± 5 Days), 60 (± 5 Days) 90 (± 5 Days) Visits ........................................ 25 
5.4.4 
Radical prostatectomy ............................................................................................ 25 
5.4.5 
End of study visit (Day 120 (± 5 Days) ................................................................. 25 
5.4.6 
Early Termination Visit (Early Cessation of Study Drug) ..................................... 25 
5.4.7 
Identity of investigational product ......................................................................... 26 
5.4.8 
Dose and treatment regimen .................................................................................. 26 
5.4.9 
Storage ................................................................................................................... 27 
5.4.10 
Management of toxicity of olaparib ....................................................................... 27 
5.4.11 
Management of hematological toxicity.................................................................. 28 
5.4.11.1 Management of anemia .......................................................................................... 28 
5.4.11.2 Management of neutropenia, leukopenia and thrombocytopenia .......................... 28 
5.4.11.3 Management of prolonged hematological toxicities while on study 
treatment................................................................................................................. 29 
5.4.12 
Management of non-hematological toxicity .......................................................... 29 
5.4.12.1 Management of new or worsening pulmonary symptoms ..................................... 30 
5.4.12.2 Management of nausea and vomiting .................................................................... 30 
5.4.12.3 Interruptions for intercurrent non-toxicity related events ...................................... 30 
5.5 
Concomitant and post-study treatment(s) .............................................................. 31 
5.5.1 
Medications that may NOT be administered ......................................................... 33 
5.6 
Treatment compliance ............................................................................................ 33 
5.6.1 
Accountability ........................................................................................................ 33 
5.7 
Discontinuation of investigational product ............................................................ 33 
5.7.1 
Procedures for discontinuation of a subject from investigational product............. 33 
5.8 
Withdrawal from study .......................................................................................... 34 
6. 
COLLECTION OF STUDY VARIABLES ........................................................... 34 
6.1 
Recording of data ................................................................................................... 34 
6.2 
Efficacy .................................................................................................................. 34 
6.3 
Safety ..................................................................................................................... 34 
6.3.1 
Definition of adverse events .................................................................................. 34 
6.3.2 
Olaparib adverse events of special interest ............................................................ 34 
6.3.3 
Definitions of serious adverse event ...................................................................... 35 
6.3.4 
Recording of adverse events .................................................................................. 35 
6.3.4.1 
Adverse events after the 30 day follow up period ................................................. 35 
6.3.5 
Reporting of serious adverse events ....................................................................... 38 
6.3.6 
Laboratory safety assessment................................................................................. 39 
6.3.7 
Physical examination ............................................................................................. 40 
6.3.8 
ECG ........................................................................................................................ 40 


Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Consortium Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
 
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6.3.8.1 
Resting 12-lead ECG ............................................................................................. 40 
6.3.9 
Vital signs .............................................................................................................. 41 
6.3.9.1 
Pulse and blood pressure ........................................................................................ 41 
6.3.9.2 
Body temperature ................................................................................................... 41 
6.3.10 
Other safety assessments ........................................................................................ 41 
6.3.10.1 Bone marrow or blood cytogenetic analysis .......................................................... 41 
7. 
BIOLOGICAL SAMPLING PROCEDURES ....................................................... 41 
7.1 
Volume of blood .................................................................................................... 41 
7.2 
Handling, storage and destruction of biological samples ...................................... 42 
7.2.1 
Circulating DNA samples ...................................................................................... 42 
7.3 
Chain of custody of biological samples ................................................................. 42 
7.4 
Withdrawal of informed consent for donated biological samples ......................... 43 
8. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 43 
8.1 
Ethical conduct of the study ................................................................................... 43 
8.2 
Subject data protection ........................................................................................... 43 
8.3 
Ethics and regulatory review .................................................................................. 43 
8.4 
Informed consent.................................................................................................... 43 
8.5 
Changes to the protocol and informed consent form ............................................. 44 
8.6 
Audits and inspections ........................................................................................... 44 
9. 
STUDY MANAGEMENT .................................................................................... 45 
9.1 
Training of study site personnel ............................................................................. 45 
9.2 
Monitoring of the study.......................................................................................... 45 
Trial monitoring will be in accordance with the Fred Hutchinson Cancer Research 
Center (FHCRC)/University of Washington (UW) Cancer Consortium 
Institutional Data and Safety Monitoring Plan. Under the provisions of this 
plan, FHCRC Clinical Research Support coordinates data and compliance 
monitoring conducted by consultants, contract research organizations, or 
FHCRC employees unaffiliated with the conduct of the study. Independent 
monitoring visits occur at specified intervals determined by the assessed 
risk level of the study and the findings of previous visits per the 
institutional DSMP. ................................................................................................ 45 
9.3 
Source data ............................................................................................................. 45 
9.4 
Study timetable and end of study ........................................................................... 45 
9.5 
Data management ................................................................................................... 45 
10. 
EVALUATION AND CALCULATION OF VARIABLES ................................. 46 


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Drug Substance Olaparib (AZD2281, KU-0059436) 
Consortium Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
 
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10.1 
Calculation or derivation of efficacy variable(s) ................................................... 46 
10.2 
Other significant adverse events (OAE) ................................................................ 47 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............ 47 
11.1 
Description of analysis sets .................................................................................... 47 
11.1.1 
Efficacy Analysis Set ............................................................................................. 47 
11.1.2 
Safety Analysis Set ................................................................................................ 47 
11.2 
Determination of sample size ................................................................................. 47 
11.3 
Methods of statistical analysis ............................................................................... 48 
12. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR .................................................................................................. 49 
12.1 
Medical emergencies and AstraZeneca contacts ................................................... 49 
12.2 
Overdose ................................................................................................................ 49 
12.3 
Pregnancy ............................................................................................................... 49 
12.3.1 
Paternal exposure ................................................................................................... 49 
13. 
LIST OF REFERENCES ....................................................................................... 51 
 
LIST OF TABLES 
Table 1 
Adverse Drug Reactions from completed clinical studies .................................... 11 
Table 2 
Management of anemia ........................................................................................ 28 
Table 3 
Management of neutropenia, leukopenia and thrombocytopenia ......................... 28 
Table 4 
Dose reductions for study treatment ..................................................................... 31 
Table 5 
Volume of blood to be drawn from each subject .................................................. 41 
Table 6 
Schedule of Assessments ...................................................................................... 54 
 
LIST OF FIGURES 
Figure 1 
Study flow................................................................................................. 18 
 
LIST OF APPENDICES 
Appendix A: 
Eastern Cooperative Oncology Group Performance Status 
 


Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Consortium Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
 
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Appendix B: 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law  
Appendix C:         Acceptable Birth Control Methods  


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Drug Substance Olaparib (AZD2281, KU-0059436) 
Consortium Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
BRCA1 
Breast Cancer Susceptibility Gene 1 
BRCA2 
Breast Cancer Susceptibility Gene 2 
CFR 
Code of Federal Regulations 
CT 
Computerized Tomography 
ECOG 
Eastern Cooperative Oncology Group  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HRD 
IRB 
Homologous Recombination Deficiency  
Institutional Review Board 
kg 
Kilogram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeters of Mercury 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NYHA 
New York Heart Association 
PARP 
Polyadenosine 5’diphosphoribose [poly (ADP ribose)] 
PARPi 
PARP inhibitor 
pCR 
Pathological Complete Remission 
PSA 
Prostate-Specific Antigen 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Half-Life 
US 
United States 
WBC 
White Blood Cell Count 
 


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Drug Substance Olaparib (AZD2281, KU-0059436) 
Consortium Study Number 9985 
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Date 04/12/2020 
 
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1. 
INTRODUCTION 
This is a pilot open-label study designed to assess the pathological complete response rate 
following 3 months of neoadjuvant therapy with olaparib in patients with germline or somatic 
DNA repair deficiency with localized prostate cancer for whom radical prostatectomy is 
indicated.   
1.1 
Background 
Prostate cancer is the most common cancer of men and among the most lethal, with an estimated 
26,000 men per year dying of prostate cancer anticipated in 2017. 1  Surgery, radiation, and 
androgen deprivation therapy (ADT) have been standard therapies for locally advanced prostate 
cancer.  The principal reason for progression after primary therapy is systemic micrometastases, 
which are not adequately addressed at the time of local treatment.  The determinants of lethality 
at the time of diagnosis of prostate cancer have been poorly defined.  
Homologous Recombination Deficiency (HRD) in prostate cancer - Metastatic prostate 
cancer is enriched in pathogenic inactivation of homologous recombination (HR) genes such as 
BRCA2 and ATM (20-25% of metastatic castration resistant prostate cancer (mCRPC)) as 
defined in the PCF/SU2C biopsy study of mCRPC 2. Approximately half of the HR deficient 
(HRD) tumors (12% of all mCRPC patients) have a pathogenic germline variant in HR genes 
which is part of the mechanism of inactivation. The University of Washington/Fred Hutchinson 
Cancer Research Center was the leading clinical site in both efforts and the lead group in the 
work defining germline deficiencies in men with metastatic prostate cancer 2,3. The enrichment 
in patients with an inherited, germline HR deficiency presumably results from the 
aggressiveness of these tumors which has been demonstrated in BRCA2 mutated localized 
prostate cancer 4-6.   Men who are carriers of pathogenic germline BRCA variants diagnosed 
with prostate cancer carry an 8 fold higher risk of prostate cancer specific death than unselected 
men with prostate cancer when unadjusted for other risks.  Carrier men with metastatic prostate 
cancer had a shorter survival than unselected men with metastatic prostate cancer, implying that 
these cancers develop resistance to androgen deprivation and subsequent therapies more rapidly 
and are less dependent on androgen receptor signaling than non-mutated cancers. Men with 
intermediate/high risk localized prostate cancer in The Cancer Genome Atlas study (TCGA) 
demonstrated a 4.6% frequency of pathogenic germline HRD variants 7.  The presence of 
germline HRD is well known to increase the risk of malignancy, particularly in women who 
carry BRCA variants 8.  In the vast majority of carrier women who develop breast or ovarian 
cancer, both BRCA alleles are inactive due to either copy loss or a second mutational event in 
the other allele resulting a loss of DNA repair capacity in tumor, which is greater than that of 
normal tissue, in which only one allele is inactivated9,10.   
Activity of Polyadenosine 5’diphosphoribose [poly (ADP ribose)] polymerisation (PARP) 
inhibitors in HRD cancer –  DNA repair is critical to maintenance of cellular function and a 
primary mechanism of preventing carcinogenesis.  Multiple pathways to repair DNA have 
evolved, including base excision repair and homologous recombination, among others 11.  


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DNA repair relies on sensing of DNA damage, excision and repair.  The pathway which 
repairs the lesions with the most carcinogenic potential, double strand breaks, with the greatest 
fidelity is the homologous recombination (HR) pathway.  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 (HR).  Tumors 
with HRD, such as ovarian cancers in patients with BRCA1/2 mutations, cannot accurately 
repair the DNA damage, which may become lethal to cells as it accumulates.  In such tumor 
types,  PARP inhibition may offer a potentially efficacious and less toxic cancer treatment 
compared with currently available chemotherapy regimens. BRCA1 and BRCA2 defective 
tumors are intrinsically sensitive to PARP inhibitors, both in tumor models in vivo 12,13 and in 
the clinic 14.  Olaparib (AZD2281, KU-0059436) is a potent PARP inhibitor (PARP-1, -2 and 
-3) that is being developed as an oral therapy, both as a monotherapy (including maintenance) 
and for combination with chemotherapy and other anti-cancer agents.  The mechanism of 
action for olaparib results from the trapping of inactive PARP onto the single-strand breaks 
preventing their repair 15,16. Persistence of SSBs during DNA replication results in their 
conversion into the more serious DNA DSBs that would normally be repaired by HR repair.  
Olaparib has been shown to inhibit selected tumor cell lines in vitro and in xenograft and 
primary explant models as well as in genetic BRCA knock-out models, either as a stand-alone 
treatment or in combination with established chemotherapies 
Clinical experience in the treatment of breast ovarian and prostate cancer.  In epithelial 
ovarian cancer, the use of olaparib as maintenance therapy after chemotherapy provided 
significant improvements in progression free and overall survival in patients with germline 
BRCA mutations and led to FDA approval of olaparib17,18.   A second PARP inhibitor, 
rucaparib, was recently FDA approved for the treatment of ovarian cancer in BRCA carriers 
because of significant improvements in progression free survival compared to historical 
comparisons 19.  The data for activity of olaparib in prostate cancer comes from an initial study 
of olaparib in an unselected cohort of men with heavily pretreated metastatic, castration resistant 
prostate cancer. In this study 16 of 50 patients responded and 14 of those tumors contained an 
inactivating HR mutation in the tumor, providing a potential predictive biomarker 20.  A range 
of mutations were found to be sensitive, including BRCA, PALB2, ATM, FANCA and CHEK2.  
The response rate in patients whose tumors contained HRD was 88%.  All 7 patients with 
BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM 
aberrations responded.  This remarkably high response rate in a heavily pretreated population 
with prostate cancer has resulted in the initiation of multiple phase II and III studies of PARP 
inhibitors in men with HRD prostate cancer.  This extraordinary response rate justifies 
consideration for using this drug earlier in the disease course for HRD prostate cancers 
anticipated to be highly lethal.     
Neoadjuvant therapy as a means to improve outcomes in prostate cancer.  Early systemic 
therapy to address micrometastatic disease is an established paradigm.  The response of primary 


Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Consortium Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
 
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tumor to neoadjuvant therapy, and particularly pathologic complete response (pCR) after 
neoadjuvant therapy has been credentialed as a surrogate for improved outcomes in multiple 
malignancies, most notably bladder cancer and locally advanced breast cancer 21,22  After 
neoadjuvant therapy surgical resection is the only adequate means of assessing response given 
the limited sensitivity of imaging and biopsy to evaluate residual disease. Assessment of pCR 
after targeted neoadjuvant therapy is the basis for randomized studies evaluating the relative 
activity of targeted therapies.  I-SPY and I-SPY2 have tested the addition of targeted agents to 
standard of care for 12 weeks prior to surgical resection as a means of assessing activity against 
molecularly characterized breast cancers considered to be at high risk. This approach has thus 
far identified two agents, including PARPi and HER inhibitors as appropriate agents for phase 
III study 23,24. Although the histologies being treated are different from that proposed in this 
study, use of pCR as a readout for activity has demonstrated potential for identifying active and 
important agents for early therapy.  The role of neoadjuvant therapy prior to definitive therapy 
for localized prostate cancer remains uncertain.  Androgen deprivation therapy (ADT) 
concurrent and adjuvant to radiation therapy is standard of care, likely due to radiosensitizing 
effects of ADT (concurrent) and suppression of micrometastasis (adjuvant) in patients with high 
risk disease.  There is no clear data that demonstrates that neoadjuvant ADT provides better 
outcomes compared to concurrent and adjuvant ADT with radiation.  Neoadjuvant ADT prior 
to surgery has demonstrated that ADT alone has a low likelihood of achieving a complete 
response, reflecting the inability of ADT to induce apoptosis even when combined with next 
generation androgen receptor targeting agents 25-27.  Multiple studies from our group and others 
have been attempting to improve pCR by adding more effective suppressors of androgen 
receptor signaling, with some improvement in pCR, although at rates below the level justifying 
large randomized studies 28-30. Androgen deprivation alone rarely induces prostate cancer cell 
apoptosis in preclinical models and patients (< 5%) in contrast to PARP inhibition which 
induces apoptosis in 50% of cells in preclinical models 12,31,32.  The ability to exploit synthetic 
lethality using PARP inhibition holds the promise of potentially more effective local and 
systemic control in HRD prostate cancer through induction of apoptotic cell death.  As noted 
above, HRD tumors are more likely to metastasize early, be refractory to standard therapies and 
are therefore appropriate for assessment of efficacy of neoadjuvant olaparib given its activity in 
resistant disease. In this study, we will evaluate inhibition of a novel, and potentially critical 
pathway in HRD prostate cancer due to mutation and/or copy loss of the relevant gene.  The 
impact of olaparib on the pCR rate will be evaluated and compared to the historical CR rate of 
3-10% with androgen deprivation.  Surgical endpoints will be evaluated, including positive 
margins, extracapsular extension, seminal vesicle involvement and positive lymph nodes all of 
which correlate with risk of progression after prostatectomy 33. Mechanisms of resistance to 
PARP inhibition will be assessed in prostatectomy specimens.  
1.2 
Olaparib 
Olaparib is a small molecule inhibitor of PARP currently approved for the treatment of HRD 
ovarian cancer after prior platinum therapy. Olaparib has been shown to potently inhibit 
PARP-1-3, and has demonstrated activity in cells, animal models and patients with BRCA 1 
and 2 germline pathogenic variants  17,18 


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1.2.1 
Pre-clinical experience 
The pre-clinical experience is fully described in the current version of the olaparib 
Investigator’s Brochure (IB).    
1.2.2 
Toxicology and safety pharmacology summary 
The toxicology and safety pharmacology is fully described in the current version of the 
olaparib Investigator’s Brochure (IB).    
1.2.3 
Clinical experience 
This section lists those AEs and laboratory abnormalities that are currently regarded as 
expected for regulatory reporting purposes. 
Administration of olaparib monotherapy has been associated with reports of the following 
laboratory findings and/or clinical diagnoses (Table 1), generally of mild or moderate 
severity (CTCAE Grade 1 or 2) and generally not requiring treatment discontinuation. 
 
Table 1 
Adverse Drug Reactions from completed clinical studies 
 
 
MedDRA SOC 
MedDRA term 
CIOMS descriptor/ 
overall frequency 
(All CTCAE grades) 
Frequency of CTCAE 
Grade 3 and above 
Blood and lymphatic 
system disorders 
Anaemiaa 
Very common 
Very common 
Neutropeniaa 
Very common 
Common 
Leukopeniaa 
Very common 
Common 
Thrombocytopeniaa 
Very common 
Common 
Lymphopeniaa 
Common 
Uncommon 
Immune system 
disorders 
Rasha 
Common 
Rare 
Hypersensitivitya 
Uncommon 
Rare 
Dermatitisa 
Uncommon 
- 
Metabolism and 
nutrition disorders 
Decreased appetite 
Very common 
Uncommon 
Nervous system 
disorders 
Dizziness 
Very common 
Uncommon 
Headache 
Very common 
Uncommon 
Dysgeusia 
Very common 
- 
Respiratory, thoracic 
and mediastinal 
disorders 
Cougha 
Very common 
Uncommon 
Dyspnoeaa 
Very common 
Common 
Gastrointestinal 
disorders 
Vomiting 
Very common 
Common 
Diarrhoea 
Very common 
Common 


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Nausea 
Very common 
Common 
Dyspepsia 
Very common 
- 
Stomatitisa 
Common 
Uncommon 
Upper abdominal pain 
Common 
Uncommon 
General disorders 
Fatigue (including 
asthenia) 
Very common 
Common 
Investigations 
Increase in blood 
creatinine 
Common 
Uncommon 
Mean corpuscular 
volume elevation 
Uncommon 
- 
a                   Anaemia includes preferred terms (PTs) of anaemia, anaemia macrocytic, erythropenia, haematocrit 
decreased haemoglobin decreased, normochromic anaemia, normochromic normocytic anaemia, 
normocytic anaemia and red blood cell count decreased; Neutropenia includes PTs of agranulocytosis, 
febrile neutropenia, granulocyte count decreased, granulocytopenia, idiopathic neutropenia, 
neutropenia, neutropenic infection, neutropenic sepsis and neutrophil count decreased; 
Thrombocytopenia includes PTs of platelet count decreased, platelet production decreased, plateletcrit 
decreased and thrombocytopenia; Leukopenia includes PTs of leukopenia and white blood cell count 
decreased; Lymphopenia includes PTs of B-lymphocyte count decreased, lymphocyte count decreased, 
lymphopenia and T-lymphocyte count decreased; Cough includes PTs of cough and productive cough; 
Rash includes PTs of exfoliative rash, generalised erythema, rash, rash erythematous, rash generalised, 
rash macular, rash maculo-papular, rash papular and rash pruritic; Hypersensitivity includes PTs of drug 
hypersensitivity and hypersensitivity; Dermatitis includes PTs of dermatitis, dermatitis allergic and 
dermatitis exfoliative; Dyspnoea includes PTs of dyspnoea and dyspnoea exertional; Stomatitis includes 
PTs of aphthous ulcer, mouth ulceration and stomatitis. CIOMS Council for International Organization 
of Medical Sciences; CTCAE Common Terminology Criteria for Adverse Events; MedDRA Medical 
Dictionary for Regulatory Activities; SOC System organ class. MedDRA version 22.0 
 
  
 
Summary of Risks 
As of 15 June 2016, approximately 5670 patients with ovarian, breast, pancreatic, gastric and 
a variety of other solid tumors are estimated to have received treatment with olaparib in 
AstraZeneca-sponsored, investigator-sponsored, collaborative group studies and a Managed 
Access Program. Olaparib has been given as either monotherapy (an estimated  3624 patients) 
or in combination with other chemotherapy/anti-cancer agents (an estimated  2046 patients).  
 
Monotherapy studies 
Serious adverse events 
A review of the AstraZeneca Patient Safety database (which includes AstraZeneca-sponsored, 
investigator-sponsored/collaborative group monotherapy studies and Managed Access 
Program reports) as of 15 June 2016 identified a total of 1413 SAEs (1093 unblinded, 
320 blinded) received from 752 patients in olaparib monotherapy studies. SAE reports of 
≥1% (≥36 patients treated with olaparib/placebo monotherapy) were anemia (n=143), 
abdominal pain (n=40), vomiting (n=47), nausea (n=42) and dyspnoea (n=41). The most 


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Date 04/12/2020 
 
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commonly reported SAEs from these monotherapy studies were similar for the tablet and 
capsule formulation. 
 
Myelodysplastic syndrome/acute myeloid leukaemia events 
As of 15 June 2016, 23 reports of MDS and/or AML have been received out of a total of 
5670 patients estimated to have received olaparib in the clinical study program, giving an 
estimated cumulative incidence of 0.41% for MDS/AML. Six additional reports of 
MDS/AML from 6 patients have been received from 2 blinded studies (D0816C00002 and 
D0818C00001) in which the treatment of the 6 patients (olaparib or placebo) is unknown. If 
these patients are considered to have been on olaparib treatment, the estimated incidence 
would be 0.51%.  Of the 23 olaparib-treated patients and 6 patients on blinded treatment, the 
MDS/AML events have been reported in patients receiving a range of doses from both 
monotherapy and combination studies and for a variety of tumor types; ovarian, peritoneal or 
fallopian tube cancer (n= 26), breast cancer (n=1) and pancreatic cancer (n=2). Twenty-one of 
the 29 patients died: in 12 of these patients, MDS/AML or myelodysplasia was recorded as 
either a primary or secondary cause of death.   In 16 patients, the event of MDS/AML is 
reported as not recovered (including patients that died of other causes).  
 
As of 15 June 2016, pneumonitis has been reported in 22 olaparib-treated patients out of a 
total of 5670 patients estimated to have received olaparib in the clinical study program, 
giving an estimated cumulative incidence of 0.39%. Eleven additional reports of pneumonitis 
have been received from 4 blinded studies, where the treatment of the patients is unknown 
(7 either olaparib or placebo [D0816C00002 or D0818C00001]; 2 either olaparib + paclitaxel 
or placebo + paclitaxel [D081BC00004] and 2 olaparib + abiraterone or placebo + abiraterone 
[D081DC00008]). If these patients were considered to have been on olaparib treatment, the 
estimated cumulative incidence would be 0.58% (33/5670). Pneumonitis has also been 
reported for 1/128 (0.78%) patient randomised to placebo in Study D0180C00019, 1/62 
(1.61%) patient randomised to placebo + paclitaxel in a double-blind study in recurrent or 
metastatic gastric cancer (Study D0810C00039) and 1/262 (0.38%) patient randomised to 
placebo + paclitaxel in a double-blind, phase III study in advanced gastric cancer (Study 
D081BC00004). The reports of pneumonitis were from patients receiving olaparib at a range 
of doses, given either as monotherapy or in combination with the other chemotherapy 
treatments. The diagnosis of pneumonitis was made whilst on treatment or within a 60-day 
follow-up period for all patients. The patients were treated with olaparib for ovarian cancer 
(n=14), breast cancer (n=4), NSCLC or small cell lung cancer (SCLC; n=7), pancreatic cancer 
(n=1), gastric cancer (n=4), prostate cancer (n=2) and thymic cancer (n=1). 
 
Four of the 33 patients died due to pneumonitis (2 of these patients who were receiving 
olaparib in combination with liposomal doxorubicin [Study D0810L00001] and the cause of 
death also included pulmonary insufficiency); in 1 patient receiving olaparib and radiotherapy, 
the cause of death included bronchopulmonary hemorrhage, The reports of pneumonitis 
presented with no consistent clinical pattern and were heavily confounded by a number of pre-
disposing factors (including disease under investigation, underlying pulmonary disease, pre-


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existing medical conditions, smoking history and/or previous chemotherapy and 
radiotherapy). The majority of patients had received prior radiotherapy and/or chemotherapy 
and had other risk factors within the medical histories including pneumonitis, interstitial lung 
fibrosis, dyspnoea, hemoptysis, chest infection, allergic asthma, pleural effusion, pleural 
metastases, smoking. Seven patients had current SCLC or NSCLC. An independent review of 
available chest computed tomography (CT) scans and radiographs associated with the reports 
of pneumonitis concluded that there appeared to be no clear consistent clinical pattern. 
 
MDS/AML, and pneumonitis have been identified as important potential risks for olaparib. 
The cumulative incidences are consistent with that expected for the patient population under 
study according to the available literature. These events are being closely monitored in 
ongoing studies. Clinical experience with olaparib is fully described in the current version of 
the olaparib Investigator’s Brochure.  Investigators should be familiar with the current 
olaparib (AZD2281) Investigator Brochure.  
 
1.3 
Research hypothesis 
The hypothesis of this pilot study is that neoadjuvant treatment with the PARP inhibitor 
olaparib in men with germline or somatic HRD will induce significant tumor reduction, 
assessed as pCR.  
1.4 
Rationale for conducting this study 
The frequency of HRD in prostate cancer increases substantially from the population of 
patients with localized prostate cancer to those with metastatic disease, reflecting the lethal 
phenotype mediated by HRD.  Lethality is a reflection of early micrometastatic dissemination 
and an inability of local therapy alone to cure the disease.  Men with localized prostate cancer 
with HRD either as a result of germline or somatic inactivation require better systemic therapy 
to improve their outcomes.  The primary objective of this study is to assess whether the use of 
the PARP inhibitor olaparib prior to prostatectomy will result in pCR, which is credentialed in 
other malignancies as a surrogate for effective systemic elimination of tumor and long term 
cure.  This is a pilot study to assess the feasibility of this approach in men with localized 
disease, with assessment of pCR, surgical margin status, extracapsular extension, seminal 
vesicle and nodal involvement, all of which are pathologic indicators of activity of 
neoadjuvant therapy.  It is anticipated that the majority of patients will be known to be carriers 
of pathogenic germline variants, although a subset with purely somatic inactivation and HRD 
may identified in other ways.  There is no evidence that tumors with germline vs. somatic 
inactivation will be differentially sensitive to PARP inhibition, so both populations will be 
eligible. A neoadjuvant PARP inhibitor study has not been performed in patients with prostate 
cancer and this study will also assess the safety and toxicity of olaparib in this patient 
population.  If neoadjuvant therapy does not result in pCR, the remaining tissue is by 
definition resistant to therapy and remaining tumor tissue will be interrogated for mechanisms 
of resistance to inform future combination studies in advanced and localized HRD prostate 
cancer.  


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1.5 
Benefit/risk and ethical assessment 
The risk/benefit associated with the use of olaparib administered prior to prostatectomy must 
weigh the risks of the drug, both acute and long term, vs. potential benefits.  The justification 
for adding systemic therapy for patients with HRD prostate cancer is related to the 
significantly increased risk of relapse and death associated with HRD.  Patients who are 
BRCA2 carriers have a 4-5 fold increased risk of developing prostate cancer 34,35. Once 
germline carriers are diagnosed with prostate cancer, their crude risk of metastasis and cancer 
specific mortality is increased approximately 8 fold 4-6.  Although in multivariate analysis the 
overall risk of cancer specific mortality decreases,  the presence of a germline mutation 
significantly increases the risk of being diagnosed with high risk or metastatic disease 
reflecting an aggressive biology 6. The frequency of other germline DNA repair genes is so 
low in the general population of men diagnosed with localized disease that no studies of their 
impact on relapse and cancer specific mortality has been carried out. Given the rarity of these 
variants in localized disease and the increased incidence in patients with metastatic disease, 
we anticipate that a similar increase in mortality attends the presence of these mutants  36. As 
noted, cancer specific relapse and death after definitive therapy is essentially always related to 
regional nodal or systemic metastasis, which can only be addressed with better systemic 
treatment. The relative risk/benefit calculation for treatment men with localized HRD prostate 
cancer with olaparib must balance risks of morbidity and mortality of the disease with 
toxicities of the therapy. The risks of cancer related morbidity and mortality are outlined 
above. The risks of olaparib outlined in section 1.2.2 and 1.2.3 are primarily 
myelosuppression, which in patients with advanced prostate cancer not receiving concurrent 
therapy was grades 1 or 2 and nausea and vomiting grades 1 or 220. In other settings the 
frequency of more significant toxicities, including pneumonitis, myelodysplasia and leukemia 
are rare (Section 1.2) and MDS/leukemia frequency is confounded by prior therapy for the 
majority of patients (ovarian cancer) with the DNA damaging agent platinum, and known to 
cause MDS/AML at a very similar frequency in this patient population 37.  There is no 
evidence from neoadjuvant studies of PARPi in patients with breast cancer that PARPi 
increases the risk of perioperative complications 24. The use of prostatectomy in this study as 
definitive therapy is appropriate as there is clear evidence that radiation and prostatectomy are 
at least equivalent with some studies suggesting better outcomes in high risk patients 38,39. The 
potential benefits of neoadjuvant PARPi for patients with HRD tumors could be reduced risk 
of relapse, metastasis or death which is significant in this patient population. This study will 
not formally evaluate long term outcomes but will provide pilot data regarding frequency of 
pCR, and improvement of other pathologic criteria which are predictive of relapse, as well as 
providing tissues which will allow interrogation of mechanisms of resistance if olaparib does 
not improve pCR rate.  


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2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
• To assess the pathological complete response rate following olaparib when administered 
as neoadjuvant therapy prior to prostatectomy in patients with localized prostate cancer 
containing homozygous or complementary DNA repair deficiency 
The primary objective is to assess the pathological complete response (pCR) rate following 
olaparib when administered as neoadjuvant therapy prior to prostatectomy in patients with 
localized prostate cancer containing homozygous or complementary DNA repair deficiency. 
The rationale for this as a primary endpoint is discussed in section 1.1.  Complete response 
after preoperative cytotoxic or targeted therapy is a surrogate for long term outcomes in 
bladder and breast cancer.  Although not credentialed as a surrogate in prostate cancer, this 
appears likely due to the lack of agents which cause apoptosis in prostate cancer, and PARP 
inhibition has the potential for induction of apoptosis through leveraging of synthetic lethality 
in HRD tumors, as seen in preclinical studies.  
2.2 
Secondary objective 
To determine the rate of positive surgical margins, extracapsular extension, positive 
seminal vesicles and lymph nodes at the time of prostatectomy. 
2.3 
Exploratory objectives 
To assess potential mechanisms of resistance to neoadjuvant olaparib by assessing residual 
tumor for PARP1, 53BP1, reversion mutations in BRCA1 or 2, and mutations of ERCC. 
These mechanisms have all been proposed as relevant mechanisms of resistance to PARP 
inhibition in vitro or in vivo studies.


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3. 
STUDY PLAN AND PROCEDURES 
3.1 
Overall study design and flow chart 
 
Figure 1 
Study flow
Localized HRD prostate cancer 
(germline or somatic HRD) 
AND: 
Gleason 4+3 (intermediate risk) 
OR  
 Gleason 8-10, PSA > 20, > cT3a 
(high risk) 
Olaparib 600 mg daily 
x 90 days 
Radical 
Prostatectomy 


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3.2 
Rationale for study design, doses and control groups 
This is an open-label, single center pilot study designed to assess the pathological complete 
response rate following neoadjuvant therapy (olaparib) of patients with localized prostate 
cancer for whom radical prostatectomy is indicated.  Eligible patients are those with localized 
prostate cancer who are referred for radical prostatectomy. Patients should be either 1) carriers 
of a pathogenic germline variant of a gene involved in the homologous recombination 
pathway of DNA repair or 2) have evidence by somatic sequencing of biallelic inactivation of 
a gene involved in the homologous recombination pathway of DNA repair.  It is anticipated 
that the majority of patients will be germline carriers of a pathogenic variant of BRCA1, 
BRCA2 or ATM.  As previously discussed these patients are at high risk of micrometastatic 
disease at diagnosis and are therefore appropriate for approaches designed to test therapies 
which might induce tumor apoptosis, using pCR as a reflection of apoptosis and potential for 
elimination of micrometastases.  
Screening of patients for study will take place through multiple approaches.  The University of 
Washington and Fred Hutchinson Cancer Research Center have opened a registry study 
offering free germline testing of all men in the state of Washington with a diagnosis of 
metastatic prostate cancer (GENTLEMAN study).  This study will take place through website 
enrollment, optimizing access anywhere in the state, with germline testing kits mailed to 
patients for return to the center for testing.  Patients with advanced disease and an identified 
pathogenic variant will be offered counseling, discussion of their case at precision tumor 
board and contact with their treating physicians regarding potential therapy with DNA 
damaging agents, PARP inhibitors or participation in open studies.  This study is attempting to 
to optimize access to treatment options for these men. It is anticipated that families of these 
men will undergo “cascade” testing so that they will have appropriate screening for HRD 
related malignancy, including breast, ovarian, prostate and ovarian cancer, if they are carriers 
of a pathogenic germline variant.  Carrier men are anticipated to undergo more intensive 
screening for prostate cancer and identification of localized prostate cancer in carrier men in 
the state of Washington40.  The University of Washington/Seattle Cancer Care Alliance has an 
active breast and ovarian cancer prevention clinic for families known to be germline carriers 
of BRCA (Elizabeth Swisher and Larissa Korde).  Male family members will be offered 
germline testing through a substudy of GENTLEMAN.  The investigators on the current study 
are advisors to national advocacy groups of patients who have known BRCA and other 
germline mutations (FORCE – Facing Our Risk of Cancer) and currently make clinical studies 
available through their website, allowing nationwide recognition of the current study.   
 
 
 
Starting on Day 1, all patients will ingest olaparib (300 mg twice daily) at the same times each 
day, without breaks (except as outlined for toxicity), for 90 days.   The 90 day duration is 
chosen as a duration adequate to assess impact of neoadjuvant therapy on downstaging but not 
so prolonged that if patients do not respond to therapy, that potentially curative local therapy 
is being significantly delayed. Multiple studies have demonstrated in unselected populations 
that 90 day delay to surgery is not associated with any change in long term outcomes 41,42.   
During neoadjuvant therapy, dose reduction of olaparib is allowed for toxicity as detailed in 
the protocol.  Patients should receive olaparib until 1 day prior to prostatectomy, until the 


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patient can no longer tolerate the treatment due to an adverse event, until the patient initiates 
another systemic antineoplastic drug or an investigational drug, or at the discretion of the 
Investigator.  Safety and tolerability will be documented throughout the study and 30 days 
after prostatectomy by assessment of adverse events, vital signs, and laboratory assessments 
as defined in the Schedule of Activities. All adverse events will be monitored and recorded 
until the Safety Follow-up visit.  Adverse events will be graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03 (NCI-
CTCAE v4.03).  In the event a patient discontinues olaparib due to a related adverse event, 
follow up will continue until adequate resolution of the adverse event, the physician deems the 
adverse event to be stable, the patient initiates another systemic antineoplastic drug or an 
investigational drug, or the patient withdraws consent from the study.  A safety follow-up visit 
will be conducted approximately 30 days after the last dose of olaparib or before the initiation 
of a new systemic antineoplastic therapy or investigational agent, whichever occurs first.  Any 
ongoing adverse event thought to be related to study treatment will be followed until the event 
has resolved to baseline grade, the event is assessed by the Investigator as stable, the patient 
initiates another systemic antineoplastic drug or an investigational drug, the patient is lost to 
follow-up, the patient withdraws consent, or it has been determined that study treatment or 
participation is not the cause of the adverse event.    
 
 
 
 
 
Efficacy Variables 
Patients will be evaluated for pathological complete response following neoadjuvant therapy, 
based on tissue obtained via prostatectomy.    
Primary Variable(s) 
The primary efficacy variable is the proportion of patients achieving a pathological complete 
response of localized prostate cancer.  Pathologic complete response is defined as the absence 
of morphologically identifiable carcinoma in the prostatectomy specimen, as evaluated by the 
site pathologist using standard methods (see the Laboratory Manual for detailed instructions).  
The expected complete response rate at prostatectomy without intervention is 1% or less and 
is 4% to 9%, with standard androgen deprivation in a mixed population of low-to-intermediate 
risk disease. 
Tissue may also be assessed using methodologies in addition to standard morphological 
analysis, however, this will not be used to downgrade a pathological complete response.    
Surgical Endpoints  
At the time of radical prostatectomy, pathology specimens will be assessed for surgical 
margins, and stage to include assessment of extracapsular extension, seminal vesicle and 
lymph node involvement.  All of these endpoints when present represent risks for relapse after 
prostatectomy 
Exploratory endpoints 


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To assess potential mechanisms of resistance to neoadjuvant olaparib by assessing residual 
tumor for molecular changes previously defined in vitro or in vivo to represent de novo or 
acquired mechanisms of resistance to PARP inhibitors. These include upregulation of the 
PARP1 and REV7, downregulated 53BP1 or PTIP, reversion mutations in BRCA1 or 2, and 
drug export by P-glycoprotein 12,43-48  These have all been proposed as relevant mechanisms of 
resistance to PARP inhibition in vitro and preclinical studies.  
4. 
PATIENT SELECTION CRITERIA 
4.1 
Inclusion criteria 
For inclusion in the study patients should fulfill the following criteria: 
1. Provision of informed consent prior to any study specific procedures  
2. Men ≥ 18 years of age;  
3. Histologically confirmed adenocarcinoma of the prostate without morphologic 
neuroendocrine differentiation or small cell features  
4. The presence of homologous recombination deficiency defined by either; A) 
Inherited pathogenic variant of BRCA2, ATM, BRCA1, PALB2 by a CLIA level 
germline assay or B) have evidence by somatic sequencing using a CLIA level 
assay of biallelic inactivation of  BRCA1, BRCA2, PALB2, FANCA or biallelic 
inactivation or monoallelic inactivating mutation of ATM.  It is anticipated that the 
majority of patients will be germline carriers of a pathogenic variant of BRCA1, 
BRCA2 or ATM.  Other germline mutations will be considered at investigator’s 
discretion.   
5. Must be candidates for radical prostatectomy and considered surgically resectable 
by urologic evaluation 
6. No evidence of metastatic disease or nodal disease as determined by radionuclide 
bone scans and computed tomography (CT)/magnetic resonance imaging (MRI);  
non-pathological lymph nodes must be less than 20 mm in the short (transverse) 
axis; 
7. Provided written authorization for use and release of health and research study 
information. 
8. Patients must have normal organ and bone marrow function measured within 28 
days prior to administration of study treatment as defined below: 
− 
Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days   
− 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 


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− 
Platelet count ≥ 100 x 109/L 
− 
Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) 
− 
Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase 
(SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate 
Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver 
metastases are present in which case they must be ≤ 5x ULN 
− 
Patients must have creatinine clearance estimated using the Cockcroft-Gault 
equation of ≥51 mL/min: 
Estimated creatinine clearance = 
(140-age [years]) x weight (kg)     
  
 
 
 
 
 
serum creatinine (mg/dL) x 72 
9. 
Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (see 
Appendix 1). 
10. Patients must have a life expectancy ≥ 16 weeks. 
11. 
Male patients and their partners, who are sexually active and of childbearing 
potential, must agree to the use of two highly effective forms of contraception 
in combination throughout the period of taking study treatment and for 3 
months after last dose of study drug(s) to prevent pregnancy in a partner.  
12. Patient is willing and able to comply with the protocol for the duration of the 
study including undergoing treatment and scheduled visits and examinations. 
4.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled  
1. Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site) 
2. Any previous treatment with PARP inhibitor, including olaparib. 
3. Other malignancy within the last 5 years except: adequately treated non-melanoma 
skin cancer, or other solid tumours including lymphomas (without bone marrow 
involvement) curatively treated with no evidence of disease for ≥5 years.   
4. Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour 
period or family history of long QT syndrome 
5. Patients receiving any systemic chemotherapy, hormonal therapy or radiotherapy  
 


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6. Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, 
telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or 
cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate 
CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, 
verapamil). The required washout period prior to starting olaparib is 2 weeks. 
7. Concomitant use of known strong (e.g. phenobarbital, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort ) or moderate 
CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period 
prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents. 
8. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features 
suggestive of MDS/AML. 
9. Major surgery within 2 weeks of starting study treatment and patients must have 
recovered from any effects of any major surgery. 
10. Patients considered a poor medical risk due to a serious, uncontrolled medical 
disorder, non-malignant systemic disease or active, uncontrolled infection.  
Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent 
(within 3 months) myocardial infarction, uncontrolled major seizure disorder, 
extensive interstitial bilateral lung disease on High Resolution Computed 
Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining 
informed consent. 
11. Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication.  
12. Immunocompromised patients, e.g., patients who are known to be serologically 
positive for human immunodeficiency virus (HIV). 
13. Patients with a known hypersensitivity to olaparib or any of the excipients of the 
product. 
14. Patients with known active hepatitis (i.e., Hepatitis B or C) due to risk of 
transmitting the infection through blood or other body fluids 
15. Previous allogenic bone marrow transplant or cord blood transplantation  
16. Whole blood transfusions in the last 120 days prior to entry to the study (packed red 
blood cells and platelet transfusions are acceptable, for timing refer to inclusion 
criteria no.3) 
Procedures for withdrawal of incorrectly enrolled subjects see Section 5.3 


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5. 
STUDY CONDUCT 
5.1 
Restrictions during the study 
 
5.1.1 
Grapefruit juice 
It is not recommended to consume grapefruit juice while on olaparib therapy. 
 
5.1.2 
Contraception 
Male patients with partners of child bearing potential, who are sexually active, must agree to 
the use of two highly effective forms of contraception throughout period of taking study 
treatment and for 3 months after last dose of study drug.  For details refer to Appendix C 
Acceptable Birth Control Methods. 
5.1.3 
Androgen deprivation 
The use of androgen deprivation is not allowed during the neoadjuvant period 
5.2 
Subject enrollment and initiation of investigational product 
Patients will be enrolled on study after eligibility criteria are met and begin open label 
olaparib within 30 days of consent.  As this is a study in patients with localized prostate 
cancer who have not previously received treatment for malignancy, no run in period is 
required.  
5.3 
Procedures for handling subjects incorrectly enrolled or initiated 
on investigational product 
Patients enrolled to study who are determined to have been ineligible or who develop 
conditions prior to administration of olaparib which are in the opinion of the principal 
investigator contraindications to olaparib or surgery will be removed from study.   
5.4 
Treatments 
5.4.1 
Enrollment procedure 
Before or during this visit, the patient will be thoroughly informed about all aspects of the 
study, including all scheduled visits and activities, and will be requested to sign and date the 
informed consent form before any study-specific screening assessments that are not 
considered standard care.  A patient wishing to participate must also sign the study specific 
HIPAA Authorization Form prior to any study-related procedures or change in treatment.  The 
original signed and dated informed consent form must be retained by the Investigator in the 
patient’s file and a copy must be provided to the patient. The original signed and dated 
HIPAA authorization form will be filed in the research chart. 


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Patients will be identified by their urologist, oncologist, or radiation oncologists as eligible for 
the study and the study will be discussed with the patient by an investigator.  Patient eligibility 
will be assessed and confirmed by the Investigator.  All inclusion criteria must be met and 
none of the exclusion criteria may apply.  All results from the screening procedures must be 
available before determining a patient’s eligibility for the study.  
Protocol-specified procedures at the Screening visit must occur within 28 days of enrollment, 
unless otherwise noted in the Schedule of Activities; otherwise the Screening visit must be 
repeated.  Assessments performed as standard-of-care within the screening window may be 
used for screening.  
The following procedures will be performed during the Screening period unless otherwise 
noted:   
• Informed consent (before or during the Screening visit and within 28 days of 
enrollment);  
• Assign screening number; 
• Medical history and demographics including PSA history, currently active 
conditions, and significant inactive conditions;  
• Record concomitant medications including all vitamins, herbal remedies, over 
the counter medications, nutritional supplements, and prescription medications 
used by the patient for up to 7 days preceding the Screening evaluation;  
• Laboratory assessments (hematology and chemistry)   
• PSA 
• Complete physical examination  
• Digital rectal examination (if not already performed by urologist) 
• ECOG performance status  
• 12-lead ECG  
• PT/PTT 
• Testosterone  
• Vital signs (heart rate and systolic and diastolic blood pressures)  
• Weight will be recorded at every visit.  Height will be recorded at the Screening 
visit only; 
• Assess tumor and document clinical stage of disease.  Patients will undergo 
bone scan and CT/MRI of the pelvis if defined as having high risk disease or at 
the investigator’s discretion.   
• Review inclusion and exclusion criteria and determine if the patient is eligible 
for the study; 
 
5.4.2 
Study Evaluations 
Baseline (Day 1) 
• Limited physical examination  


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• Vital signs including temperature, blood pressure, and heart rate; weight if 
performed ≥ 96 hours prior; 
• Laboratory assessments (hematology and chemistry) if screening 
assessments were done >28 days prior; 
• Blood will be collected for circulating tumor DNA/serum    
• Update concomitant medications listing; 
• Instruct patient to self-administer olaparib at approximately the same times 
every day. Instruct patient to return all unused tablets at the end of each 
treatment period to assess compliance; 
• Adverse event review. 
5.4.3 
Day 30 (± 5 Days), 60 (± 5 Days) 90 (± 5 Days) Visits 
• Vital signs including weight, temperature, blood pressure, and heart rate; 
• ECOG performance status; 
• Safety laboratory assessments (chemistry and hematology);  
• PSA 
• Plasma and Serum will be collected and frozen  
• Update concomitant medications listing; 
• Adverse event review; 
• Assess drug compliance for olaparib;  
• Dispense olaparib (30-day supply as indicated)  
• Day 30, 60, 90 limited physical examination (directed towards patient 
reported symptoms; and cardiac, respiratory, and gastrointestinal systems) 
 
5.4.4 
Radical prostatectomy  
Day 90 (± 14 Days) 
• 
Tissue will be obtained per standard procedures  
5.4.5 
End of study visit (Day 120 (± 5 Days) 
• Vital signs including weight, temperature, blood pressure, and heart rate; 
• Safety laboratory assessments (chemistry and hematology);  
• PSA 
• Plasma and Serum will be collected and frozen  
• Adverse event review 
• Pathologic stage review/documentation 
5.4.6 
Early Termination Visit (Early Cessation of Study Drug) 
Patients will be advised in the written informed consent that they have the right to withdraw from the 
study at any time without prejudice.  The Principal Investigator or the Sponsor may discontinue a 
patient from study in the event of an intercurrent illness, adverse event, other reasons concerning the 
health or well-being of the patient, or in the case of lack of cooperation, non-compliance, protocol 
violation, or other administrative reasons.  


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For patients who have started study drug and terminate the study prematurely, every effort should be 
made to ensure the collection of safety data by means of unscheduled visits, the frequency and timing 
of which will be determined by the Principal Investigator, and the follow-up visit.  If the patient is 
withdrawn from the study because of an adverse event or a serious adverse event, the event(s) must be 
followed as per section 6.4.3.  
Patients who discontinue the trial prematurely may be replaced at the discretion of the Investigator. 
 
 
5.4.7 
Identity of investigational product 
The AstraZeneca Pharmaceuticals will supply olaparib to the investigator  
Investigational product 
Dosage form and strength 
Olaparib 
100 mg and 150 mg tablets 
a 
Descriptive information for olaparib can be found in the Investigator’s Brochure 
5.4.8 
Dose and treatment regimen 
Olaparib 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 will be dispensed to patients on Day 1 and approximately every 
28 days thereafter until the patient completes the study, withdraws from the study or closure 
of the study.   
Study treatment is available in the form of film-coated tablets containing 100 or 150 mg of 
olaparib. 
Patients will take olaparib orally twice daily at 300 mg bid continually. 300 mg olaparib 
tablets should be taken at the same time each day, approximately 12 hours apart with one glass 
of water.  The olaparib tablets should be swallowed whole and not chewed, crushed, dissolved 
or divided. Olaparib 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 (e.g., 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. 
Dose Reductions  
For guidance on dose reductions for management of AEs refer to section 5.4.11 
For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors 
cannot be avoided see section5.5 


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Renal Impairment    
If subsequent to study entry and while still on study therapy, a patient’s 
estimated 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 creatinine clearance by Cockcroft-Gault equation of between 31 and 50 ml/min) 
for any reason during the course of the study: the dose of olaparib should be reduced to 200mg 
BD. 
 
Because the CrCl determination is only an estimate of renal function, in 
instances where the CrCl falls to between 31 and 50 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 (creatinine clearance 
≤ 30 ml/min) or end-stage renal disease; if patients develop severe impairment or end stage 
disease it is recommended that olaparib be discontinued. 
 
 
5.4.9 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label on the bottle and the Investigator Brochure specifies the 
appropriate storage. 
5.4.10 
Management of toxicity of olaparib  
Any toxicity observed during the course of the study could be managed by interruption of the 
dose of study treatment or dose reductions. Repeat dose interruptions are allowed as required, 
for a maximum of 4 weeks on each occasion, until improved Hb ≥10 g/dl. If the interruption is 
any longer, the study team must be informed. Upon recovery, study treatment can be dose 
reduced to 250 mg twice daily as a first step and to 200 mg twice daily as a second step in the 
case of repeat Hb decrease. If the reduced dose of 200 mg twice daily is not tolerable, no 
further dose reduction is allowed and study treatment should be discontinued.  
Once dose is reduced, escalation is not permitted. 


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5.4.11 
Management of hematological toxicity 
5.4.11.1 Management of anemia 
Table 2 
Management of anemia 
Hemoglobin 
Action to be taken 
Hb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2) 
Give appropriate supportive treatment and investigate causality.  
Investigator judgement to continue olaparib with supportive treatment  (eg 
transfusion) or interrupt dose for a maximum of 4 weeks.  
If repeat Hb< 10 but ≥ 8 g/dl, dose interrupt (for max of 4 weeks) until Hb 
≥ 10 g/dl and upon recovery dose reduction to 250 mg twice daily as a 
first step and to 200 mg twice daily as a second step may be considered. 
Hb < 8 g/dl 
(CTCAE Grade 3) 
Give appropriate supportive treatment (e.g. transfusion) and investigate 
causality.  
Interrupt olaparib for a maximum of 4 weeks. until improved to Hb ≥ 10 
g/dl. 
Upon recovery dose reduce to 250 mg twice daily as a first step and to 
200 mg twice daily as a second step in the case of repeat Hb decrease. 
 
Common treatable causes of anemia (e.g., 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 CTC 
grade 3 or worse anemia and/or development of blood transfusion dependence), refer to 
Section 6.7.1.3 for the management of this.  
 
5.4.11.2 Management of neutropenia, leukopenia and thrombocytopenia 
Table 3 
Management of neutropenia, leukopenia and thrombocytopenia 
Toxicity 
Study treatment dose adjustment 
CTCAE Grade 1-2 
Investigator judgement to continue treatment or if dose interruption, this 
should be for a maximum of 4 weeks; appropriate supportive treatment 
and causality investigation 
CTCAE Grade 3-4 
Dose interruption until recovered to CTCAE gr 1 or better for a maximum 
of 4 weeks. If repeat CTCAE grade 3-4 occurrence, dose reduce olaparib 
to 250 mg twice daily as a first step and 200 mg twice daily as a second 
step 
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by 
the investigator with close follow up and interruption of study drug if CTC grade 3 or worse 
neutropenia occurs. 
Primary prophylaxis with Granulocyte colony stimulating factor (G-CSF) is not 
recommended, however, if a patient develops febrile neutropenia, study treatment should be 


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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 h (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 guidelines. 
For cases where patients develop prolonged hematological toxicity (≥2 week 
interruption/delay in study treatment due to CTC grade 3 or worse), refer to Section 6.7.1.3.  
5.4.11.3 Management of prolonged hematological toxicities while on study treatment 
If a patient develops prolonged hematological toxicity such as: 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse anemia and/or 
development of blood transfusion dependence 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse neutropenia (ANC 
< 1 x 109/L) 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse thrombocytopenia 
and/or development of platelet transfusion dependence (Platelets < 50 x 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 CTC gr 1 or better within 4 weeks of dose interruption. 
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should 
be reported as an SAE 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 AML is confirmed. 
5.4.12 
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, then the patient should be 
considered for dose reduction or must permanently discontinue study treatment. 
Study treatment can be dose reduced to 250 mg bid as a first step, and to 200 mg bid as a 
second step. Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 adverse event 
occurs which the investigator considers to be related to administration of study treatment. 


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5.4.12.1 Management of new or worsening pulmonary symptoms  
If new or worsening pulmonary symptoms (e.g., 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 CT scan) should be performed to 
exclude pneumonitis. 
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. 
5.4.12.2 Management of nausea and vomiting 
Events of nausea and vomiting are known to be associated with olaparib treatment. In study 
D0810C00019 nausea was reported in 71% of the olaparib treated patients and 36% in the 
placebo treated patients and vomiting was reported in 34% of the olaparib treated patients and 
14% in the placebo treated patients. These events are generally mild to moderate (CTCAE 
grade 1 or 2) 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). 
As per international guidance on anti-emetic use in cancer patients (NCCN), generally a single 
agent antiemetic should be considered, e.g., dopamine receptor antagonist, antihistamines or 
dexamethasone. 
5.4.12.3 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 AZ study physician. 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF.  
Study treatment should be stopped 1 day before prostatectomy. No stoppage of study 
treatment is required for any needle biopsy procedure. 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
radiation treatment. Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered. 


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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 4 
Dose reductions for study treatment 
Initial Dose 
Following re-challenge post 
interruption: Dose reduction 1 
Dose reduction 2 
300mg twice daily 
250mg twice daily 
200mg twice daily 
 
5.5 
Concomitant and post-study treatment(s) 
The use of any natural/herbal products or other traditional remedies should be discouraged, 
but use of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the case report form (CRF). 
Medications that may NOT be administered 
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (Hormone 
replacement therapy (HRT) is acceptable), radiotherapy, biological therapy or other novel 
agent) is to be permitted while the patient is receiving study medication. 
Live virus and live bacterial vaccines should not be administered whilst the patient is 
receiving study medication and during the 30 day follow up period. An increased risk of 
infection by the administration of live virus and bacterial vaccines has been observed with 
conventional chemotherapy drugs and the effects with olaparib are unknown. 
Restricted concomitant medications 
Strong or Moderate CYP3A inhibitors  
Known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, boosted 
protease inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate 
CYP3A inhibitors (ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) should not 
be taken with olaparib. 
If there is no suitable alternative concomitant medication then the dose of olaparib should be 
reduced for the period of concomitant administration. The dose reduction of olaparib should 
be recorded in the CRF with the reason documented as concomitant CYP3A inhibitor use.  
• 
Strong CYP3A inhibitors – reduce the dose of olaparib to 100mg 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 to 150mg 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 dose can be re-escalated. 


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Strong or Moderate CYP3A inducers 
Strong (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide and St John’s Wort) and moderate CYP3A inducers (eg. bosentan, 
efavirenz, modafinil) of CYP3A should not be taken with olaparib. 
If the use of any strong or moderate CYP3A inducers are considered necessary for the 
patient’s safety and welfare this could diminish the clinical efficacy of olaparib. 
If a patient requires use of a strong or moderate CYP3A inducer or inhibitor then they must be 
monitored carefully for any change in efficacy of olaparib. 
P-gp inhibitors 
It is possible that co-administration of P-gp inhibitors (eg amiodarone, azithromycin) may 
increase exposure to olaparib. Caution should therefore be observed. 
Effect of olaparib on other drugs 
Based on limited in vitro data, olaparib may increase the exposure to substrates of CYP3A4, 
P-gp, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K.  
Based on limited in vitro data, olaparib may reduce the exposure to substrates of CYP3A4, 
CYP1A2, 2B6, 2C9, 2C19 and P-gp.  
The efficacy of hormonal contraceptives may be reduced if co administered with olaparib.  
Caution should therefore be observed if substrates of these isoenzymes or transporter proteins 
are co-administered. 
Examples of substrates include: 
• CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine 
• CYP1A2 – duloxetine, melatonin 
• CYP2B6 – bupropion, efavirenz 
• CYP2C9 – warfarin  
• CYP2C19 - lansoprazole, omeprazole, S-mephenytoin 
• P-gp - simvastatin, pravastatin, digoxin, dabigatran, colchicine 
• OATP1B1 - bosentan, glibenclamide, repaglinide, statins and valsartan 
• OCT1, MATE1, MATE2K – metformin 
• OCT2  - serum creatinine 
• OAT3  -furosemide, methotrexate 
Anticoagulant Therapy 
Patients who are taking warfarin may participate in this trial; however, it is recommended that 
international normalised ratio (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. 


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Anti-emetics/Anti-diarrheals 
If a patient develops nausea, vomiting and / or diarrhea, then these symptoms should be 
reported as AEs and appropriate treatment of the event given. 
Administration of other anti-cancer agents 
Patients must not receive any other concurrent anti-cancer therapy, including investigational 
agents, while on study treatment.  
5.5.1 
Medications that may NOT be administered 
No chemotherapy, immunotherapy, hormonal therapy or other novel agent is to be permitted 
while the patient is receiving study medication. 
5.6 
Treatment compliance 
5.6.1 
Accountability 
At each study visit patients will be asked about missed or lost doses.  Pill diaries will be 
completed by the patients while on study.  Pill bottles and any unused medications will be 
returned by the patient at each study visit. If diary is not returned at the time of the visit, the 
patient will be required to send the pill diary to the research coordinator.  The investigational 
drug service (IDS) will count returned pills; the pill diaries and pill counts will be reconciled 
by the study coordinator using drug accountability CRF.  Treatment compliance will be 
defined as the number of tablets taken during the study divided by the expected number of 
tablets, multiplied by 100%.  Tablets that are not returned will be considered to have been 
taken, unless otherwise reported by the patient as not having been taken.  Unused pills will be 
destroyed on site by the IDS.   
5.7 
Discontinuation of investigational product 
Patients may be discontinued from investigational product (IP) in the following situations: 
Patient decision.  The patient is at any time free to discontinue treatment, without prejudice to 
further treatment 
Adverse Event 
Severe non-compliance with the study protocol  
Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute myeloid 
leukemia (AML) 
 
5.7.1 
Procedures for discontinuation of a subject from investigational product  
If patient is discontinued from olaparib for one month continuous duration due to toxicity or 
other conditions, the patient will proceed to prostatectomy as clinically indicated.   


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5.8 
Withdrawal from study 
Patients may withdraw from study at any time. Patients who are unable to receive more than 6 
weeks of olaparib prior to prostatectomy will be replaced to reach total target enrollment.  
6. 
COLLECTION OF STUDY VARIABLES 
6.1 
Recording of data 
Data delineated in section 5.4 will be collected and will also be entered into a study specific 
Redcap database for collation of patient characteristics and adverse events. Patients will 
maintain pill diaries which will be returned at each study visit and reconciled by the research 
coordinator and IDS as previously described. Pathologic stage at prostatectomy will be as per 
the pathology report by site pathologist and kept in the study binders.  
6.2 
Efficacy 
The primary endpoint is to determine the pathologic complete response induced by the 
administration of olaparib at approximately 90 days (12 weeks).  The primary efficacy 
analysis will estimate the proportion of patients who achieve a pathological complete response 
after neoadjuvant therapy upon radical prostatectomy.  Pathologic stage (and complete 
response) will be assessed by pathologists at the institution.  The detailed procedures for 
assessment of pathologic endpoints is contained in the laboratory manual.  
6.3 
Safety 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
6.3.1 
Definition of adverse events 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
6.3.2 
Olaparib adverse events of special interest 
Adverse events of special interest [AESI] are events of scientific and medical interest specific 
to the further understanding of olaparib’s safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca. An AESI may be serious or non-serious. 
Adverse Events of Special Interest for olaparib are the Important Potential Risks of 
MDS/AML, new primary malignancy (other than MDS/AML) and pneumonitis.   


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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’s assessment of causality or knowledge of the 
treatment arm.    
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. 
6.3.3 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, 
treatment, wash-out, follow-up), at any dose of the study drugs that fulfills one 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 
intervention to prevent one of the outcomes listed above. 
 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed 
by the investigator(s) and communicated to AstraZeneca. 
6.3.4 
Recording of adverse events 
Adverse events will be assessed at study visits and if necessary, at unscheduled evaluations.  
Time period for collection of adverse events 
Adverse events and SAE will be collected from the time of patient consent until 30 days after 
prostatectomy.  
6.3.4.1 
Adverse events after the 30 day follow up period  
For Pharmacovigilance purposes and characterization, any case of MDS/AML or new primary 
malignancy occurring after the 30 day follow up period should be reported to AstraZeneca 
Patient Safety whether it is considered a non-serious AE (e.g., non-melanoma skin cancer) or 
SAE, and regardless of investigator’s assessment of causality or knowledge of the treatment 
arm.  Investigators will be asked during the regular follow up for overall survival if the patient 
has developed MDS/AML or a new primary malignancy and prompted to report any such 
cases.   


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Drug Substance Olaparib (AZD2281, KU-0059436) 
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Edition Number 4.0 
Date 04/12/2020 
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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/she considers there is a reasonable 
possibility that the event is causally related to the investigational product, the investigator 
should notify AstraZeneca, Patient Safety. 
If patients who are gaining clinical benefit are allowed to continue study treatment post data 
cut off and/or post study completion then all SAEs must continue to be collected and reported 
to Patient Safety within the usual timeframe. 
Otherwise, after study treatment completion (i.e. 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 (30 
days). 
Follow-up of unresolved adverse events 
Adverse events will be followed until resolution or until the investigator determines that the 
adverse event is not expected to return to baseline.   
The following variables will be collected for each AE: 
AE (verbatim) 
The date when the AE started and stopped 
NCI CTCAE grade and the maximum CTC grade attained 
Whether the AE is serious or not 
Investigator causality rating against the Investigational Product (yes or no)  
Action taken with regard to investigational product/comparator/combination agent 
Outcome. 
 
In addition, the following variables will be collected for SAEs: 
Date AE met criteria for serious AE 
Date Investigator became aware of serious AE 
AE is serious due to 
Date of hospitalization 
Date of discharge 
Probable cause of death 
Date of death 
Autopsy performed 
Description of AE 
Causality assessment in relation to Study procedure(s) 
Causality assessment in relation to Other medication 
 


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It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.3.3.  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 a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE. 
Adverse Events based on signs and symptoms 
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. 
Adverse Events based on examinations and tests 
Deterioration as compared to baseline in protocol-mandated 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 investigational product. 
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 hemoglobin value). In the absence of 
clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
Note: Cases where a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN may 
need to be reported as SAEs, please refer to Appendix B ‘Actions required in cases of 
combined increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for further 
instructions. 
Disease progression 
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  The 
development of worsening urinary symptoms or metastases 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. 


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New cancers 
The development of a new primary cancer (including skin cancer) should be regarded as an 
AE (see Olaparib Adverse Events of Special Interest).  New primary malignancies are those 
that are not the primary reason for the administration of the study treatment and have 
developed after the inclusion of the patient into the 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. 
Lack of efficacy 
When there is deterioration in the condition for which the study treatment(s) is being used  
(prostate cancer) there may be uncertainty as to whether this is lack of efficacy or an AE.  In 
such cases, unless the Sponsor or the reporting physician considers that the study treatment 
contributed to the deterioration of the condition, or local regulations state to the contrary, the 
deterioration should be considered to be a lack of efficacy and not an AE. 
Deaths 
All deaths that occur during the study, or within the protocol-defined 30-day post-study 
follow-up period after the administration of the last dose of study treatment, must be reported 
as follows: 
Death clearly the result of disease progression should be reported to the study monitor at the 
next monitoring visit and should be documented in the eCRF but 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 as a SAE within 24 hours (see 
Section 6.3.5 for further details).  The report should contain a comment regarding the 
co-involvement of progression of disease, if appropriate, and should assign main and 
contributory causes of death.  This information can be captured in the ‘death eCRF’. 
Deaths with an unknown cause should always be reported as a SAE.  A post mortem maybe 
helpful in the assessment of the cause of death, and if performed a copy of the post-mortem 
results should be forwarded to AstraZeneca within the usual timeframes. 
6.3.5 
Reporting of serious adverse events 
Investigators and other site personnel must inform the FDA, via a MedWatch/AdEERs form, 
of any serious or unexpected adverse events that occur in accordance with the reporting 
obligations of 21 CFR 312.32, and will concurrently forward all such reports to AZ.  A copy 
of the MedWatch/AdEERs report must be faxed to AstraZeneca at the time the event is 
reported to the FDA.  It is the responsibility of the investigator to compile all necessary 
information and ensure that the FDA receives a report according to the FDA reporting 
requirement timelines and to ensure that these reports are also submitted to AstraZeneca at the 
same time. 


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* A cover page should accompany the MedWatch/AdEERs form indicating the following: 
External Scientific Research (ESR) 
The investigator IND number assigned by the FDA 
The investigator’s name and address 
The trial name/title and AstraZeneca ESR reference number 
 
* Investigative site must also indicate, either in the SAE report or the cover page, the causality 
of events in relation to all study medications and if the SAE is related to disease progression, 
as determined by the principal investigator. 
* Send SAE report and accompanying cover page by way of Email to 
AEMailboxClinicalTrialTCS@astrazeneca.com or by fax to AstraZeneca’s designated fax 
line:  
If a non-serious AE becomes serious, this and other relevant follow-up information must also 
be provided to AstraZeneca and the FDA. 
Serious adverse events that do not require expedited reporting to the FDA need to be reported 
to AstraZeneca preferably using the MedDRA coding language for serious adverse events.  
This information should be reported on a monthly basis and under no circumstance less 
frequently than quarterly. 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to 
the investigational product.  All SAEs will be documented.  The investigator is responsible for 
informing the IRB and/or the Regulatory Authority of the SAE as per local requirements. 
Non-serious adverse events and SAEs will be collected from the time study drug is given, 
throughout the treatment period and up to and including the 30 day follow-up period.  After 
withdrawal from treatment, subjects must be followed-up for all existing and new AEs for 30 
calendar days after the last dose of trial drug and/or until event resolution.  All new AEs 
occurring during that period must be recorded (if SAEs, then they must be reported to the 
FDA and AstraZeneca).  All study-related toxicities/ SAEs must be followed until resolution, 
unless in the Investigator’s opinion, the condition is unlikely to resolve due to the patient’s 
underlying disease. 
6.3.6 
Laboratory safety assessment 
Full hematology assessments for safety (hemoglobin, red blood cells (RBC), platelets, mean 
cell volume (MCV), median cell hemoglobin concentration (MCHC), mean cell hemoglobin 
(MCH), white blood cells (WBC), absolute differential white cell count (neutrophils, 
lymphocytes, monocytes, eosinophils and basophils) and absolute neutrophil count or 
segmented neutrophil count and Band forms should be performed at each visit and when 
clinically indicated.  If absolute differentials not available please provide % differentials. 
Coagulation, activated partial thromboblastin time (APTT) and international normalized ratio 
(INR) will be performed at baseline and if clinically indicated unless the patient is receiving 


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warfarin. Patients taking warfarin may participate in this study; however, it is recommended 
that prothrombin time, INR and APTT, be monitored carefully at least once per week for the 
first month, then monthly if the INR is stable. 
Biochemistry assessments for safety (sodium, potassium, calcium, magnesium, random 
glucose, creatinine, total bilirubin, alkaline phosphatase [ALP], aspartate transaminase [AST], 
alanine transaminase [ALT], urea or blood urea nitrogen [BUN], and total protein will be 
monitored per the schedule of activities. 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
hematological toxicities as defined in Section 5.4.11. These tests will be performed by the 
hospital’s local laboratory.  Additional analyses may be performed if clinically indicated.  Any 
clinically significant abnormal laboratory values should be repeated as clinically indicated and 
recorded on the eCRF. 
Abnormal laboratory values which fall with the ranges defined as requiring dose modification 
(Section 6.4.11) will be addressed as described. 
In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer to 
Appendix B ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions 
For blood volume see Section 7.1. 
6.3.7 
Physical examination 
A complete physical examination includes assessment of the following; General appearance, 
respiratory, cardiovascular, abdomen, skin, head and neck, lymph nodes, spine and extremity 
and neurologic systems.  Complete physical examination will occur at screening, baseline, 90 
day visit prior to prostatectomy and at the time of any evaluations outside of scheduled visits 
for toxicity or progression. Limited physical examination is directed towards patient reported 
symptoms; and cardiac, respiratory, and gastrointestinal systems. This will occur at 30 and 60 
day visits.  
 
6.3.8 
ECG 
6.3.8.1 
Resting 12-lead ECG 
ECGs are required within 28 days prior to starting study treatment and when clinically 
indicated. 
Twelve-lead ECGs will be obtained after the patient has been rested in a supine position for at 
least 5 minutes in each case.  The Investigator or designated physician will review the paper 
copies of each of the timed 12-lead ECGs on each of the study days when they are collected. 
Heart rate, P and QRS durations, PR, QT and QTc intervals will be recorded from standard 
lead of the computerized quantitative 12-lead ECG.  


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ECGs will be recorded at 25 mm/sec.  All ECGs should be assessed by the investigator as to 
whether they are clinically significantly abnormal / not clinically significantly abnormal.  If 
there is a clinically significant abnormal finding, the Investigator will record it as an AE on 
the eCRF.  The original ECG traces must be stored in the patient medical record as source 
data. 
6.3.9 
Vital signs 
Vital signs will be performed as per the schedule of events (Table 6) 
6.3.9.1 
Pulse and blood pressure 
Blood pressure and pulse rate will be measured using standard clinic vital signs monitoring 
devices or with cuff in the clinic rooms. For timings of assessments refer Schedule of events 
(Table 6) 
6.3.9.2 
Body temperature 
Body temperature will be measured in degrees Celsius using an automated thermometer at the 
times indicated in the Study Plan and Time Schedule (Table 6)  
6.3.10 
Other safety assessments 
6.3.10.1 Bone marrow or blood cytogenetic analysis 
Bone marrow or blood cytogenetic analysis may be performed according to standard 
hematological practice for patients with prolonged hematological toxicities as defined in 
Section 5.4.11. 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.  If findings are 
consistent with MDS/AML, study drug should be discontinued and a full description of 
findings should be submitted with an SAE report by the investigator to AstraZeneca Patient 
Safety for documentation on the Patient Safety database. Presence or absence of blood 
cytogenetic abnormalities and flow cytometry will be documented on the clinical database.      
7. 
BIOLOGICAL SAMPLING PROCEDURES 
7.1 
Volume of blood 
The total volume of blood that will be drawn from each subject in this study is as follows: 
Table 5 
Volume of blood to be drawn from each subject 
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
Safety 
Clinical chemistry 
5 
5 
25 


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Table 5 
Volume of blood to be drawn from each subject 
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
 
Hematology 
3 
 
5 
15 
 
Coagulation 
2 
1 
2 
 
PSA 
3 
4 
15 
Biomarker 
ctDNA/serum 
20 
5 
100 
 
 
 
 
Total 
33 
21 
157 
 
7.2 
Handling, storage and destruction of biological samples 
7.2.1 
Circulating DNA samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality.  DNA is a finite resource that may be used up 
during analyses.  Samples will be stored and used until no further analyses are possible or the 
maximum storage time has been reached (15 years). 
For all samples irrespective of the type of coding used the DNA will be extracted from the 
blood sample.  The DNA sample will be assigned a unique number replacing the information 
on the sample tube. Thereafter, the DNA sample will be identifiable by the unique DNA 
number only.  The DNA number is used to identify the sample and corresponding data.  No 
personal details identifying the individual will be available to any person (AstraZeneca 
employee or laboratory staff working with the DNA). 
The samples and data for genetic analysis in this study will be single coded.  The link between 
the subject enrollment code and the DNA number will be maintained and stored in a secure 
environment, with restricted access.  The link will be used to identify the relevant DNA 
samples for analysis, facilitate correlation of genotypic results with clinical data, allow 
regulatory audit and to trace samples for destruction in the case of withdrawal of consent 
when the subject has requested disposal/destruction of collected samples not yet analyzed.  
 
7.3 
Chain of custody of biological samples 
The Principal Investigator ensures that samples are labelled and stored in accordance with the 
Laboratory Manual. The PI keeps traceability of the samples while in storage until disposed of 
or used in entirety.  


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7.4 
Withdrawal of informed consent for donated biological samples 
If a subject withdraws consent for the use of their donated samples, their unused samples will 
be disposed of/destroyed, and the action documented.  In the event some or all of their 
samples have already been used at the time of consent withdrawal, data from these samples 
may still be included in the study analysis at the Investigator’s discretion. 
The Principal Investigator: 
Ensures that biological samples from that subject, if stored at the study site, are immediately 
identified, disposed of /destroyed, and the action documented 
Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn consent 
immediately and that samples are disposed/destroyed, the action documented and the signed 
document returned to the study site 
Ensures that the subject is informed about the sample disposal. 
The Principal Investigator must notify AstraZeneca if consent is withdrawn.   
8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements.  
8.2 
Subject data protection  
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law. 
8.3 
Ethics and regulatory review 
The Cancer Consortium IRB provides ethics oversight and should approve the final clinical 
study protocol, including the final version of the informed consent form and any other written 
information and/or materials to be provided to the patients. This will include an approval of 
the exploratory biomarker research.  The investigator will ensure the distribution of these 
documents to the applicable review committees and study staff.  
8.4 
Informed consent 
The principal investigator will: 


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• Ensure that each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study and the biomarker research 
components.  
• Ensure that each patient is notified that they are free to withdraw from the study or the 
research components at any time 
• Ensure that each patient is given the opportunity to ask questions and allowed time to 
consider the information provided 
• Ensure that each patient provides signed and dated informed consent before 
conducting any procedure specifically for the study 
• Ensure each original, signed informed consent form is stored in the Investigator’s 
study file 
• Ensure a copy of each signed informed consent form is given to the patients 
Subjects may withdraw at any time from study.  
 
8.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without mutual agreement of the Principal Investigator 
and AstraZeneca. If there are any substantial changes to the protocol, then these changes will 
be documented in a protocol amendment and where required in a new version of the protocol. 
The amendment should be approved by the IRB and any other applicable authorities before 
implementation. Local requirements should be followed for revised protocols.   
If a protocol amendment requires a change to the informed consent form, AstraZeneca and the 
center’s IRB should approve the revised consent form before it is used.  
 
 
8.6 
Audits and inspections 
Authorized representatives of AstraZeneca, regulatory authories or IRB committee may 
perform audits or inspections, including source data verification. The purpose of an audit is to 
systematically and independently examine all study activities and documents to determine 
whether these activities were conducted and data were receord, analyzed and reported 
according to Good Clinical Practice (GCP) guidelines of the International Conference on 
Harmonisation (ICH) and any applicable regulatory requirements.  The investigator will 
contact AstraZeneca immediately if contacted by a regulatory agency about an inspection.  


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9. 
STUDY MANAGEMENT 
9.1 
Training of study site personnel 
Before the first patient is entered into the study, an AstraZeneca representative 
will visit the study site to review and discuss the requirements of the Clinical Study Protocol 
and related documents with the investigational staff and also to train them in any study 
specific procedures.  The Principal Investigator will ensure that appropriate training relevant 
to the study is given to all of the staff, and that any new information relevant to the 
performance of this study is forwarded to the staff involved. The Principal Investigator will 
maintain a record of all staff members involved in the study.  
9.2 
Monitoring of the study  
Trial monitoring will be in accordance with the Fred Hutchinson Cancer Research Center 
(FHCRC)/University of Washington (UW) Cancer Consortium Institutional Data and Safety 
Monitoring Plan. Under the provisions of this plan, FHCRC Clinical Research Support 
coordinates data and compliance monitoring conducted by consultants, contract research 
organizations, or FHCRC employees unaffiliated with the conduct of the study. Independent 
monitoring visits occur at specified intervals determined by the assessed risk level of the study 
and the findings of previous visits per the institutional DSMP.  
In addition, protocols are reviewed at least annually and as needed by the Consortium Data 
and Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) and 
the FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB).  
The review committees evaluate accrual, adverse events, stopping rules, and adherence to the 
applicable data and safety monitoring plan for studies actively enrolling or treating patients.  
The IRB reviews the study progress and safety information to assess continued acceptability 
of the risk-benefit ratio for human subjects.  Approval of committees as applicable is 
necessary to continue the study. 
The trial will comply with the standard guidelines set forth by these regulatory committees 
and other institutional, state and federal guidelines. 
9.3 
Source data 
Source data will be maintained as a combination of the electronic medical record and/or paper 
CRFs in the patient’s study binder which will kept in a secure location at UW/SCCA and in a 
password protected REDCAP database.  
9.4 
Study timetable and end of study 
Enrollment is projected to be 36 months from the time of IRB approval and End of Study/Last 
patient visit to be four months later.  
9.5 
Data management 
Data management will be performed using paper CRFs and subsequently recorded in 
institutional REDCAP database.    


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Adverse events and medical/surgical history will be classified according to the terminology of 
CTCAE 4.03 and the Medical Dictionary for Regulatory Activities (MedDRA). Medications 
will be classified according to the MedImmune/ AstraZeneca Drug Dictionary.  Data queries 
will be raised for inconsistent, impossible or missing data. All entries to the study database 
will be available in an audit trail. 
 
10. 
EVALUATION AND CALCULATION OF VARIABLES 
10.1 
Calculation or derivation of efficacy variable(s) 
At the time of prostatectomy the pathologic stage will be assessed by the site pathologists, 
including presence or absence of detectable tumor on histology.  Pathologic complete 
response will be based purely on light microscopy without immunohistochemistry.  The 
pathologic stage T0-T4, presence or absence of margin involvement (R0 vs .R1), presence or 
absence of nodal metastasis (N0 vs. N1) Calculation or derivation of safety variable(s). 
Tumor load is a metric that may be explored if there is evidence of downstaging and will be 
calculated using 1) largest cross-sectional dimension of tumor in reconstructed “whole cross-
sectional slices,” with minimal residual disease (MRD) defined as ≤ 0.5 cm; and 2) RCB, with 
tumor volume calculated by using 3D volume estimation based on the largest cross-sectional 
tumor dimension and number of cross-sections involved by tumor, corrected for tumor 
cellularity, with MRD defined as RCB ≤ 0.25 cc (TV ≤ 0.5 cc × TC ≤ 50%).  Residual tumor 
volume will be determined and analyzed as both a continuous and dichotomized variable as a 
function of type of therapy, residual androgen receptor signaling and subsequent analyses of 
PSA relapse that may be performed in the future.   Pathologic complete response, defined as 
the absence of morphologically identifiable carcinoma in the prostatectomy specimen, will be 
determined following radical prostatectomy.  A needle biopsy will be reviewed initially to 
confirm malignancy.  The evaluation of prostatectomy specimens without residual cancer will 
be based on ISUP working guidelines for specimen handling (Samaratunga et al, 2011) and 
modified as appropriate for postneoadjuvant treatment.  Atypical foci should be 
immunostained for alpha methyl CoA racemase (AMACR) and basal cell markers, and 
cytokeratin and prostate specific antigen (PSA), where appropriate.  If no cancer is found in 
the radical prostatectomy specimen after detailed examination, the tumor should be classified 
as pT0 (pathologic complete response).   
Gleason scoring of the prostatectomy sample will be performed, however may not be 
appropriate as is the case following treatment with hormonal therapy.  However, morphologic 
tumor response will be documented by applying post therapy histologic classification 
according to the guidelines of the MD Anderson Cancer Center (Efstathiou et al, 2010).   
Safety and tolerability will be assessed in terms of AEs, laboratory data, vital signs, ECG 
changes. These will be collected for all subjects. Summaries of data will be presented.  


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10.2 
Other significant adverse events (OAE) 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and DAEs.  Based on the expert’s judgment, 
significant adverse events of particular clinical importance may, after consultation with the 
Global Patient Safety Physician, be considered OAEs and reported as such.  A similar review 
of laboratory/vital signs/ECG data may be performed for identification of OAEs. 
Examples of these are marked hematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment. 
There are currently no identified OAEs for olaparib. 
11. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
11.1 
Description of analysis sets 
11.1.1 
Efficacy Analysis Set   
Patients who receive olaparib for the complete planned neoadjuvant cycle and proceed to 
prostatectomy with tissue available for analysis of pathologic endpoints will be the efficacy 
analysis set.  Patients who do not complete the treatment regimen or do not proceed to 
prostatectomy may be replaced in order to reach the target accrual for efficacy after discussion 
with principal investigator and sponsor 
11.1.2 
Safety Analysis Set 
Patients who have receive at least one dose of treatment and are evaluable for toxicity will be 
included in the Safety Analysis Set 
11.2 
Determination of sample size 
This is a pilot study assessing whether PARP inhibition with olaparib has the capacity to 
induce high pathologic complete respone (pCR) rates in men with tumors harboring DNA 
repair deficiencies (i.e. induce synthetic lethality). The primary efficacy endpoint will be the 
pCR rate as determined on prostatectomy specimens following 12-weeks of neoadjuvant 
olaparib. The historical complete response rate to 3-8 months of androgen deprivation with 
LHRH agonist and androgen receptor antagonist is ~10% (H0). We anticipate a complete 
response rate of ≥40% (H1) following 12-weeks of olaparib in patients with homologous 
DNA repair deficient tumors (truncal mutations/copy loss). Therefore, a sample size of 15 
patients would yield 80% power to detect a difference between the null and alternative 
pathologic complete response rates at a two-sided alpha = 0.05 


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11.3 
Methods of statistical analysis 
Statistical analyses will be performed using all patients with evaluable data (e.g., pathologic 
staging among those who had a prostatectomy, and safety data among those who receive a 
dose of olaparib).   
For efficacy analysis pathologic complete response is defined as the absence of 
morphologically identifiable carcinoma in the prostatectomy specimen, as evaluated by the 
site pathologist using standard methods. Formalin-fixed, paraffin-embedded slides will be 
evaluated by a central pathology review at completion of the study.  Comparison of the actual 
pathologic complete response rate with the historial rate of 10%.   
For safety analyses, all patients who received at least one dose of study drug and had at least 
one post-baseline safety assessment will be evaluated. Data will be descriptive, describing 
frequency of grade 1-5 adverse events. Data from all cycles of treatment will be combined in 
the presentation of safety data. AE will be listed individually by subject.  The number of 
subjects experiencing each AE will be summarized by the Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class, MedDRA preferred term and CTCAE grade. The 
number and percentage of subjects with adverse events in different categories (e.g. causally 
related, CTCAE grade ≥3 etc.) will be summarized. Any AE occurring before the first dose of 
investigational product (i.e. before study Day 1) will be included in the data listings but will 
not be included in the summary tables of adverse events. Any AE occurring within the defined 
90 day follow-up period after discontinuation of olaparib will be included in the AE 
summaries. Hematology, clinical chemistry, vital signs, ECG data, demographic data, medical 
histories and concomitant medications will be listed individually by subject. For all laboratory 
variables, which are included in the current version of CTCAE, the CTCAE grade will be 
calculated. Summary statistics of mean, median, standard deviation, minimum, maximum and 
number of observations will be used. Details of any deaths will be listed for all subjects. 
  
 
 
 
 


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12. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
12.1 
Medical emergencies and AstraZeneca contacts 
The Principal Investigator(s) is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes a SAE and is to be reported as such. In the case of a medical emergency the 
investigator may contact the Study Team Physician. 
12.2 
Overdose  
There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established.  Olaparib must only be used in accordance with the 
dosing recommendations in this protocol. Any dose or frequency of dosing that exceeds the 
dosing regimen specified in this protocol should be reported as an overdose. The Maximum 
Tolerated Dose is 300 mg bid (tablet). 
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 CRF module. 
An overdose without associated symptoms is only reported on the Overdose CRF module. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
investigators or other site personnel inform appropriate AstraZeneca representatives within 
one day, i.e., immediately but no later than the end of the next business day of when he or 
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 SAE, standard reporting timelines apply.  For other overdoses, 
reporting should be done within 30 days.  
12.3 
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca. 
12.3.1 
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
3 months following the last dose. 


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Pregnancy of the patient’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should, if possible, be followed up and documented.  
The outcome of any conception occurring from the date of the first dose until 3 months after 
the last dose should be followed up and documented. 
 
 


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13. 
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Castro E, Goh C, Olmos D, et al: Germline BRCA mutations are associated with higher 
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Cancer Genome Atlas Research N: The Molecular Taxonomy of Primary Prostate 
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10. Gudmundsson J, Johannesdottir G, Bergthorsson JT, et al: Different tumor types from 
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11. Lord CJ, Ashworth A: The DNA damage response and cancer therapy. Nature 481:287-
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17. Ledermann J, Harter P, Gourley C, et al: Olaparib maintenance therapy in patients with 
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sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: 


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an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. 
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19. Swisher EM, Lin KK, Oza AM, et al: Rucaparib in relapsed, platinum-sensitive high-
grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, 
phase 2 trial. Lancet Oncol 18:75-87, 2017 
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21. Grossman HB, Natale RB, Tangen CM, et al: Neoadjuvant chemotherapy plus 
cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl 
J Med 349:859-66, 2003 
22. Center for Drug Evaluation and Research. Food and Drug Administration UDoHaHSSS, 
MD: Food and Drug Administration; : : Guidance for Industry: Pathological Complete 
Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an 
Endpoint to Support Accelerated Approval. 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm305501.pdf.  
23. Park JW, Liu MC, Yee D, et al: Adaptive Randomization of Neratinib in Early Breast 
Cancer. N Engl J Med 375:11-22, 2016 
24. Rugo HS, Olopade OI, DeMichele A, et al: Adaptive Randomization of Veliparib-
Carboplatin Treatment in Breast Cancer. N Engl J Med 375:23-34, 2016 
25. Chi KN, Chin JL, Winquist E, et al: Multicenter phase II study of combined neoadjuvant 
docetaxel and hormone therapy before radical prostatectomy for patients with high risk 
localized prostate cancer. J Urol 180:565-70; discussion 570, 2008 
26. Gleave ME, Goldenberg SL, Chin JL, et al: Randomized comparative study of 3 versus 8-
month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and 
pathological effects. J Urol 166:500-6; discussion 506-7., 2001 
27. Ohlson N, Wikstrom P, Stattin P, et al: Cell proliferation and apoptosis in prostate tumors 
and adjacent non-malignant prostate tissue in patients at different time-points after 
castration treatment. Prostate 62:307-15, 2005 
28. Mostaghel EA, Nelson PS, Lange P, et al: Targeted androgen pathway suppression in 
localized prostate cancer: a pilot study. J Clin Oncol 32:229-37, 2014 
29. Taplin ME, Montgomery B, Logothetis CJ, et al: Intense androgen-deprivation therapy 
with abiraterone acetate plus leuprolide acetate in patients with localized high-risk 
prostate cancer: results of a randomized phase II neoadjuvant study. J Clin Oncol 
32:3705-15, 2014 
30. Montgomery B, Tretiakova MS, Joshua AM, et al: Neoadjuvant Enzalutamide Prior to 
Prostatectomy. Clin Cancer Res, 2016 
31. Agus DB, Cordon-Cardo C, Fox W, et al: Prostate cancer cell cycle regulators: response 
to androgen withdrawal and development of androgen independence. J Natl Cancer Inst 
91:1869-76, 1999 
32. Westin P, Stattin P, Damber JE, et al: Castration therapy rapidly induces apoptosis in a 
minority and decreases cell proliferation in a majority of human prostatic tumors. Am J 
Pathol 146:1368-75, 1995 
33. Hull GW, Rabbani F, Abbas F, et al: Cancer control with radical prostatectomy alone in 
1,000 consecutive patients. J Urol 167:528-34, 200234. 
Breast Cancer Linkage C: 
Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91:1310-6, 1999 


Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
53(61) 
35. Mersch J, Jackson MA, Park M, et al: Cancers associated with BRCA1 and BRCA2 
mutations other than breast and ovarian. Cancer 121:269-75, 2015 
36. Pritchard CC, Mateo J, Walsh M, et al: Inherited DNA-Repair Gene Mutations in Men 
with Metastatic Prostate Cancer. N Engl J Med 1056/NEJMoa1603144, 2016 
37. Travis LB, Holowaty EJ, Bergfeldt K, et al: Risk of leukemia after platinum-based 
chemotherapy for ovarian cancer. N Engl J Med 340:351-7, 1999 
38. Cooperberg MR, Vickers AJ, Broering JM, et al: Comparative risk-adjusted mortality 
outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for 
localized prostate cancer. Cancer 116:5226-34, 2010 
39. Zelefsky MJ, Eastham JA, Cronin AM, et al: Metastasis after radical prostatectomy or 
external beam radiotherapy for patients with clinically localized prostate cancer: a 
comparison of clinical cohorts adjusted for case mix. J Clin Oncol 28:1508-13, 2010 
40. Bancroft EK, Page EC, Castro E, et al: Targeted prostate cancer screening in BRCA1 and 
BRCA2 mutation carriers: results from the initial screening round of the IMPACT study. 
Eur Urol 66:489-99, 2014 
41. Fossati N, Rossi MS, Cucchiara V, et al: Evaluating the effect of time from prostate 
cancer diagnosis to radical prostatectomy on cancer control: Can surgery be postponed 
safely? Urol Oncol, 2016 
42. Korets R, Seager CM, Pitman MS, et al: Effect of delaying surgery on radical 
prostatectomy outcomes: a contemporary analysis. BJU Int 110:211-6, 2012 
43. Faraoni I, Compagnone M, Lavorgna S, et al: BRCA1, PARP1 and gammaH2AX in 
acute myeloid leukemia: Role as biomarkers of response to the PARP inhibitor olaparib. 
Biochim Biophys Acta 1852:462-72, 2015 
44. Xu G, Chapman JR, Brandsma I, et al: REV7 counteracts DNA double-strand break 
resection and affects PARP inhibition. Nature 521:541-4, 2015 
45. Jaspers JE, Kersbergen A, Boon U, et al: Loss of 53BP1 causes PARP inhibitor resistance 
in Brca1-mutated mouse mammary tumors. Cancer Discov 3:68-81, 2013 
46. Ray Chaudhuri A, Callen E, Ding X, et al: Replication fork stability confers 
chemoresistance in BRCA-deficient cells. Nature 535:382-7, 2016 
47. Wang Y, Krais JJ, Bernhardy AJ, et al: RING domain-deficient BRCA1 promotes PARP 
inhibitor and platinum resistance. J Clin Invest 126:3145-57, 2016 
48. Norquist B, Wurz KA, Pennil CC, et al: Secondary somatic mutations restoring BRCA1/2 
predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol 29:3008-
15, 2011 
 


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Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
54(61) 
 
Table 6 
Schedule of Assessments 
 
Study Day 
-28 to -1 
Baseline 1 
30 
(±5 days) 
60 
(±5 days) 
90 
(±5 days) 
Surgery 
90 (±14 
days) 
Unscheduled 
visitsa 
End of studyb 
Obtain written informed consent  
X 
 
 
 
 
 
 
 
Medical history, demographics, PSA history 
X 
 
 
 
 
 
 
 
Physical examination c  
X 
[X] 
X 
X 
X 
 
[X] 
X 
Digital rectal examination d 
X 
 
 
 
 
 
[X] 
 
ECOG Performance Status 
X 
[X] 
X 
X 
X 
 
[X] 
X 
Disease staging (CT/MRI, bone scan)e 
X 
 
 
 
 
 
[X] 
 
Inclusion/exclusion review 
X 
X 
 
 
 
 
 
 
Obtain weight, height, vital signs f 
X 
[X] 
X 
X 
X 
 
[X] 
X 
Obtain ECGl 
X 
 
 
 
X 
 
[X] 
 
Hematology and chemistry g 
X 
[X] 
X 
X 
X 
 
[X] 
X 
PSA 
X 
[X] 
X 
X 
X 
 
[X] 
 
PT/PTT 
X 
[X} 
 
 
 
 
 
 
Research blood h 
 
X 
X 
X 
X 
 
[X] 
X 
Adverse event review 
 
X 
X 
X 
X 
 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
 
X 
X 
Dispense oral study drug(s)i 
 
X 
X 
X 
[X] 
 
 
 
Study drug(s) accountability 
 
 
X 
X 
X 
 
[X] 
 
Archival Tissue Sample j 
X 
 
 
 
 
 
 
 
Prostatectomy k 
 
 
 
 
 
X 
 
 
 
NOTE: [X] denotes an optional procedure for that day. 
a Unscheduled visits can be performed at any time to assess the patient for an adverse event or at the discretion of the Investigator. 


Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
55(61) 
b The safety follow-up visit will be conducted approximately 30 days (± 5 days) after the last dose of Olaparib or prior to the initiation of a new systemic antineoplastic 
therapy or investigational agent, whichever occurs first.   
c Patients will undergo a complete physical examination at the Screening visit and Day 90 visit.  For other assessments: limited physical examination (directed towards 
patient reported symptoms; areas of cancer spread; and cardiac, respiratory, and gastrointestinal systems).   
d 
Digital rectal examination should be performed either by the urologic surgeon or the investigator, if not previously performed.  
e Patients will undergo bone scan and computerized tomography (CT)/magnetic resonance imaging (MRI) of the pelvis if defined as having high risk disease or at the 
investigator’s discretion. Any evaluable and measurable disease must be documented within 4 weeks prior to enrollment with a CT scan and/or bone scan (bone scans 
obtained within 8 weeks will be acceptable).  Imaging of the chest, abdomen or head should be performed if clinically indicated. 
f 
Height only at baseline.  Weight and vital signs (blood pressure, heart rate, and temperature) will be taken at each visit.  These assessments do not need to be repeated at the 
Baseline Visit if screening assessments were completed ≤4 days prior to first dose.   
g Blood will be collected and sent to the local laboratory for the analysis of the following:  clinical chemistry, hematology, PSA, serum testosterone.  Baseline: collect if 
screening assessments were done > 28 days prior.  Additional blood will be collected at Baseline and followup visits for ctDNA and plasma. 
h 
Research blood drawn per laboratory manual 
i 
Therapy will continue for 90 days and be discontinued 1 day before prostatectomy for all patients.  If prostatectomy is delayed, dispense an additional bottle of olaparib.     
j 
Tissue from the diagnostic biopsy will be requested (tissue blocks wherever possible; if not possible, 10 unstained slides are to be sent to the study site.  See the Lab Manual 
for processing instructions.  Pathology report (including the assessment of the local pathologist regarding Gleason score) from diagnostic biopsy must accompany 
registration materials.   
k Radical prostatectomy should occur on Day 90; a window of ±14 days is permitted, however oral dosing should continue until 1 day before surgery.  Preoperative and 
postoperative evaluation and treatment will be administered as per the instructions of the surgeon.   
l 
ECG is required within 28 days prior to starting study treatment and when clinically indicated.   


Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
56(61) 
 
Appendix A: Eastern Cooperative Oncology Group Performance Status 
Grade 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all 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.  Cannot carry on any self-care.  Totally confined to bed or chair 
5 
Dead 
 
 
 


Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
57(61) 
Appendix B 
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.  Specific guidance on the managing liver abnormalities can 
be found in Section 5.4.13 of the protocol. 
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. 
The Investigator participates, in review and assessment of cases meeting PHL criteria to agree 
whether Hy’s Law (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 Medicinal Product (IMP, olaparib).  
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. 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication  irrespective of an increase in Alkaline 
Phosphatase (ALP).  
Hy’s Law (HL) 
AST or ALT ≥ 3x ULN  together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, 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 (i.e. on the same day) the elevation in TBL, but there is no specified 
timeframe within which the elevations in transaminases and TBL must occur. 
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 ≥ 3xULN 


Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
58(61) 
• 
AST ≥ 3xULN 
• 
TBL ≥ 2xULN 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• 
Notify the AstraZeneca representative 
• 
Determine whether the patient meets PHL criteria (see Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory CRF 
Follow-up 
Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
• 
Inform the AstraZeneca representative that the patient has not met PHL criteria. 
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
• 
Notify the AstraZeneca representative  
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 three Liver CRF Modules as information becomes available  
• 
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures 


Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
59(61) 
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. 
No later than 3 weeks 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 
IMP.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate.   
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If 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, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
• 
Report an 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 3 weeks 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: 
• 
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above 
• 
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 SAE report according to the outcome of the 
review 
 


Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
60(61) 
References 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436) 
Study Number 9985 
Edition Number 4.0 
Date 04/12/2020 
61(61) 
Appendix C 
Acceptable Birth Control Methods 
Olaparib is regarded as a compound with medium/high fetal risk. 
• 
Women of childbearing potential and their partners, who are sexually active, must 
agree to the use of TWO highly effective forms of contraception in combination (as 
listed below), throughout the period of taking study treatment and for at least 1 month 
after last dose of study drug(s), or they must totally/truly abstain from any form of 
sexual intercourse (see below). 
• 
Male patients and their partners, who are sexually active and of childbearing potential, 
must agree to the use of TWO highly effective forms of contraception in combination 
(as listed below), throughout the period of taking study treatment and for 3 months 
after last dose of study drug(s) due to the unknown effects of the study drug on the 
sperm, or they must totally/truly abstain from any form of sexual intercourse (see 
below). Male patients should not donate sperm throughout the period of taking study 
treatment and for 3 months following the last dose of study drug(s).  
 
Acceptable Non-hormonal birth control methods include: 
• 
Total sexual abstinence.  Abstinence must continue for the total duration of study 
treatment and for at least 1 month after the last dose (for 3 months after last dose for 
male patients). Periodic abstinence (eg, calendar ovulation, symptothermal post 
ovulation methods) and withdrawal are not acceptable methods of contraception. 
• 
Vasectomized sexual partner PLUS male condom. With participant assurance that 
partner received post-vasectomy confirmation of azoospermia. 
• 
Tubal occlusion PLUS male condom  
• 
IUD PLUS male condom.  Provided coils are copper-banded 
Acceptable hormonal methods: 
• 
Normal and low dose combined oral pills PLUS male condom  
• 
Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the only highly 
efficacious progesterone based pill. 
• 
Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom 
• 
Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom  
• 
Norelgestromin / EE transdermal system PLUS male condom  
• 
Intrauterine system [IUS] device (e.g., levonorgestrel releasing IUS -Mirena®) PLUS 
male condom  
• 
Intravaginal device (e.g., EE and etonogestrel) PLUS male condom 

ICF_000.pdf: 
CC9985 
IRO RECD JAW 08 2019 
University of Washington 
Seattle Cancer Care Alliance 
Fred Hutchinson Cancer Research Center 
Consent to take part in a research study: 
OPEN-LABEL, PILOT STUDY OF OLAPARIB AS A NEOADJUVANT 
THERAPY FOR PATIENTS UNDERGOING PROSTECTOMY FOR LOCALIZED 
PROSTATE CANCER 
Principal Investigator Robert Bruce Montgomery, MD. University of Washington; Seattle 
Cancer Care Alliance. Telephone: (206) 598-0860 
Emergency (24-hour) phone: 
(206) 598-6190 Request the on-call Oncology Fellow 
Or 
Emergency (24-hour) pager: 
(206) 559-5058 Robert Bruce Montgomery, MD 
Important things to know about this research study. 
We are inviting you to participate in a research study. Research studies only 
include those who choose to participate. A person who takes part in a research 
study is called a research subject, or research participant. As a research 
participant, you have the right to know about the procedures that will be used in 
this research study so that you can make an informed decision whether or not to 
participate. 
The purpose of this research study is to determine if the study drug (olaparib) 
has an effect on prostate cancer in men planning to undergo prostatectomy 
(surgical removal of the prostate) as treatment for their prostate cancer. If you 
agree to join the study, you will be required to take olaparib twice daily for 90 
days. Following the 90 days of taking olaparib, you will undergo your planned 
prostatectomy. You will also be required to come in for a follow-up visit 
approximately 30 days after the last dose of olaparib. 
We do not know if olaparib will help treat prostate cancer. There could also be 
side effects from taking olaparib. These side effects are described below in this 
form. 
Page 1 of 16 
 
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You do not have to join this study. You could choose to receive standard 
methods to treat prostate cancer instead of participating in this study. We will 
give you details about the purpose, procedures, risks and possible benefits 
related to this study. We will also explain other treatment options to you. We will 
give you any other information that you need in order to make an informed 
decision about whether or not you would like to participate in this study. 
The following is a more complete description of this study. Please read this 
description carefully. You can ask any questions you want to help you decide 
whether to join the study. If you decide to join this study, we will give you a 
signed and dated copy of this consent form to keep for future reference. 
We invite you to join this research study. 
We invite you to join this research study because you have prostate cancer and 
are planning to have your prostate surgically removed. We will enroll up to 15 
patients on this research study. 
Research is not the same as treatment or medical care. The purpose of a 
research study is to answer scientific questions. 
You do not have to be in this research study. You are free to say "yes" or "no," or 
to drop out after joining. There is no penalty or loss of benefits if you say "no." 
Whatever you decide, your regular medical care would not change. 
Why are we doing this research study? 
We are doing this research study to determine whether the study drug olaparib, 
when given to men with prostate cancer prior to surgical removal of their prostate 
will result in favorable changes in the prostate cancer. Specifically, we want to 
know if taking olaparib for 90 days can result in more men with no evidence of 
prostate cancer in their prostate at the time of its surgical removal (this is also 
called a higher pathological complete response rate). In theory, a higher 
pathological complete response rate could increase the chances that men with 
prostate cancer will remain cancer free following their prostatectomy. 
Olaparib is a drug that works by interfering with the activity of a substance called 
PARP, which is inside cells (individual unit that makes up the tissues of the 
body). PARP repairs DNA. DNA is the substance in cells that controls cell 
growth. By interfering with DNA repair, olaparib can decrease the growth of 
cancer cells. A capsule formulation of olaparib (tradename LynparzaTM) is 
approved by both the European Commission (EC), US Food and Drug 
Administration (FDA) and other countries for the treatment of women with 
advanced ovarian cancer. 
A tablet formulation of olaparib is being tested in this study. Olaparib is not 
approved to treat prostate cancer, thus its use in this research study is 
considered investigational or experimental. Olaparib is a drug taken by mouth. 
Page 2 of 16 
 
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CC9985 
If you join this study, we would give you olaparib for 90 days and watch carefully 
for any side effects. 
What research tests, procedures, and treatments are done in 
this study? 
If you join this study, we would do these tests and procedures: 
STUDY PROCEDURES 
Screening Visit (Up to 28 days prior to starting study drugs) 
If you choose to participate in this study, you will first sign this Informed Consent 
Form before any study-related procedures are performed, and your study doctor 
will have up to 28 days to complete screening tests and procedures to see if you 
qualify for the study. Your study doctor will be collecting specific information 
regarding your previous and current treatments you may have had. The following 
tests and procedures will be done at the beginning of the study, also known as 
screening period. Your study doctor can give you more details about these tests 
and procedures. 
• 
We will ask you questions about your medical history, your current health, 
if you suffer from pain or other problems, and if you are taking any other 
medications or have recently been on any other research studies. 
• 
Collect a blood sample (approximately 20 mL or 4 teaspoons) 
o 
to study biomarkers. Biomarkers are DNA, RNA, proteins and other 
molecules in your blood. The intent of this research is to discover 
ways that the study drugs work and how your body responds to 
them. Your blood and tissue samples contain genes, which are 
made up of DNA (deoxyribonucleic acid) and which serve as the 
"instruction manual" for the cells that make up our bodies. RNA 
(ribonucleic acid) helps to carry out DNA's "instructions". Genomic 
research is the study of how variation in DNA and RNA, including 
mutations, can contribute to disease and drug response. The 
Sponsor will look at variation in your genomic and other 
biomarkers. Biomarker information will be analyzed together with 
the clinical data collected in this study. Your samples may also be 
used to help develop new tests. These results are for research 
only. 
o 
for standard laboratory tests 
o 
to measure prostate-specific antigen (PSA) 
• 
Give you a physical examination and digital rectal examination. 
• 
Evaluate ECOG performance status (criteria used to assess how your 
disease is progressing and how the disease affects the daily living 
abilities). 
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• 
Perform an electrocardiogram (ECG) to check the electrical activity of your 
heart. 
• 
Record your vital signs such as heart rate, blood pressure, height and 
weight. 
• 
Assess tumor and document clinical stage of disease. Patients will 
undergo bone scan and Computed Tomography (CT)/Magnetic 
Resonance Imaging (MRI) of the pelvis if defined as having high risk 
disease or at the investigator's discretion. 
Treatment Period  
If you are eligible for this study and choose to participate, you will start the 
study medication, olaparib. You will take two 150 mg tablets of olaparib (300 
mg total) twice daily for 90 days. You should take olaparib tablets at the same 
time each day, approximately 12 hours apart with one glass of water. The 
olaparib tablets should also be swallowed whole, not chewed or crushed, 
dissolved or divided. You should also not drink grapefruit juice while taking 
olaparib, as this can affect the way the study medication works. Olaparib 
tablets can be taken with or without food. You will be given a diary to record 
your study drug dosing. Study staff will instruct you on how to fill out your 
diary. 
If vomiting occurs shortly after the study drug tablets are swallowed, the dose 
should only be replaced if all of the intact tablets can be seen and counted. 
Should you miss a scheduled dose for whatever reason (e.g., as a result of 
forgetting to take the tablets or vomiting), you 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 you should take your next dose at the next scheduled time. 
Olaparib must be taken only by you. It must also be kept out of the reach of 
children or persons of limited capacity to understand. 
Day 1 Visit 
• 
Give you a physical examination. 
• 
Record your vital signs such as heart rate, blood pressure, height and 
weight if performed 96 hours prior. 
• 
Collect a blood sample (approximately 20 mL or 4 teaspoon) if screening 
assessments were done > 28 days prior 
o 
to study biomarkers. 
o 
for standard laboratory tests 
o 
to measure prostate-specific antigen (PSA) 
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• 
Dispense olaparib (30-day supply as indicated). 
Day 30 (± 5 Days), 60 (± 5 Days), and 90 (± 5 Days) Visits 
• 
Give you a physical examination. 
• 
Evaluate ECOG performance status. 
• 
Record your vital signs such as heart rate, blood pressure, height and 
weight. 
• 
Collect a blood sample (approximately 20 mL or 4 teaspoon) 
o 
to study biomarkers 
o 
for standard laboratory tests 
o 
to measure prostate-specific antigen (PSA) 
• 
Dispense olaparib (30-day supply as indicated) 
Day 90 (± 14 Days) 
• 
Prostatectomy 
Day 132 (± 5 Days) or End of Study Visit 
• 
Give you a physical examination. 
• 
Evaluate ECOG performance status. 
• 
Record your vital signs such as heart rate, blood pressure, height and 
weight. 
• 
Collect a blood sample (approximately 20 mL or 4 teaspoon) 
o 
to study biomarkers 
o 
for standard laboratory tests 
o 
to measure prostate-specific antigen (PSA) 
How long would you stay in this study? 
If you join this study, you will take the study drug for 90 days. After you finish the 
study drug, you will undergo your planned surgery and follow-up with your 
surgeon per their advice. We will also follow-up with you in clinic approximately 
30 days after your last dose of olaparib. 
Doctors could take you out of this study at any time. This would happen if: 
• 
They think it is in your best interest not to continue in the study. 
• 
You are not able or willing to follow study procedures. 
• 
The whole study is stopped. 
If you leave the study for any reason, previously collected information would 
remain in the study records and would be included in the analysis of results. This 
information could not be removed from the study records. 
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If you leave the study for any reason before completing 90 days of treatment, we 
will follow-up with you until 30 days after your last dose of olaparib. 
What are the side effects (risks)? 
In this part of the consent form, we tell you the side effects from the tests and 
treatments in this study. There may be side effects we do not know about yet. 
We carefully watch everyone in the study for side effects. Side effects may be 
mild or very serious. Your health care team may give you medicines to help 
lessen side effects. Many side effects go away soon after you stop taking 
olaparib. In some cases, side effects can last a long time or never go away. 
There also is a risk of death. 
If you join this study, we would tell you if we discover new side effects that could 
affect you. You should talk to your study doctor about any side effects that you 
have while you are in this study. 
Olaparib (also known as Lynparza®): 
Olaparib is available by prescription to treat ovarian cancer. The following side 
effects thought to be caused by olaparib occurred in women treated with olaparib 
for ovarian cancer. 
Tell your study doctor right away if you notice any of the following side effects — 
you may need urgent treatment: 
Common Side Effects (affects more than 1 in 10 patients) 
• 
Nausea (feeling sick) 
• 
Vomiting (being sick) 
• 
Weakness and/or tiredness 
• 
Indigestion and/or heartburn (dyspepsia) 
• 
Loss of appetite 
• 
Headache 
• 
Cough 
• 
Change in taste of foods (dysgeusia) 
• 
Dizziness 
• 
Diarrhea. Your doctor may prescribe a medicine to treat this. If it 
gets severe, tell your doctor right away. 
• 
Decrease in the number of red blood cells (anemia) which can be 
associated with symptoms of shortness of breath, fatigue, pale skin 
or fast heartbeat. 
• 
Decrease in the number of white blood cells that support the 
immune system (Iymphopenia) which can be associated with 
increased susceptibility to infection. 
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Common Side Effects (affects more than 1 in 10 patients) 
• 
Increase in blood creatinine seen from a laboratory test showing 
how your kidneys are working. 
• 
Mean cell volume elevation (an increase in size of red blood cells): 
This will be monitored by the laboratory safety tests that will be 
done in this study because this doesn't normally have any 
symptoms. 
• 
Decrease in the number of platelets in blood (thrombocytopenia) 
which can be associated with symptoms of bruising or bleeding for 
longer if injured. 
• 
Decrease in the total number of white blood cells (leukopenia) and 
.  in certain white blood cells (neutropenia) that protect from infection, 
which can be associated with symptoms of fever. 
Less Common Side Effects (affects 1 to 10 in 100 patients) 
• 
Sore mouth (stomatitis) 
• 
Pain in the stomach area under the ribs (upper abdominal pain) 
• 
Rash 
• 
Allergic reactions 
• 
Itchy rash on swollen, reddened skin (dermatitis) 
Olaparib taken in combination with other medications may be associated with 
other risks that are unknown at this time. You need to tell your study doctor of all 
medications and supplements (i.e., herbal products, vitamins and nutritional 
supplements) that you take. While you are in this research study, you will not be 
allowed to receive other anti-cancer therapy (i.e., chemotherapy, immunotherapy, 
hormonal therapy, radiotherapy, biological therapy) and certain vaccines. Your 
study doctor will be provided with a list of medication that you must avoid while 
you are taking your study medication so it is important to consult with the study 
doctor before taking anything new. 
Driving and using machines: The study drug may affect your ability to drive or 
use machines. If you feel dizzy, weak, or tired while taking your study treatment, 
take special care when driving or using tools or machines. 
Other potential risks: 
Other side effects have been seen in previous studies, but it is not yet known if 
these were related to olaparib, or if they were unrelated events possibly due to 
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the patient's cancer or other cause. Assessing the full range of side effects of 
olaparib is an important part of this study. 
Pneumonitis (lung inflammation) has been reported in less than 1% of patients 
treated with olaparib in previous studies, and some reports have been fatal. It is 
not known if olaparib caused the pneumonitis in these patients as they had other 
possible causes such as lung cancer and/or metastases in the lungs, pre-existing 
lung disease, were smokers, or had been treated previously with chemotherapy 
or radiotherapy. If you experience any new or worsening symptoms of shortness 
of breath, cough and fever, you should contact your study doctor as soon as 
you can. 
Mvelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have 
been reported in less than 1% of all patients treated with olaparib in previous 
studies and the majority of cases have been fatal. It is not known if olaparib 
caused MDS and/or AML in these patients as they had other possible causes, in 
particular they had received extensive previous chemotherapy. 
• 
MDS is a pre-cancerous condition where the bone marrow is not as good 
at producing blood cells as it was before (can be red blood cells and/or 
white blood cells and/or platelets). This condition has the potential to 
transform into acute myeloid leukemia. 
• 
AML is a cancer of the bone marrow where many abnormal and immature 
white blood cells (blast cells) are made while normal functioning blood 
cells are not made. 
The study doctor may decide to interrupt and/or reduce your olaparib dose if you 
experience certain side effects. If your dose is reduced you will be given a new 
bottle of tablets. 
The study doctor will monitor your blood cell levels during the study and may 
decide you need to have further tests, which may include obtaining your bone 
marrow sample or blood sample. Your study doctor will stop treatment with 
olaparib if you develop MDS or AML. 
Let your study doctor know of any questions you have about possible side 
effects. You can ask the study doctor questions about side effects at any time. 
Blood draw risks: 
You may feel some discomfort or pain from where the needle is placed in your 
vein to draw blood sample. Sometimes bruising may develop at the site where 
the blood was drawn or needle was placed, and occasionally infection or 
bleeding may occur at the puncture site. Light-headedness and/or fainting may 
also occur during blood collection. 
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Electrocardiogram (ECG) risks: 
You may feel discomfort during the attachment and removal of the ECG leads to 
and from the skin. 
Radiation risks: 
During your screening visit, bone scans, and computerized tomography (CT) 
scans or magnetic resonance imaging (MRI) may be used to evaluate your 
disease. 
A CT scan provides multiple detailed pictures of the inside of the body, like an 
MRI scan but the CT scan uses radiation, and therefore exposes you to a small 
dose of radiation. Although all radiation you receive builds up over your lifetime, 
this amount of radiation should not create a significant risk to your health. 
There is also a small risk with using a contrast agent that is injected into a vein 
during the CT scan. The contrast agent is a special dye that highlights organs, 
blood vessels or tissue to make them more visible. Depending on the type of 
contrast agent that is used, it may cause decreased kidney function or worsen 
kidney function in people who already have decreased kidney function. 
Uncommonly, some people have allergic reactions (such as hives and itching) to 
the contrast agent. Serious reactions (for example, drop in blood pressure, 
difficulty breathing or severe allergic reaction and death) are rare. 
The bone scan involves an injection, in the vein of your arm, of a radiotracer 
(radioactive compound that localizes in the bone). The injection of the radiotracer 
may feel like a small sting and there may be possible bruising at the injection 
site. Bone scan side effects are not common, and when encountered are usually 
mild, such as nausea and vomiting, or you may become uncomfortable lying still 
for the duration of the examination. You will be exposed to a limited and 
medically acceptable dose of radiation during the procedure. There is always a 
slight risk of damage from being exposed to any radiation. 
Everyone receives a small amount of radiation every day called "background 
radiation". This radiation is natural and comes from space, air, water, soil, and 
the food you eat. Each year you are exposed to about 3 milliSieverts (mSv) of 
this background radiation. A milliSievert is a unit of radiation dose. For 
comparison, the estimated radiation dose from each of these tests is listed 
below. The risk to your health from this level of radiation exposure is too low to 
be detectable and may be nonexistent. For comparison, the estimated radiation 
dose from each of these tests is listed below. 
• 
CT pelvis: 6 mSv 
• 
Bone Scan: 6.3 mSv 
In the long term, over many years, there is a very low risk of developing a new 
cancer as a result of the radiological evaluation and treatment for your cancer. 
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Magnetic Resonance Imaging (MRI) risks: 
Risks of MRI include claustrophobia, discomfort due to lying still for a prolonged 
period of time, and other factors which will be described to you and discussed 
with you at the MRI center. The most common contrast material used for MRIs is 
gadolinium. Persons with acute or chronic severe kidney insufficiency, or chronic 
liver disease experiencing kidney insufficiency, may develop a severe disease 
called nephrogenic systemic fibrosis (NSF) from gadolinium based contrast 
material. NSF triggers thickening of the skin, organs, and other tissues. The 
exact cause is unclear, and there is no effective treatment. Your kidney and liver 
function will be checked to see if you are eligible to receive gadolinium. The 
contrast solution that may be given for an MRI scan may cause an allergic 
reaction (rare). Severe allergic reactions can be life threatening. MRI contrast 
solution can cause kidney damage, especially if you are diabetic, dehydrated 
(lost body water) or elderly. 
Reproductive risks: 
If you join this study, you would have to use condoms while taking the study 
drug, and for 3 months after the last dose of olaparib when having sexual 
intercourse with a female partner, even if they are pregnant. Your female partner 
must also use a suitable method of contraception. You must not donate sperm 
while taking study treatment and for 3 months after the last dose of study 
treatment. Tell your study doctor immediately if your partner becomes pregnant 
while taking study treatment or within 3 months of your last dose of study 
treatment. 
Non-physical risks: 
In addition to the physical risks and/or discomforts associated with this study, 
there may be psychological, emotional, financial, social, and legal risks that might 
result. If you join this study, non-physical risks are: 
• 
You may get tired or bored when we are asking you questions or you are 
completing questionnaires. You do not have to answer any question you 
do not want to answer. 
• 
There is risk that information about you may become known to people 
outside this study. 
• 
You might not be able to work. 
• 
Results of genetic tests might be released by accident. This risk is very 
low, because we keep personal information private. If these results 
became known, you could have problems with family members or 
insurance. 
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What are the benefits? 
We do not know if this study would help you. There may or may not be a direct 
benefit to you from taking part in this study. We are testing olaparib to see its 
effects on people with prostate cancer. You might get better if you receive 
olaparib, but your condition could stay the same or even get worse. We hope the 
information from this study will help other people with prostate cancer in the 
future. 
You have other choices besides this study. 
You do not have to join this study. You are free to say "yes" or "no." Your regular 
medical care would not change if you decide to say "no." 
You have other choices for treatment. Each of these choices has risks and 
benefits. You should talk to your doctor or healthcare provider about these 
choices. 
Other choices include: 
• 
No treatment. 
• 
Other research studies. 
• 
Prostatectomy. 
• 
Prostate radiation therapy. 
Enrollment in this study may exclude you from other research studies. 
What if I change my mind about taking part in this research 
study? 
You are free to change your mind at any time. Your participation in this study is 
voluntary. You have the right to choose whether or not you want to take part in 
this research study and you may decide to stop participating in the study once 
you have started. You may discontinue study drug at any time, for any reason. 
Leaving the study will not result in any loss of benefits that you already have. 
It is very important that you tell your study doctor right away if you decide 
you want to stop participating in this study. Your study doctor will talk with 
you about your choices. 
If you decide to stop study drug, you will still come in for a follow-up visit 30 days 
after the last dose of study drug or before you start new cancer treatment, 
whichever happens first. Study procedures which include blood sample collection 
will be performed at this follow-up visit. 
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Protecting Privacy as an Individual and the Confidentiality 
of Personal Information 
If you join this study, some people or organizations might need to look at your 
medical records and research records for quality assurance or data analysis. 
They include: 
• 
Researchers involved with this study 
• 
AstraZeneca (the manufacturers of olaparib) and their agents 
• 
Institutional Review Board (IRB), including the Fred Hutchinson Cancer 
Research Center IRB. An IRB is a group that reviews the study to protect 
the rights and welfare of research participants 
• 
Fred Hutchinson Cancer Research Center, University of Washington, and 
Seattle Cancer Care Alliance 
• 
Office for Human Research Protections, Food and Drug Administration, 
and other regulatory agencies as required 
We will do our best to keep personal information confidential. But we cannot 
guarantee total confidentiality. Personal information may be given out if required 
by law. For example, workplace safety rules may require health workers to 
contact you about lab tests. Or a court may order study information to be 
disclosed. Such cases are rare. 
We will not use personal information in any reports about this study, such as 
journal articles or presentations at scientific meetings. 
If you join this study, information about your participation would be made part of your 
permanent medical record. This information would include a copy of this consent 
form. If an insurance company or employer or anyone else were authorized to see 
your medical record, they would see a copy of this consent form. 
How is my genetic information protected? 
A federal law called the Genetic Information Nondiscrimination Act (GINA) helps 
protect genetic information about people who join research studies. 
GINA restricts access to genetic information so that it cannot be used for health 
insurance coverage decisions. GINA prevent health insurance companies or 
group health plans from 
• 
Asking for genetic information obtained in research studies, or 
• 
Using genetic information when making decisions regarding your eligibility 
or premiums 
GINA does not help or protect against genetic discrimination by companies that 
sell life, disability or long term care insurance. 
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How long will my samples be stored? 
Your samples will be used for the purposes of this study and may be stored for 
up to 5 years following the completion of this study. Samples will be stored at 
University of Washington and/or Fred Hutchinson Cancer Research Center. 
Researchers will not report their results to you or your doctor. Your samples will 
be destroyed after use for the purposes of this study. All samples will be kept in 
locked research laboratories at University of Washington and/or Fred Hutchinson 
Cancer Research Center. These samples will not contain your name or other 
identifiable information. The samples will be given a unique number replacing 
any identifiable information. This unique number will be used to identify the 
sample and corresponding data. No personal details identifying the research 
participant will be available to any person. Analyses will be conducted at the 
University of Washington and/or Fred Hutchinson Cancer Research Center. 
If you decide you no longer want your samples to be used for research purposes, 
you can inform the study doctor. Then, any sample that remains will no longer be 
used and destroyed/disposed of. Samples or related information that have 
already been used for this research study would not be returned. 
If you stop the study for any reason, the information previously collected will 
remain in the study records and may be included in the analysis of results. This 
information cannot be removed from the study records. 
Would we pay you if you join this study? 
There is no payment for being in this study. 
Would you have extra costs if you join this study? 
If you join this study, you would have some extra costs. Your insurance company 
might pay these costs, but some insurance policies do not cover these costs. We 
could help find out whether your insurance company would cover these costs. 
The extra costs are: 
• 
Cost of standard doctor visits and laboratory tests. 
• 
Cost of tests that are given more often than usual. 
• 
Cost of any other medical care needed because of this study. 
If you join this study, you or your insurance company would have to pay for the 
costs of standard treatment in this study. 
You would not be billed for: 
• 
Olaparib (study drug) 
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What if you get sick or hurt after you join this study? 
For a life threatening problem, call 911 right away or seek help immediately. 
Contact your study doctor when the medical emergency is over or as soon as 
you can. 
For all other medical problems or illness related to this research, immediately 
contact the study doctor, Dr. Robert Bruce Montgomery at 206-598-0860. They 
will treat you or refer you for treatment. You or your health insurance will have to 
pay for the treatment. There are no funds to pay you for a research-related injury, 
added medical costs, loss of a job, or other costs to you or your family. 
You or your insurer will be billed for treatment of problems or complications that 
result from your condition or from standard clinical care. 
You would not lose any legal right to seek payment for treatment if you sign this 
form. 
What will my information and/or tissue samples be used for? 
Your information and tissue samples will only be used for the purposes of this 
research study. 
During this study, if the researchers learn new information that may be important 
to your general health or to you disease or condition, they will not share that 
information with you. 
Your rights 
• 
You do not have to join this study. You are free to say "yes" or "no." 
• 
If you get sick or hurt in this study, you do not lose any of your legal rights 
to seek payment by signing this form. 
• 
During the study, we might learn new information that you need to know. 
For example, some information may affect your health or well-being. Other 
information might make you change your mind about being in this study. If 
we learn these kinds of information, we would tell you. 
• 
If you join this study, you would not have to stay in it. You could stop at 
any time (even before you start). Your regular medical care would not 
change. You would have no penalty for stopping, but it would be better not 
to join the study if you think that you would change your mind later. 
• 
If you decide to drop out, we would want you to tell the study doctor. The 
study doctor could tell you about the effects of stopping olaparib. You and 
the study doctor could talk about the follow-up care and testing that would 
help the most. 
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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This Web site will not include information that can 
identify you. At most, the Web site will include a summary of the results. You can 
search this Web site at any time. 
Your responsibilities 
If you join this study, you would have some responsibilities. 
• 
Follow the schedule of study visits and procedures. 
• 
Takes study medication as directed. 
• 
Prevent pregnancy. 
• 
Tell us about side effects. 
For more information 
If you have questions or concerns about this study, you could talk to your doctor 
anytime. Other people you could talk to are listed below. 
If you have questions about: 
This study (including 
complaints and requests for 
information) 
Call: 
(206) 598-0860 (Dr. Robert Bruce Montgomery) 
If you get sick or hurt in this 
study 
(206) 598-0860 (Dr. Robert Bruce Montgomery) 
Your rights as a research 
participant 
(206) 667-5900 or email 
irodirector@fredhutch.org (Director of Institutional 
Review Office, Fred Hutchinson Cancer 
Research Center) 
(206) 543-0098 (Human Subjects Division, 
University of Washington) 
Your bills and health 
insurance coverage 
(206) 598-8260 (UWMC Patient Financial 
Services) 
(206) 606-1091 (SCCA Patient Financial 
Clearance) 
Emergency (24-hour) phone: 
(206) 598-6190 Request the on-call Oncology Fellow 
Or 
Emergency (24-hour) pager: 
(206) 559-5058 Robert Bruce Montgomery, MD 
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Signatures 
I have carefully read this consent form. This study has been explained to me and 
I have had the chance to ask questions about it. All questions have been 
answered to my satisfaction. I understand I have a choice whether to take part or 
not to take part in this study. The risks, benefits and alternative treatments have 
been explained to me. I agree to take part in this research study. 
Participant Printed Name 
Participant Signature and Date 
If you served as an interpreter or witness during the consent process, sign below 
to indicate you attest to the accuracy of the presentation to the participant and 
the apparent understanding of the research by the participant. 
Witness or Interpreter / Printed Name, Signature, and Date 
Researcher's statement 
I have discussed the research study, including the study purpose, procedures, 
risks and benefits, and alternative treatment options with the person signing 
above. I have answered all questions to his/her satisfaction. All elements of the 
consent form were reviewed in detail and discussed with the subject. The subject 
understands that participation is completely voluntary and consent may be 
revoked at any time. A copy of the signed consent form will be given to the 
participant. 
Person obtaining consent Printed Name 
Person obtaining consent Signature and Date 
Protocol: 9985 
Current version date: 11/20/2018 
Previous version date: 06/29/2018 
Copies to: Researcher's File 
Subject 
Subject's Medical Records 
FHCRC IRB Approval 
JAN 14 '19  JUN 1319 
Consent Released Date Consent Expiradon Date 
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