Durvalumab (MEDI4736) and Olaparib (AZD2281) for Treatment of Biochemically Recurrent Prostate Cancer in Men Predicted to Have a High Neoantigen Load: A Multicenter Pilot Study
Phase: PHASE2
Conditions: Biochemically Recurrent Prostate Carcinoma, Prostate Adenocarcinoma
Sponsor: University of Washington

Clinical Study Protocol
Investigational Drug Substance:  Durvalumab (MEDI4736), Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
1
Investigational 
Drug Substance(s)
Durvalumab (MEDI4736) 
Olaparib (AZD2281)
Study Number
ESR-19-14545
Version Number
V9
Date
11/25/2022
Durvalumab (MEDI4736) and Olaparib (AZD2281) for treatment of biochemically recurrent 
prostate cancer in men predicted to have a high neoantigen load: a multicenter pilot 
study
Investigator / Lead Investigator: Michael Schweizer, MD
Statistician: Roman Gulati, MS
Financial/ Drug Support: AstraZeneca
Fred Hutch IRB
Approved 
8/16/2023

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
2
PROTOCOL SYNOPSIS
Clinical Protocol ESR-19-14545
Study Title:  Durvalumab and Olaparib for treatment of biochemically recurrent prostate cancer 
in men predicted to have a high neoantigen load: a multicenter pilot study
Protocol Number: ESR-19-14545
Clinical Phase: Pilot phase II
Study Duration: 36 months: 12 months recruitment and 24 months individual patient participation (6 
months active treatment +6 months of follow-up to primary endpoint+12 months follow up to 
secondary endpoints)
Investigational Product(s) and Reference Therapy:
Durvalumab (MEDI4736) solution for infusion after dilution will be supplied in glass vials containing 
500 mg durvalumab at a concentration of 50 mg/mL.
Olaparib (AZD2281) will be supplied as round or oval green film coated tablets at dosage form 100 mg 
tablet and150 mg tablet.
Research Hypothesis We hypothesize that high neoantigen load – reflected through loss of function 
mutations in CDK12 (lfCDK12), mismatch repair deficiency/ microsatellite instability-high 
(MMRd/MSI-high) or homologous recombination deficiency (HRD) – will result in sensitivity to both 
immune checkpoint blockade and PARP inhibition.
Objectives:
Primary Objective(s):

To assess clinical activity of durvalumab and olaparib in men with biochemically recurrent 
prostate cancer predicted to have a high neoantigen load  
Secondary Objective(s): 

Assess safety of durvalumab monotherapy 

Assess safety of durvalumab and olaparib combination therapy

Assess PSA changes in relationship to intervention  

Assess quality of life changes 
Exploratory Objective(s):

Assess radiographic progression free survival (rPFS) 
Fred Hutch IRB
Approved 
8/16/2023

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
3

Assess PSA progression free survival (PSA-PFS)

Assess event free survival (EFS)

Assess time to start of androgen deprivation therapy (ADT) 
Study Assessments and Criteria for Evaluation: 
Primary Endpoint(s):

Undetectable PSA1,2(post-prostatectomy patients; including those that also received salvage 
radiation) or PSA <0.5 ng/ml1 (post-radiation patients) at 12-month timepoint after initiation 
(cycle 1, day 1) of therapy.
Secondary Endpoint(s): 

Adverse events during durvalumab monotherapy per CTCAE v5.0 guidelines

Adverse events during durvalumab and olaparib combination therapy per CTCAE v5.0 
guidelines

PSA50 response1 (at least 50% decline in PSA from baseline at enrollment) at 3- and 6-month 
timepoints

Quality of life changes using:
a.
RANDSF-36 two- step 8-scale score (see Appendix IV for algorithm) and 
b.
IIEF surveys score in erectile function, orgasmic function, sexual desire, intercourse 
satisfaction and overall satisfaction (see Appendix VI for assessment details)
1 confirmed by repeat measurement at least 2 weeks later
2 Undetectable PSA defined as PSA <0.1 ng/ml  
Exploratory Endpoint(s):

rPFS, defined as time from enrollment to date of first objective radiographic evidence of 
metastatic disease (soft tissue or bone lesion) or death; in the absence of an event, PFS will be 
censored at date of last disease assessment

PSA-PFS, defined as time from enrollment to PSA progression (increase in PSA by 2 ng/ml and 
by 25% from baseline/nadir), in the absence of an event, PSA-PFS will be censored at date of 
last disease assessment and/or visit documenting no next therapy.

EFS; defined as time from enrollment to initiation of next line of therapy, development of 
metastatic disease or death; in the absence of an event, EFS is censored at date of last disease 
assessment and/or visit documenting no next therapy.

Time to start of ADT; defined as time from enrollment to initiation of ADT; in the absence of 
an event, the endpoint is censored at date of last visit documenting no ADT initiation
Correlative Objectives and Endpoints:
1. Objective: identify favorable tumor microenvironment associated with response to durvalumab 
and olaparib
    Endpoint: CD8, CD4, FOXB3, PDL1 by IHC with quantitative output on archival prostate 
cancer tissue
2. Objective: identify genetic characteristics associated with response to durvalumab and olaparib
Fred Hutch IRB
Approved 
8/16/2023

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
4
    Endpoint: number of somatic mutations, mutational signature, and DNA variants on whole 
exome or targeted gene sequencing of archival prostate cancer tissue
3. Objective: to evaluate tumor clonal evolution
    Endpoint: next generation sequencing of peripheral blood cell-free circulating tumor DNA 
(ctDNA) to evaluate mutational burden, and DNA variants in ctDNA at enrollment, at 6 
months and at the time of progression 
4. Objective: evaluate systemic immune response at 3 and 6 months and at the time of progression
    Endpoint: on peripheral blood measure cytokines using Cytokine Human Magnetic 35-Plex 
Panel for the Luminex™ platform; T-cells population using flow cytometry and T-cell receptor 
sequencing. 
Study Design: This is a multicenter pilot phase 2, prospective, single arm, three cohort, open label trial 
that will investigate the clinical activity of durvalumab and olaparib in men with biochemically 
recurrent (BCR) prostate cancer predicted to have a high neoantigen load inferred by the presence of 
either loss of function mutations in CDK12 (lfCDK12; Cohort A), MMRd/MSI-high (Cohort B), or 
loss of function mutations in homologous recombination genes (i.e. HRD; Cohort C). Patients in cohort 
A and B will receive durvalumab monotherapy for 3 months followed by durvalumab plus olaparib for 
an additional 3 months. Patients in Cohort C will receive 6 months of durvalumab and olaparib 
combination therapy. Patients will be seen by research and oncology teams every 4 weeks while 
receiving durvalumab, and then every 3 months with PSA testing until completion of 24 months. 
Radiographic assessment (i.e., CT chest, abdomen and pelvis and bone scan) will be performed upon 
enrollment (within 6 weeks before study therapy start date) and then obtained as prompted by signs and 
symptoms of metastatic disease and/or at the time of PSA progression (increase in PSA by 2 ng/ml and 
by 25% from baseline). Upon completion study visits (24 months from starting durvalumab) patients 
will continue to be followed as per standard of care. Clinical data after 24 months will be extracted 
from the clinical chart by the study team, as permitted by the patient. Patient will be followed passively 
through following clinical chart data up to 5 years total.  
Number of Centers: 2
Performance Sites: 
Coordinating Center:       
University of Washington / 
Fred Hutch Cancer Center         
Lead Investigator: Michael Schweizer, MD
Participating Site: Oregon 
Health and Science University 
(OHSU)
Investigator: Alexandra Sokolova, MD
Number of Patients: 30
Fred Hutch IRB
Approved 
8/16/2023

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
5
Study Population: The study aims to enroll patients with BCR prostate cancer with one of the 
following biomarkers: lfCDK12, MMRd/MSI-high, or HRD.
Inclusion Criteria:

Histologic confirmation of adenocarcinoma of the prostate 

The patient must have received definitive local therapy for prostate cancer, consisting of either 
radiation therapy and/or prostatectomy (salvage or adjuvant radiation post-prostatectomy is not 
exclusionary).

PSA must be ≥2 ng/ml if received only prior definitive radiation (no PSA threshold required if 
prior prostatectomy was performed) with a PSA doubling time (PSADT) ≤10 months:
o
PSADT calculation must include all recorded PSA values >0.1 ng/ml over the past 6 
months prior to randomization, with a minimum of 3 values spaced at least 2 weeks 
apart, with each included value preferably measured at the same laboratory. PSA 
values obtained prior to localized therapy will be excluded. 
o
The calculation of PSADT is based on the natural log of PSA. 
o
The actual calculation of the PSADT can be obtained from the following online 
calculator: http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx

Prior salvage radiation or not a candidate for localized salvage radiation due to subject 
preference or clinical assessment based upon disease characteristics and/or subject co-
morbidities.

Prior hormonal therapy (e.g. androgen deprivation therapy, oral AR-signaling inhibitors) is 
allowed, provided this was stopped ≥ 6 months prior to starting treatment per protocol, 
testosterone is ≥150 ng/dl and patient did not demonstrate evidence of castration-resistance 
while on hormonal therapy (i.e. PSA was not rising on treatment). 

No evidence of metastatic disease on imaging by whole body bone scan and CT or MRI of the 
chest/abdomen/pelvis within 6 weeks before study therapy start day. PSMA PET or Fluciclovine 
scan within 6 weeks of start day may substitute other imaging studies. 
o
Patients with oligometastatic disease (i.e., ≤3 sites) detectable on advanced imaging 
only (e.g., PSMA or Fluciclovine PET) are eligible. Note: Prior site directed radiation 
is allowed; however, PSA must be rising following radiation as indicated above. 
o
Abdominal or pelvic lymph nodes measuring ≤2 cm in short axis are allowed.
Fred Hutch IRB
Approved 
8/16/2023

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
6

Biomarker positive:
o
Biallelic CDK12 inactivating mutations as documented using a clinical grade 
sequencing assay performed in a Clinical Laboratory Improvement Amendments 
(CLIA) or College of American Pathologists (CAP) certified laboratory 
or
o
MMRd/MSI-high as documented using a clinical grade sequencing assay performed in 
a CLIA/CAP certified laboratory 
or
o
Loss of function mutations in homologous recombination genes (i.e., homologous 
recombination deficiency; HRD) as documented using a clinical grade sequencing 
assay performed in a CLIA/CAP certified laboratory. Homologous recombination 
genes include, but not limited to BRCA1, BRCA2, ATM, CHEK2, PALB2, RAD51D, 
NBN, GEN1, RAD51C, MRE11A, BRIP11A, FAM175A.

Capable of giving signed informed consent which includes compliance with the requirements 
and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed 
consent and any locally required authorization (e.g., Health Insurance Portability and 
Accountability Act) obtained from the patient/legal representative prior to performing any 
protocol-related procedures, including screening evaluations.  

Age > 18 years at time of study entry.

Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 

Adequate normal organ and marrow function as defined below measured within 28 days prior 
to administration of study treatment as defined below: 
o
Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days  
o
Absolute neutrophil count (ANC) be ≥1.5 x 109/L
o
Platelet count ≥100 x 109/L 
o
Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply 
to patients with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or 
hepatic pathology), who will be allowed only in consultation with their physician.
o
AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver 
metastases are present, in which case it must be ≤5x ULN
o
Patient must have creatinine clearance (CL) ≥51 mL/min by the Cockcroft-Gault 
formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination 
of creatinine clearance:
Fred Hutch IRB
Approved 
8/16/2023

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
7
Creatinine CL 
(mL/min)
=
Weight (kg) x (140 – Age)   
72 x serum creatinine (mg/dL)

Patient is willing and able to comply with the protocol for the duration of the study including 
undergoing treatment and scheduled visits and examinations including follow up.

Patients must have a life expectancy ≥ 16 weeks.

Body weight >30 kg

Male patients must use a condom during treatment and for 3 months after the last dose of 
olaparib when having sexual intercourse with a pregnant woman or with a woman of 
childbearing potential.  Female partners of male patients should also use a highly effective 
form of contraception (Table10 for acceptable methods]) if they are of childbearing potential.
Exclusion Criteria:

Prior chemotherapy for prostate cancer, unless done in the neoadjuvant setting, and if the last 
dose was >6 months prior to enrolment

Any prior treatment with a PD1 or PD-L1 inhibitor, including durvalumab

Any prior treatment with PARP inhibitor, including olaparib

History of another primary malignancy except for
o
Malignancy treated with curative intent and with no known active disease ≥3 years 
before the first dose of durvalumab and of low potential risk for recurrence
o
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease
o
Adequately treated carcinoma in situ without evidence of disease

History of leptomeningeal carcinomatosis

Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by 
the treating physician (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, 
congestive heart failure, QTcF prolongation >470 ms, electrolyte disturbances, etc.), or 
patients with congenital long QT syndrome.

Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the 
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria 
Fred Hutch IRB
Approved 
8/16/2023

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
8
o
Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician.
o
Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab or olaparib may be included only after consultation with 
the Study Physician. 

Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of 
MDS/AML.

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, extensive bilateral lung disease on High Resolution Computed Tomography 
(HRCT) scan, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial 
infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior 
vena cava syndrome, interstitial lung disease, serious chronic gastrointestinal conditions 
associated with diarrhea or any psychiatric disorder that prohibits obtaining informed consent.

Patients unable to swallow orally administered medication and patients with gastrointestinal 
disorders likely to interfere with absorption of the study medication. 

Immunocompromised patients, e.g., patients with uncontrolled human immunodeficiency virus 
(HIV). HIV+ patients will be allowed on the study if on HAART and disease is controlled: 
CD4≥350cell/mcl, undetectable viral load, and no PPX antibiotics.
Note: HIV screening is not required to be eligible for this study.

Active infection including tuberculosis (TB testing only performed if deemed necessary per 
standard clinical practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), 
hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of 
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for 
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV 
RNA.

Active or prior documented autoimmune or inflammatory disorders (including inflammatory 
bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of 
diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome 
[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, 
etc]). The following are exceptions to this criterion:
o
Patients with vitiligo or alopecia
o
Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement 
Fred Hutch IRB
Approved 
8/16/2023

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
9
o
Any chronic skin condition that does not require systemic therapy
o
Patients without active disease in the last 5 years may be included but only after 
consultation with the Investigator 
o
Patients with celiac disease controlled by diet alone

 Current or prior use of immunosuppressive medication within 14 days before the first dose of 
durvalumab. The following are exceptions to this criterion:
o
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection)
o
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or its equivalent
o
Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: 
Patients, if enrolled, should not receive live vaccine whilst receiving durvalumab and up to 30 
days after the last dose of durvalumab.

Patients receiving any chemotherapy, immunotherapy, biologic, radiotherapy or hormonal 
therapy for cancer treatment concurrently or within 3 weeks of study treatment. Concurrent use 
of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is 
acceptable.

Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation 
within 4 weeks of the first dose of study drug.

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 
study treatment is 2 weeks.

Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A 
inducers (e.g., bosentan, efavirenz, modafinil). The required washout period prior to starting 
study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.

Major surgery within 2 weeks of starting study treatment and patients must have recovered 
from any effects of any major surgery. 
Fred Hutch IRB
Approved 
8/16/2023

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
10

Previous allogenic bone marrow transplant or double umbilical cord blood transplantation 
(dUCBT).

Participation in another clinical study with an investigational product administered in the last 3 
months

Concurrent enrolment in another clinical study, unless it is an observational (non-
interventional) or supportive care, while on the clinical study or during the follow-up period of 
this interventional study

Patients with a known hypersensitivity to olaparib or durvalumab or any of the excipients of 
the product.

Involvement in the planning and/or conduct of the study
Investigational Product(s), Dose and Mode of Administration:
Patients will receive 1500 mg durvalumab via IV infusion Q4W for 24 weeks (up to 6 doses/cycles) with 
the last administration on week 20 (N.B. If a patient’s weight falls to 30kg or below (≤30 kg), then the 
patient should receive weight-based dosing equivalent to 20 mg/kg of durvalumab Q4W after 
consultation between the treating physician and Investigator, until the weight improves to above 30 kg 
(>30 kg), at which point the patient should start receiving the fixed dosing of durvalumab 1500 mg 
Q4W). 
Patients in Cohorts A and B will receive Olaparib 300 mg Q12 starting week 13 and with last dose 
administered on week 26. Patients in Cohort C will receive Olaparib 300 mg Q12 weeks starting 
concurrently with durvalumab. 
Study treatment will be discontinued if there is evidence of metastatic disease on conventional imaging 
or there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.
Statistical Methods and Data Analysis: 
Within each cohort, a response rate of 30% or greater (response as defined in Section 6.1.5) would be a 
meaningful indicator of clinical activity and a response rate below 5% would be considered not 
clinically meaningful. The sample size was selected based on precision of a two-sided 90% confidence 
interval (CI) for the response rate; the exact binomial 90% CIs for 0 to 5 responses are tabulated below. 
Observing 3 or more responses among 10 patients would provide a two-sided 90% CI with lower 
confidence limit above 5%.
N. responses3
0
1
2
3
4
5
Response3 rate
0%
10%
20%
30%
40%
50%
Fred Hutch IRB
Approved 
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Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
11
90% CI
0-25.9
0.5-39.4
3.7-50.7
8.7-60.7
15.0-69.7
22.2-77.8
   3response defined as meeting primary endpoint (see definition above and in Section 6.1.5)
Sample Size Determination: For this multicenter pilot study, ten patients will be enrolled in each 
cohort (total 30). We anticipate identifying the majority of the study cohort (N≈20) prior to screening; 
however, we are expecting to screen 50 patients without prior clinical sequencing to identify the 
remaining cohort (N≈10).
Study Schema:
Fred Hutch IRB
Approved 
8/16/2023

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
12
TABLE OF CONTENTS
PAGE
Contents
PROTOCOL SYNOPSIS .........................................................................................................2
LIST OF TABLES:.................................................................................................................18
ABBREVIATIONS AND DEFINITION OF TERMS ..........................................................19
1.
INTRODUCTION..................................................................................................24
1.1
BIOCHEMICALLY RELAPSED PROSTATE CANCER...................................24
1.2
TREATMENT OPTIONS IN BCR PROSTATE CANCER PATIENTS .............24
1.3
ADT EFFECTS ON QUALITY OF LIFE AND METABOLISM........................25
1.4
CHECKPOINT INHIBITORS IN CANCER TREATMENT ...............................25
1.5
DURVALUMAB BACKGROUND/NON-CLINICAL AND CLINICAL 
EXPERIENCE .......................................................................................................26
1.6
CDK12 DEFICIENCY AND NEOANTIGEN BURDEN ....................................27
1.7
DNA REPAIR AND HOMOLOGOUS RECOMBINATION DEFICIENCY .....27
1.8
OLAPARIB BACKGROUND/NON-CLINICAL AND CLINICAL 
EXPERIENCE .......................................................................................................27
2.
RESEARCH HYPOTHESIS .................................................................................28
3.
RATIONALE FOR CONDUCTING THIS STUDY ............................................29
3.1
RATIONALE FOR PSA AS SURROGATE ENDPOINT IN BCR .....................29
3.2
DURVALUMAB DOSE RATIONALE................................................................29
3.2.1
RATIONALE FOR DURVALUMAB FIXED DOSING......................................30
3.3
OLAPARIB DOSE RATIONALE ........................................................................31
3.4
COMBINATION OF OLAPARIB AND DURVALUMAB RATIONALE.........31
4.
BENEFIT/RISK AND ETHICAL ASSESSMENT...............................................31
4.1
POTENTIAL BENEFITS ......................................................................................31
4.2
POTENTIAL RISKS .............................................................................................32
5.
STUDY OBJECTIVES..........................................................................................32
5.1
PRIMARY OBJECTIVE(S) ..................................................................................33
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Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
13
5.2
SECONDARY OBJECTIVE(S) ............................................................................33
5.3
EXPLORATORY OBJECTIVE(S) .......................................................................33
5.4
CORRELATIVE OBJECTIVE(S).........................................................................33
6.
STUDY DESIGN...................................................................................................33
6.1
OVERVIEW OF STUDY DESIGN ......................................................................33
6.1.1
ENROLLMENT.....................................................................................................34
6.1.2
TREATMENT........................................................................................................34
6.1.3
MONITORING......................................................................................................34
6.1.4
PROGRESSION ....................................................................................................34
6.1.5
ENDPOINTS..........................................................................................................35
6.2
STUDY SCHEMA.................................................................................................37
7.
PATIENT SELECTION ........................................................................................37
7.1
INCLUSION CRITERIA.......................................................................................37
7.2
EXCLUSION CRITERIA......................................................................................40
7.3
WITHDRAWAL OF PATIENTS FROM STUDY TREATMENT AND/OR 
STUDY ..................................................................................................................43
7.3.1
PERMANENT DISCONTINUATION OF STUDY TREATMENT....................43
7.3.2
LOST TO FOLLOW-UP .......................................................................................44
7.3.3
WITHDRAWAL OF CONSENT ..........................................................................44
7.4
ADDITIONAL PATIENT ENDROLLEMENT....................................................45
8.
INVESTIGATIONAL PRODUCT(S)...................................................................45
8.1
DURVALUMAB ...................................................................................................45
8.1.1
DURVALUMAB FORMULATION/PACKAGING/STORAGE.........................45
8.1.2
DURVALUMAB DOSES AND TREATMENT REGIMENS .............................45
8.1.3
DURVALUMAB PREPARATION.......................................................................45
8.1.4
MONITORING OF DURVALUMAB DOSE ADMINISTRATION ...................46
8.2
OLAPARIB............................................................................................................47
8.2.1
OLAPARIB FORMULATION/PACKAGING.....................................................47
8.2.2
OLAPARIB LABELLING ....................................................................................47
8.2.3
OLAPARIB STORAGE ........................................................................................47
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Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
14
8.2.4
OLAPARIB DOSES AND TREATMENT REGIMENS......................................47
8.2.5
OLAPARIB DOSE REDUCTION ........................................................................48
8.2.6
OLAPARIB COMPLIANCE.................................................................................49
9.
TOXICITY MANAGEMENT GUIDELINES ......................................................49
9.1
DURVALUMAB TOXICITY GUIDELINES ......................................................49
9.2
MANAGEMENT OF OLAPARIB TOXICITY....................................................49
9.2.1
Management of olaparib haematological toxicity..................................................50
9.2.2
Management of olaparib non-haematological toxicity ..........................................52
9.2.3
Management of nausea and vomiting ....................................................................52
9.2.4
Interruptions for intercurrent non-toxicity related events ......................................52
9.2.5
Management of renal impairment ..........................................................................53
9.3
COMBINATION TREATMENT REGIMEN WITH TOXICITY 
MANAGEMENT GUIDELINES ..........................................................................53
10.
STUDY PROCEDURES .......................................................................................54
10.1
SCHEDULE OF STUDY PROCEDURES ...........................................................54
10.1.1
SCREENING PHASE............................................................................................54
10.1.2
TREATMENT PHASE..........................................................................................58
10.1.3
POST-TREATMENT FOLLOW-UP VISIT .........................................................59
10.1.4
24-MONTH END OF STUDY VISIT...................................................................59
10.1.5
STUDY WITHDRAWAL VISIT ..........................................................................59
11.
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S)...................................................................................................60
11.1
RESTRICTIONS DURING THE STUDY............................................................60
11.2
CONCOMITANT TREATMENT(S) ....................................................................61
11.2.1
Permitted concomitant medications .......................................................................62
11.2.2
Excluded concomitant medications........................................................................62
11.2.1
Restricted concomitant medications ......................................................................64
12.
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............66
12.1
STATISTICAL CONSIDERATION.....................................................................66
12.2
SAMPLE SIZE.......................................................................................................66
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12.3
PRIMARY OBJECTIVES.....................................................................................66
12.4
SECONDARY AND EXPLORATORY OBJECTIVES.......................................67
12.5
CORRELATIVE OBJECTIVES ...........................................................................68
12.6
STUDY ARM ASSIGNMENT..............................................................................68
12.7
BLINDING ............................................................................................................68
13.
ASSESSMENT OF SAFETY................................................................................69
13.1
CLINICAL LABORATORY TESTS....................................................................69
13.2
PHYSICAL EXAMINATIONS.............................................................................69
13.3
VITAL SIGNS .......................................................................................................69
13.4
EARLY PATIENT REVIEW FOR SAFETY .......................................................70
13.5
ECOG PERFORMANCE STATUS ......................................................................70
13.6
BONE MARROW OR BLOOD CYTOGENETIC ANALYSIS ..........................71
13.7
OTHER SAFETY ASSESSMENTS......................................................................71
13.8
GENOMIC INSTABILITY STATUS ...................................................................71
13.9
EXPLORATORY BIOMARKERS .......................................................................72
13.10
PATIENT REPORTED OUTCOMES ..................................................................72
14.
BIOLOGICAL SAMPLING PROCEDURES.......................................................73
14.1
VOLUME OF BLOOD..........................................................................................73
15.
HANDLING, STORAGE AND DESTRUCTION OF BIOLOGICAL 
SAMPLES..............................................................................................................74
16.
STUDY OVERSIGHT FOR SAFETY EVALUATION.......................................74
16.1.1
DEFINITION OF ADVERSE EVENTS ...............................................................74
16.1.2
DEFINITION OF SERIOUS ADVERSE EVENTS..............................................74
16.1.3
DEFINITION OF ADVERSE EVENTS OF SPECIAL INTEREST (AESI) .......75
16.2
ASSESSMENT OF SAFETY PARAMETERS.....................................................78
16.2.1
ASSESSMENT OF SEVERITY............................................................................78
16.3
RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS ................................................................................................................79
16.3.1
STUDY RECORDING PERIOD AND FOLLOW-UP FOR ADVERSE 
EVENTS AND SERIOUS ADVERSE EVENTS .................................................80
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16.3.2
CAUSALITY COLLECTION...............................................................................80
16.3.3
RELATIONSHIP TO PROTOCOL PROCEDURES............................................81
16.3.4
ADVERSE EVENTS BASED ON SIGNS AND SYMPTOMS...........................81
16.3.5
ADVERSE EVENTS BASED ON EXAMINATIONS AND TESTS..................81
16.3.6
HY’S LAW ............................................................................................................81
16.3.7
DISEASE PROGRESSION...................................................................................82
16.3.8
NEW CANCERS ...................................................................................................82
16.3.9
DEATHS................................................................................................................82
16.3.10
FOLLOW-UP OF UNRESOLVED ADVERSE EVENTS ...................................83
16.3.11
POST-STUDY EVENTS.......................................................................................83
16.4
REPORTING OF SERIOUS ADVERSE EVENTS..............................................83
16.4.1
REPORTING OF DEATHS TO ASTRAZENECA ..............................................85
16.4.2
OTHER EVENTS REQUIRING REPORTING....................................................85
16.4.3
OVERDOSE ..........................................................................................................85
16.4.4
HEPATIC FUNCTION ABNORMALITY ...........................................................86
16.4.5
PATERNAL EXPOSURE .....................................................................................86
16.4.6
MEDICATION ERROR ........................................................................................87
16.5
SAFETY MONITORING......................................................................................88
16.5.1       DOSE LIMITING TOXICITY DEFINITION ......................................................88
17.
ETHICAL AND REGULATORY REQUIREMENTS.........................................89
17.1
INFORMED CONSENT .......................................................................................90
17.2
INCENTIVES ........................................................................................................90
17.3
CONFIDENTIALITY............................................................................................90
17.4
CHANGES TO THE PROTOCOL AND INFORMED CONSENT FORM ........90
17.5
AUDITS AND INSPECTIONS.............................................................................91
18.
STUDY MANAGEMENT.....................................................................................91
18.1
TRAINING OF STUDY SITE PERSONNEL ......................................................91
18.2
MONITORING OF THE STUDY.........................................................................92
18.3
SOURCE DATA....................................................................................................92
18.4
STUDY TIMETABLE AND END OF STUDY ...................................................92
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18.5
DATA MANAGEMENT.......................................................................................93
19.
STUDY GOVERNANCE AND OVERSIGHT.....................................................93
20.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................94
20.1
IDENTITY OF INVESTIGATIONAL PRODUCT(S) .........................................94
21.
LIST OF REFERENCES .......................................................................................94
22.
APPENDICES......................................................................................................100
I SCHEDULE OF STUDY VISITS AND PROCEDURES.................................................100
II COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V5.0.................103
III RANDSF-36 SURVEY ...................................................................................................104
IV RANDSF-36 SURVEY SCORING ................................................................................109
V INTERNATIONAL INDEX OF ERECTILE FUNCTION (IIEF) ..................................114
VI ASSESMENT OF INTERNATIONAL INDEX OF ERECTILE FUNCTION (IIEF)...120
VII PILL DIARY ..................................................................................................................121
VII DURVALUMAB TOXICITY MANAGEMENT GUIDELINE TABLES...................124
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LIST OF TABLES:
Table 1. Dose reductions for olaparib to manage adverse events
Table 2. Dose reduction for olaparib if patient develops moderate renal impairment
Table 3. Dose reductions for olaparib if patient has to start taking a strong or moderate CYP3A 
inhibitor
Table 4. Management of olaparib hematological toxicity (anemia)
Table 5. Management of olaparib hematological toxicity (neutropenia, leukopenia and 
thrombocytopenia)
Table 6. Dose reductions for olaparib treatment
Table 7. Hematology Laboratory Tests
Table 8. Clinical Chemistry (Serum or Plasma) Laboratory Tests
Table 9. Urinalysis Tests
Table 10. Highly Effective Methods of Contraception (<1% Failure Rate)
Table 11. Permitted concomitant medications/Supportive Medications
Table 12. Prohibited Concomitant Medications
Table 13. Restricted concomitant medications
Table 14. Volume of Blood to be Drawn From Each Patient
Table 15. Pocock-type stopping boundary for safety monitoring
Table 16. List of Investigational Products for This Study
Table 17. RANDSF-36 survey scoring Step 1: Recoding Items
Table 18. RANDSF-36 survey scoring Step 2: Averaging Items to Form Scales
Table 19. RANDSF-36 survey scoring Reliability, Central Tendency, and Variability of Scales in 
the Medical Outcomes Study
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ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ADA
Anti-drug antibody
ADCC
Antibody-dependent cell-mediated cytotoxicity
ADT
Androgen deprivation therapy
AE
Adverse Event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AML
Acute myeloid leukemia
APC
Antigen-presenting cells
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase 
AUC
Area under the concentration-time curve
BCR
Biochemically recurrent prostate cancer
BUN 
Blood urea nitrogen
CAP
College of American Pathologists
CDC
Complement-dependent cytotoxicity
CFR 
U.S. Code of Federal Regulations 
CI
Confidence interval
CL
Clearance
CLIA
Clinical laboratory improvement amendment
Cmax
Peak concentration
Cmax,ss
Peak concentration at steady state
Cmin
Trough concentration
Cmin,ss
Trough concentration at steady state
CNS
Central nervous system
CR
Complete response
CRPC
Castration resistance prostate cancer
CT
Computed tomography
CTCAE v.50
Common Terminology Criteria for Adverse Events
ctDNA
Cell-free circulating tumor DNA
CTLA-4
Cytotoxic T-lymphocyte-associated antigen-4
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Abbreviation or 
special term
Explanation
DC
Disease control
DCR
Disease control rate
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid 
DoR
Duration of response
ds-DNA
Double strand DNA
E2A
Clinical safety data management: definitions and standards for expedited    reporting
E6
Good clinical practice: consolidated guidance 
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group performance status
EDTA
Disodium edetate dihydrate
EFS
Event free survival
Fc
Fragment crystallizable
FFPE
Formalin fixed paraffin embedded
FSH
Follicle-stimulating hormone
FTIH
First-time-in-human
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HCl
Hydrochloride
HCV
Hepatitis C virus
HDL
High Dense Lipoprotein
HIV
Human immunodeficiency virus
HR
Homologous recombination 
HRD
Homologous recombination deficient (loss of function mutation in homologous 
recombination gene)
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council on Harmonization 
iCPD
confirmed progressive disease by iRECIST
IEC
Independent Ethics Committee
IFN
Interferon
IGF
Insulin-like growth factor
IgG1
Immunoglobulin G1
IgG2
Immunoglobulin G2
IGSF
Immunoglobulin superfamily
IHC
Immunohistochemistry 
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Abbreviation or 
special term
Explanation
IIEF
International index of erectile function
IL
Interleukin
imAE
Immune-mediated adverse event
IRB
Institutional Review Board
IV
Intravenous(ly)
LC/MS/MS
Liquid chromatography/tandem mass spectrometry
LDL
Low Dense Lipoprotein
lfCDK12
Loss of function CDK12 mutation
LL
Local laboratories 
MAb
Monoclonal antibody
mCRPC          
Metastatic castration resistance prostate cancer
MDS
Myelodysplastic syndrome
MDSC
Myeloid-derived suppressor cells
MedDRA
Medical Dictionary for Regulatory Activities
miRNA
Micro ribonucleic acid
MMR
Mismatch repair
MMRd             
Mismatch repair deficiency
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
MSI
Microsatellite instability
MTD
Maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
NGS
Next generation sequencing
NHEJ             
Non-homologous end-joining pathway 
NIH               
National Institution of Health
NK
Natural killer
NOAEL
No-observed-adverse-effect level
NSCLC
Non-small cell lung cancer
OR
Objective response
ORR
Objective response rate
OS
Overall survival
PCa
Prostate cancer
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PFS
Progression free survival
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Abbreviation or 
special term
Explanation
PK
Pharmacokinetic(s)
PR
Partial response
PRO
Patient-reported outcome
PSA
Prostate specific antigen
PSA50
Decrease of PSA by ⩾ 50% from baseline
PSADT
PSA doubling time
PT
Prothrombin time 
PVC
Polyvinyl chloride
Q12W
Every 12 weeks
Q2W
Every 2 weeks
Q3M
Every 3 months
Q3W
Every 3 weeks
Q4W
Every 4 weeks
QC
Quality control 
QOL
Quality of life
QTc
Time between the start of the Q wave and the end of the T wave corrected for heart 
rate
QTcF
QT interval on ECG corrected using the Frederica’s formula
RANDSF-36
RAND 36-Item Short Form QOL Survey 
RBC
Red blood cell
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RT
Radiation therapy
SAE
Serious adverse events
SD
Stable disease
SID
Subject identification
SoAs
Schedule of Assessments 
SOCS3
Suppressor of cytokine signaling 3
sPD-L1
Soluble programmed cell death ligand 1
SUSAR
Suspected unexpected serious adverse reaction
t½
Half life
TCR
T-cell receptor
TEAE
Treatment-emergent adverse event
TIL
Tumor infiltrating lymphocyte
Tmax
Time to peak concentration
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Abbreviation or 
special term
Explanation
Tmax,ss
Time to peak concentration at steady state
TNF-α
Tumor necrosis factor alpha
TSH
Thyroid stimulating hormone 
ULN
Upper limit of normal
USA
United States of America
UW
University of Washington 
WBC
White blood cell
WFI
Water for injection
WHO
World Health Organization
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1.
INTRODUCTION
1.1
 BIOCHEMICALLY RELAPSED PROSTATE CANCER 
Prostate cancer is the most common non-cutaneous malignancy affecting American men and is expected to 
result in nearly 30,000 deaths in the U.S. in 2018.(1) This year, an estimated 174,650 men in the United 
States will be diagnosed with prostate cancer, of which about two-thirds undergo radical prostatectomy or 
definitive radiation therapy (RT). Approximately 25%-35% of patients treated with definitive surgical or 
radiation therapy for localized adenocarcinoma of the prostate will develop biochemically recurrent prostate 
cancer (BCR), characterized by elevated prostate specific antigen (PSA) without presence of overt 
metastatic disease.(2,3) Definition of BCR differs depending on what treatment patients received for local 
disease. For patients who underwent radical prostatectomy BCR is defined by American Urological 
Association as a serum PSA ≥0.2 ng/mL, which is confirmed by a second determination with a PSA 
≥0.2 ng/mL. Phoenix criteria is used to define BCR in patients who underwent definitive radiation therapy 
without prostatectomy:  a PSA rise of 2 ng/mL or more above the nadir PSA. An estimated 40,000 - 50,000 
men in the U.S develop BCR each year, yet the treatment of men in this disease state is far from 
standardized. The optimal time to initiate treatment and the choice of specific therapy for such patients 
remains controversial and highly variable in clinical practice. This may be due to several potential reasons, 
including 1) a lack of prospective randomized trial data demonstrating an overall survival advantage for 
one particular therapeutic approach and 2) a biologically heterogeneous population with variable natural 
disease course. The kinetics of PSA change over time has emerged as an important independent prognostic 
factor for patients with BCR, both with respect to time to development of metastases as well as the risk of 
prostate cancer-specific mortality. In a cohort study of 8,669 men treated with localized therapy, of the 
1,451 men with PSA recurrence, a PSA doubling time (PSADT) less than 3 months was associated with an 
approximately 50% chance of prostate-cancer specific mortality at 5 years; in contrast, those with a PSADT 
greater than 12 months had less than 10% prostate cancer-specific mortality during the same time 
interval.(4) 
1.2
TREATMENT OPTIONS IN BCR PROSTATE CANCER PATIENTS 
Guideline recommendations from the National Comprehensive Cancer Network (NCCN), for management 
of BCR include androgen deprivation therapy (ADT) or observation. Currently, there are no clear guidelines 
about the best time to start therapy for BCR patients. NCCN guidelines suggest considering observation in 
men with prolonged PSADT (>12 months) and those who are older. Earlier ADT is suggested in men with 
shorter PSADT and otherwise long-life expectancy, though the definition of earlier and late ADT is 
controversial and are not defined in guidelines. Since the benefit of early ADT is not clear and ADT can 
increase morbidity and negatively impact quality of life (Section 1.3), treatment is recommended to be 
individualized until further studies are done. (5) BCR patients who choose to proceed with ADT can be 
treated with intermittent ADT or continuous ADT as a randomized clinical trial with 1386 enrolled patients 
showed that intermittent ADT is not inferior to continuous ADT in BCR patients.(6) In this trial, BCR 
patients (defined by PSA> 3 ng/ml) were randomized to continuous ADT or to intermittent ADT (8-month 
cycles of ADT with nontreatment periods determined according to the PSA level). For the patients on 
intermittent ADT, if their PSA was >4ng/ml; rising during an ADT treatment cycle; or PSA>10 ng/ml less 
than 2 months after finishing 8-month ADT treatment cycle, they were switched to continuous ADT 
therapy. Intention to treat analysis showed that median overall survival was 8.8 years in the intermittent-
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therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% 
confidence interval, 0.86 to 1.21).(6)) Quality of life (QOL) assessment in this trial showed better scores 
with intermittent ADT for hot flashes, desire for sexual activity, and urinary symptoms. Based on this data, 
intermittent ADT can be considered over continuous ADT in BCR if the decision is to start therapy, though 
patients often end up on a long-term ADT therapy. 
1.3
ADT EFFECTS ON QUALITY OF LIFE AND METABOLISM
Patients that undergo localized prostate cancer therapy, prostatectomy or radiation therapy, suffer from 
sexual, urinary and bowel morbidities(7). ADT worsens these morbidities and further decreases quality of 
life (QOL) in prostate cancer patients. A population study assessing QOL in prostate cancer patients was 
conducted in the UK. QOL surveys were completed by 35823 men with all stages of prostate cancer, 19599 
(63.8%) had stage I or II. Compared with men who did not receive ADT, more men who received the 
therapy reported moderate to large problems with hot flushes (30·7% [95% CI 29·8–31·6] vs 5·4% [5·0–
5·8]), low energy (29·4% [95% CI 28·6–30·3] vs 14·7% [14·2–15·3]), and weight gain (22·5%, 21·7–23·3) 
vs 6·9% [6·5–7·3]). EPIC-26 score was used to assess sexual function (100 - the best, 0 - the worst) and 
showed that men on ADT had worse sexual function (score 15.3, CI 14.6-16.1) compared to men on active 
surveillance (score 44.6 CI 43.6-45.7) or men who had surgery alone (score 22.1 CI 21.5-22.6). Patients 
who had external beam radiation (EBRT) alone had sexual function score of 25.6 (CI 24.5-26.7) compared 
to score 19.1 (18.5-19.6) in patients who had EBRT and ADT. Aside from negative affect on quality of life, 
ADT also impacts metabolism. ADT causes weight gain: loss of muscle mass and increase of fat mass.(8) 
ADT causes elevated lipid profile, insulin resistance, increasing risk of diabetes and cardiovascular disease. 
(8) ADT has also been associated with cognitive impairment (9), osteoporosis and an increased risk of 
fractures(10). Despite these negative effects ADT remains the main backbone therapy for prostate cancer, 
as it is very effective for disease control, but strategies to postpone the start of ADT can help to reduce 
morbidity and improve quality of life in prostate cancer patients. 
1.4
CHECKPOINT INHIBITORS IN CANCER TREATMENT
Traditionally, prostate cancer has been treated with a one size fits all therapeutic approaches, utilizing 
hormonal therapies, chemotherapies, and radiopharmaceuticals. While advances in systemic therapy have 
resulted in improved cancer outcomes over the past decades, we are now entering an era of precision 
oncology in which our understanding of cancer biology and genomics will allow us to select a therapy with 
the greatest likelihood of benefiting an individual. Indeed, proof of principle for this concept is evidenced 
by pembrolizumab’s recent approval by the FDA for all advanced solid tumor patients with mismatch repair 
(MMR) deficiency (MMRd) or microsatellite instability (MSI) – representing the first tumor-agnostic 
approval by the Agency (11–13). About 5% of castration-resistant prostate cancer (CRPC) cases have been 
shown to be MMRd/MSI-high and would thus qualify for treatment with pembrolizumab. (14) 
While immunotherapeutics have demonstrated impressive activity in a range of malignancies, they are not 
effective for all patients and strategies to identify patients most likely to benefit from these agents are 
needed. The major role of the adaptive immune system is to recognize and destroy cells displaying foreign 
antigens, including tumor cells. A clinically relevant mechanism by which cancers are able to escape T-cell 
mediated destruction is through stimulating the programmed death 1 (PD1) pathway – a negative feedback 
system that represses Th1 cytotoxic immune responses.(15) Recent advances have shown that blocking this 
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pathway with antibodies directed towards PD1 or its ligand (PDL1) can produce remarkable clinical 
responses in some cancers.(16–21)This immune-recognition is predicated, however, on the presence of 
antigens that are recognized as foreign (i.e. tumor neoantigens). Not surprisingly, a high burden of tumor 
neoantigens – as reflected by a high somatic mutational load – has been shown to correspond with the 
response to immune checkpoint blockade (e.g. anti-CTLA4, anti-PD1, anti-PDL1). (13,22–24)
 Based on the hypothesis that hypermutation would predispose to anti-PD1 therapy, a phase II study testing 
pembrolizumab (anti-PD1 therapy) in patients with metastatic carcinoma with and without MMRd (i.e. 
MSI-high and MSI-low, respectively) was launched.(13)This study demonstrated that 40% of hypermutated 
(i.e. MSI-high) colorectal cancer patients had an immune-related objective response (irOR) compared to 
0% of MSI-low patients. Similarly, pembrolizumab was associated with a 50% response rate in 
hypermutated non-colorectal gastrointestinal malignancies – supporting the hypothesis that mutational load 
may predict for response to immune checkpoint blockade in a range of malignancies.(20) An expansion 
cohort testing pembrolizumab across 12 different MSI-high and/or MMRd cancers confirmed a response 
rate of ~50% for this group – leading to pembrolizumab’s approval in this molecularly defined group of 
patients.(11,20) However, some non-hypermutated tumors still respond to immune checkpoint blockade, 
which would indicate that neoantigens are likely being generated in the absence of MMRd.
1.5
DURVALUMAB BACKGROUND/NON-CLINICAL AND CLINICAL EXPERIENCE
The non-clinical and clinical experience is fully described in the most current version of the durvalumab 
Investigator’s Brochure. 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass that 
inhibits binding of PD-L1 and is being developed by AstraZeneca/MedImmune for use in the treatment of 
cancer (MedImmune is a wholly owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be 
referred to as AstraZeneca throughout this document). The proposed mechanism of action (MOA) for 
durvalumab is interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1).  Blockade of PD-
L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that 
may result in tumor elimination.  In vitro studies demonstrate that durvalumab antagonizes the inhibitory 
effect of PD-L1 on primary human T cells resulting in the restored proliferation of IFN-γ .(25)  In vivo 
studies have shown that durvalumab inhibits tumor growth in xenograft models via a T-cell-dependent 
mechanism.(25) Based on these data, durvalumab is expected to stimulate the patient’s antitumor immune 
response by binding to PD-L1 and shifting the balance toward an antitumor response. Durvalumab has been 
engineered to reduce antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. 
To date durvalumab has been given to more than 6000 patients as part of ongoing studies either as 
monotherapy or in combination with other anti-cancer agents.  Details on the safety profile of durvalumab 
monotherapy are summarized in Section 4.2 and Section 16.5.1. Refer to the current durvalumab 
Investigator’s Brochure for a complete summary of non-clinical and clinical information including safety, 
efficacy and pharmacokinetics. 
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27
1.6
CDK12 DEFICIENCY AND NEOANTIGEN BURDEN
Recent work conducted through the Stand Up 2 Cancer-Prostate Cancer Foundation (SU2C-PCF) Prostate 
Dream Team has found that CDK12 loss of function mutations lead to increased gene fusions, with a distinct 
mutational signature compared to cases with inactivating mutations in homologous recombination (e.g. 
BRCA1/2, ATM) or MMR genes. Interestingly, CDK12-mutant cases are associated with elevated 
neoantigen burden ensuing from fusion-induced chimeric open reading frames. Their immune phenotype 
is characterized by increased tumor T-cell infiltration, high levels of neoantigens, and T-cell clonal 
expansion. Clinically, we have observed  responses to pembrolizumab in 4/6 men with MSI-low, castration-
resistant prostate cancer (CRPC) and CDK12 inactivation, which is double the response rate in unselected 
CRPC patients.(26)  
The incidence of CDK12 mutations appears to be enriched in CRPC compared to unselected primary 
prostate cancer cases (6.9% vs. 1.2%). However, the incidence of CDK12 mutations in primary prostate 
specimens from men who subsequently developed CPRC is comparable to what is observed in metastatic 
tissue from men with CPRC – indicating that CDK12 mutations are a likely early (i.e. truncal) event.(27)
1.7
DNA REPAIR AND HOMOLOGOUS RECOMBINATION DEFICIENCY
There are several DNA repair pathways. The main repair mechanisms for double-stranded DNA (dsDNA) 
damage repair are the homologous recombination (HR) pathway and non-homologous end-joining (NHEJ) 
pathways. NHEJ joins then ends of the damaged DNA without repairing lost DNA information, leading to 
loss on DNA code and eventually cell apoptosis. The only pathway that repairs dsDNA damage without 
loss of DNA code is the HR pathway. If a patient has a mutation in a HR pathway gene (e.g. BRCA1/2, 
ATM, CHEK2, etc.), agents that induce dsDNA damage can lead to replication fork collapse and chromatid 
breaks persist, leading a cell down a pathway toward apoptosis.(28–30)
In spite of the higher neoantigen burden associated with HR deficient (HRD) prostate cancer, single agent 
checkpoint inhibitors do not appear to be very effective in these patients. The KEYNOTE-199 study 
reported a PSA response rate of only 12% in mCRPC patients post taxane-based chemotherapy with ATM 
or BRCA1/2 mutations, with a similar PSA response rate of 10% observed in the HRD unselected group.(39) 
Response rates to combined CTLA4/PD1-pathway blockade (ipilimumab + nivolumab) were reported to 
be higher in the CheckMate 650 trial, with responses potentially enriched in those with HRD; however, 
definitive conclusions about HRD status as a biomarker for response to dual checkpoint blockade are not 
possible given that few patients with HRD were enrolled to this trial (N=7). It is also worth noting that 
ipilimumab + nivolumab was associated with considerable toxicity, with >40% of patients experiencing a 
treatment-related grade 3-5 adverse event and 4 (4%) patients experiencing a treatment-related death.(40) 
1.8
OLAPARIB BACKGROUND/NON-CLINICAL AND CLINICAL EXPERIENCE
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly (ADP ribose)] 
polymerization (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. Treating physician and Investigator should be familiar with the current olaparib (AZD2281) 
Investigator Brochure (IB).
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Investigational Drug Substance:  , Olaparib (AZD2281)
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28
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 HR deficiencies 
(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, olaparib may offer a 
potentially efficacious and less toxic cancer treatment compared with currently available chemotherapy 
regimens.
Over 20% of CRPC patients harbor biallelic loss of an HR pathway gene.(41) In addition, more recent 
studies from our group have demonstrated that in men with metastatic prostate cancer, there is a high 
incidence (>10%) of deleterious germline alteration in HR genes.(42) This data provides a strong rationale 
for a precision oncology approach to treating advanced prostate cancer with drugs that impair DNA damage 
repair (e.g. PARP inhibitors). Proof of concept for this approach is derived from the TOPARP Trial, in 
which the PARP inhibitor olaparib was found to associate with a response rate of 88% in men with 
homozygous deletions, deleterious mutations, or both in DDR genes (e.g. BRCA1/2, ATM, Fanconi’s 
anemia genes, and CHEK2).(43) On this basis, larger randomized studies have been launched to further 
evaluate PAPR inhibitors in men with CRPC.
Olaparib increases genomic instability and may sensitize to checkpoint inhibitors through increasing 
mutational burden or leading to STING pathway activation. Preliminary findings from a Phase I/II trial 
testing durvalumab (anti-PDL1) in combination with olaparib, an inhibitor of poly(ADP-ribose) 
polymerase (PARPi), reported that 9 of 17 (53%) patients had a radiographic and/or PSA response, the 
majority of patients that responded to combinatorial therapy had inactivating mutations in HR genes.(44) 
Cohort A of the KEYNOTE-365 study tested pembrolizumab in combination with olaparib in unselected 
mCRPC patients and reported that ~1/3 of patients had a radiographic response per PCWG3-modified 
RECIST criteria. Overall, incidence of immune-mediated adverse events (AEs) in KEYNOTE-365 was 
consistent with studies testing pembrolizumab monotherapy. Based on these promising results, larger 
studies testing immune checkpoint inhibition plus PARP inhibitors are currently planned.
2.
RESEARCH HYPOTHESIS
ADT or observation are currently standard of care for BCR patients. Given that ADT can negatively 
impact quality of life (QOL) and often results in clinically significant morbidity (e.g. metabolic 
derangements, osteoporosis, cognitive impairment), new therapeutic strategies for BCR patients that 
avoid/postpone ADT are needed. Based on the aforementioned data, we hypothesize that BCR prostate 
cancer patients with a high neoantigen burden – as inferred by loss of function mutations in CDK12, 
MMRd/MSI-high or HRD in archival tumor tissue – will be sensitive to durvalumab plus olaparib when 
given in the absence of ADT. 
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29
3.
RATIONALE FOR CONDUCTING THIS STUDY
3.1
RATIONALE FOR PSA AS SURROGATE ENDPOINT IN BCR
Analysis of University of Washington Caisis database was done to assess the association of undetectable 
PSA with development of metastasis, prostate cancer-specific survival, and overall survival. (48) In this 
study, 93 patients after radical prostatectomy who developed BCR (defined as PSA ≥0.2 ng/mL) and 
received 6-12 months of ADT were included in the analysis. Retrospective analysis showed that 23/93 
(25%; 95%CI 16-35%; p < 0.001) patients had undetectable PSA at 12 months and 14/93 (15%; 95%CI 9-
24%; p < 0.001) at 24 months after ending ADT. Detectable PSA at 12 months was associated with 
increased risk of metastasis (p = 0.006), prostate cancer-specific death (p = 0.028), and death from any 
cause (p = 0.065). Though this study is limited by retrospective nature, it suggests that undetectable PSA at 
12 months is associated with longer prostate cancer-specific survival and lower risk of metastatic disease. 
Further, given PSA level and rate of increase regularly informs decision to start ADT and ADT is associated 
with significant morbidity (Section 1.3), achieving an undetectable PSA and delaying time to ADT can be 
beneficial for patients. Therefore, in this protocol, we chose undetectable PSA at 12 months as our primary 
endpoint for patients previously treated with radical prostatectomy, including those that also went on to 
receive salvage radiation. 
In contrast to post-prostatectomy, following definitive radiation, prostate cancer patients still have viable 
prostate tissue that can produce PSA. As such, Critz, et al. conducted work to define the PSA nadir post-
radiotherapy associated with long-term disease-free survival. This study concluded that a PSA nadir of 0.5 
ng/mL or less was associated with best outcomes. Men with a PSA nadir of ≤0.5 ng/mL were found to have 
a 5- and 10-year disease-free survival rate of 93% and 83%, respectively, as compared with a 5-year disease-
free survival rate of 26% for those achieving a nadir of 0.6 to 1.0 ng/mL (P = 0.0001). All men with a nadir 
greater than 1.0 ng/mL ultimately failed treatment.(49) Based on this data we chose PSA < 0.5 ng/ml as 
primary endpoint for BCR patients who underwent definitive radiation therapy without prostatectomy. 
3.2
DURVALUMAB DOSE RATIONALE
A durvalumab dose of 20 mg/kg Q4W is supported by in-vitro data, non-clinical activity, clinical 
PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients with advanced solid 
tumors and from a Phase I trial performed in Japanese patients with advanced solid tumor (D4190C00002).
PK/Pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging from 0.1 to 
10 mg/kg Q2W or 15 mg/kg Q3W, durvalumab exhibited non-linear (dose-dependent) PK consistent with 
target-mediated drug disposition. The PK approached linearity at ≥3 mg/kg Q2W, suggesting near complete 
target saturation (membrane-bound and sPD-L1), and further shows that the durvalumab dosing frequency 
can be adapted to a particular regimen given the linearity seen at doses higher than 3 mg/kg. The expected 
half-life with doses ≥3 mg/kg Q2W is approximately 17 days. A dose-dependent suppression in peripheral 
sPD-L1 was observed over the dose range studied, consistent with engagement of durvalumab with PD-L1. 
A low level of immunogenicity has been observed. No patients have experienced immune-complex disease 
following exposure to durvalumab. 
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A population PK model was developed using the data from Study 1108 (doses=0.1 to 10 mg/kg Q2W or 15 
mg/kg Q3W (see Investigator’s Brochure for details). Multiple simulations indicate that a similar overall 
exposure is expected following both 10 mg/kg Q2W and 20 mg/kg Q4W regimens, as represented by AUCss 
(4 weeks). Median Cmax,ss is expected to be higher with 20 mg/kg Q4W (~1.5 fold) and median Ctrough,ss is 
expected to be higher with 10 mg/kg Q2W (~1.25 fold). Clinical activity with the 20 mg/kg Q4W dosing 
regimen is anticipated to be consistent with 10 mg/kg Q2W with the proposed similar dose of 20 mg/kg 
Q4W expected to (a) achieve complete target saturation in majority of patients; (b) account for anticipated 
variability in PK, pharmacodynamics, and clinical activity in diverse cancer populations; (c) maintain 
sufficient PK exposure in case of ADA impact; and (d) achieve PK exposure that yielded maximal 
antitumor activity in animal models.
Given the similar area under the plasma drug concentration-time curve (AUC) and modest differences in 
median peak and trough levels at steady state, the observation that both regimens maintain complete sPD-L1 
suppression at trough, and the available clinical data, the 20 mg/kg Q4W and 10 mg/kg Q2W regimens are 
expected to have similar efficacy and safety profiles, supporting further development with a dose of 
20 mg/kg Q4W. 
Clinical data
Refer to the current durvalumab Investigator’s Brochure for a complete summary of clinical information 
including safety, efficacy and pharmacokinetics at the 20mg/kg Q4W regimen.
3.2.1
RATIONALE FOR DURVALUMAB FIXED DOSING
A population PK model was developed for durvalumab using monotherapy data from a Phase I study (study 
1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). Population PK analysis 
indicated only minor impact of body weight (WT) on the PK of durvalumab (coefficient of ≤0.5). The 
impact of body WT-based (10 mg/kg Q2W) and fixed dosing (750 mg Q2W) of durvalumab was evaluated 
by comparing predicted steady state PK concentrations (5th, median and 95th percentiles) using the 
population PK model. A fixed dose of 750 mg was selected to approximate 10 mg/kg (based on median 
body WT of ~75 kg). A total of 1000 patients were simulated using body WT distribution of 40–120 kg. 
Simulation results demonstrate that body WT-based and fixed dosing regimens yield similar median steady 
state PK concentrations with slightly less overall between-patient variability with fixed dosing regimen. 
Similar findings have been reported by others.(50–53) Wang and colleagues investigated 12 monoclonal 
antibodies and found that fixed and body size-based dosing perform similarly, with fixed dosing being 
better for 7 of 12 antibodies.(52) In addition, they investigated 18 therapeutic proteins and peptides and 
showed that fixed dosing performed better for 12 of 18 in terms of reducing the between-patient variability 
in pharmacokinetic/pharmacodynamics parameters.(50) 
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced dosing 
errors. Given expectation of similar pharmacokinetic exposure and variability, we considered it feasible to 
switch to fixed dosing regimens. Based on average body WT of 75 kg, a fixed dose of 1500 mg Q4W 
durvalumab (equivalent to 20 mg/kg Q4W) is included in the current study.
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31
3.3
OLAPARIB DOSE RATIONALE
The dose of olaparib used in this study is 300 mg twice daily which is the currently approved dose.
3.4
COMBINATION OF OLAPARIB AND DURVALUMAB RATIONALE
Olaparib increases genomic instability, which may sensitize tumors to immune checkpoint blockade by 
increasing mutational burden or activating pro-inflammatory pathways (e.g. STING pathway). As cited 
above, preliminary findings from a Phase I/II trial testing durvalumab in combination with olaparib 
reported 9 of 17 (53%) patients had a radiographic and/or PSA response. In addition, the KEYNOTE-365 
study also reported a favorable response rate to combination pembrolizumab plus olaparib. Both trials 
reported an acceptable safety profile. This data supports the use of durvalumab plus olaparib as a well-
tolerated, highly effective immunotherapy regimen. We anticipate that this combinatorial regimen will be 
associated with durable PSA suppression in men with BCR prostate cancer and a high neoantigen 
burden.(44)(54,54,55)
Given that we expect some BCR prostate cancer patients with lfCDK12 (Cohort A) and MMRd/MSI-high 
(Cohort B) may respond well to durvalumab alone, we are planning to treat these patients with a 3-month 
durvalumab lead-in prior to adding olaparib to their regimen. This will allow us to determine the PSA 
response rate and assess the impact on circulating immune markers following anti-PDL1 monotherapy in 
Cohorts A and B. Because prostate cancer patients with HRD have not demonstrated high response rates 
to immune checkpoint inhibitor monotherapy, we will plan to treat these patients (Cohort C) with 
durvalumab plus olaparib for the entire study treatment period. 
Safety
In the aforementioned Phase I/II study testing durvalumab plus olaparib trial (44) the most common 
treatment-related grade 3 or 4 adverse events were anemia (4/17; 24%), lymphopenia (2/17; 12%), infection 
(2/17; 12%), and nausea (2/17; 12%). Four patients had immune-related adverse events (imAEs) of any 
grade, including 2 with acute onset unilateral hearing loss, one with optic neuritis, and one who developed 
remitting seronegative symmetrical synovitis with pitting edema (RS3PE). All imAEs were treated with 
high-dose steroids. Symptoms improved to near complete resolution with high-dose steroids in the patient 
with optic neuritis and one patient with acute onset unilateral hearing loss, and to complete resolution in 
the patient with RS3PE. The second patient with acute onset unilateral hearing loss required use of a hearing 
aid. Durvalumab was discontinued in all patients who developed imAEs, but olaparib was continued. No 
patients were taken off-study due to toxicity. Patients received a median of 7 cycles of treatment (range: 2–
17).(44)
4.
BENEFIT/RISK AND ETHICAL ASSESSMENT
4.1
 POTENTIAL BENEFITS
Durvalumab and Olaparib have been reported to have clinical activity in PCa patients with high neoantigen 
burden. Because durvalumab seems to be more effective in patients with high mutational burden, we expect 
that combining it with olaparib to activate immunogenic pathways (e.g. the STING pathway)(31–33) and 
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to impair DNA damage repair increasing mutational burden will potentiate the clinical effects of 
durvalumab — leading to durable PSA suppression. Potential benefit to participants could be postponing 
starting ADT and side effects associated with it. If effective, patients enrolled to this study would benefit 
by receiving an effective combination therapy that is otherwise unavailable. There may be no direct benefits 
to participants in this pilot study, however, participants and others may benefit in the future from 
information learned from this study. Specifically, information learned in this study may lead to the 
development of a safe and effective intervention that prevents progression of metastasis in patients with 
biochemically recurrent prostate cancer and one of the genomic markers (lfCDK12, MMRd/MSI-high, 
HRD).
4.2
POTENTIAL RISKS
Potential risks with durvalumab include, but are not limited to, diarrhea/colitis pneumonitis/ILD, 
endocrinopathies (hypo- and hyperthyroidism, type I diabetes mellitus (which may present as diabetic 
ketoacidosis), 
hypophysitis 
and 
adrenal 
insufficiency) 
hepatitis/increases 
in 
transaminases, 
nephritis/increases in creatinine, pancreatitis/increases in amylase and lipase, rash/pruritus/dermatitis, 
myocarditis, myositis/polymyositis, other rare or less frequent inflammatory events including 
neuromuscular toxicities (eg, Guillain-Barré syndrome, myasthenia gravis), diabetes insipidus,  
noninfective 
encephalitis, 
pemphigoid, 
immune 
thrombocytopenia, 
infusion-related 
reactions, 
hypersensitivity reactions, and infections/serious infections, and psoriasis.
For information on all identified and potential risks with durvalumab please always refer to the current 
version of the durvalumab IB. 
Potential risks with olaparib include hematologic toxicities, infections associated with myelosuppression, 
gastrointestinal disorders. For information on all identified and potential risks with olaparib please refer to 
the current version of the olaparib IB. Please refer to Section 9, as well as olaparib and durvalumab IB for 
list of common toxicities. Additional important potential risks include infusion-related reactions, 
hypersensitivity, anaphylaxis or serious allergic reactions, serious infections, and immune complex disease. 
If the participant is sexually active and their female partner is of child-bearing potential, they must agree to 
use a medically acceptable form of birth control to reduce the potential for harm to an unborn child.
5.
STUDY OBJECTIVES
As stated above, Durvalumab and Olaparib have been reported to have clinical activity in PCa patients with 
high neoantigen burden. Because durvalumab seems to be more effective in patients with high mutational 
burden, we expect that combining it with olaparib to impair DNA damage repair and increase mutational 
burden will potentiate the clinical effects of durvalumab — leading to durable PSA suppression. Potential 
benefit to participants could be postponing starting ADT and side effects associate with it. If effective, 
patients enrolled to this study would benefit by receiving an effective combination therapy that is otherwise 
unavailable. 
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33
5.1
PRIMARY OBJECTIVE(S)

To assess clinical activity of durvalumab and olaparib in men with biochemically recurrent 
prostate cancer predicted to have a high neoantigen load  
5.2
SECONDARY OBJECTIVE(S)

Assess safety of durvalumab monotherapy 

Assess safety of durvalumab and olaparib combination therapy

Assess PSA changes in relationship to intervention  

Assess quality of life changes 
5.3
EXPLORATORY OBJECTIVE(S)

Assess radiographic progression free survival (rPFS) 

Assess PSA progression free survival (PSA-PFS)

Assess event free survival (EFS)
Assess time to start of ADT
5.4
CORRELATIVE OBJECTIVE(S)

identify favorable tumor microenvironment associated with response to durvalumab and olaparib

identify genetic characteristics associated with response to durvalumab and olaparib

to evaluate tumor clonal evolution

evaluate systemic immune response at 3 and 6 months and at the time of progression
6.
STUDY DESIGN
6.1
OVERVIEW OF STUDY DESIGN
This is a phase 2, open-label, single arm, three cohort, multicenter clinical trial. The trial will be conducted 
at two sites: 1) University of Washington Medical Center/Fred Hutchinson Cancer Center, and 2) Oregon 
Health and Sciences University (OHSU). This pilot clinical trial will test the clinical activity of durvalumab 
and olaparib in men with biochemically recurrent prostate cancer predicted to have a high neoantigen load 
inferred by the presence of either loss of function CDK12 mutations (Cohort A) or MMRd/MSI-high 
(Cohort B) or HRD (Cohort C). Patients will be screened for these genomic markers as part of the trial and 
those identified will be enrolled in the respective cohort. We anticipate identifying the majority of the study 
cohort (~20) prior to screening; however, we are expecting to screen 50 patients without prior clinical 
sequencing to identify rest of the cohort (~10). Patients in cohort A and B will receive durvalumab 
monotherapy for 3 months followed by durvalumab plus olaparib for an additional 3 months. Patients in 
Cohort C will receive 6 months of durvalumab and olaparib combination therapy.  
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34
6.1.1
ENROLLMENT
This study will enroll men with biochemically recurrent prostate cancer who have received definitive local 
therapy (e.g. prostatectomy, radiation) and have a PSA doubling time ≤10 months, but no evidence of 
metastatic disease on conventional imaging (i.e. bone and CT scans). Note, patients with oligometastatic 
disease (i.e. ≤3 sites) detectable on advanced imaging only (e.g. PSMA or Fluciclovine PET) will still be 
eligible. If a study candidate did not have prior clinical grade NGS testing to assess for MMRd/MSI-high, 
lfCDK12 and HRD performed prior to screening for the study, archival tissue will be requested and 
sequenced using a clinical grade NGS assay and performed in a CLIA/CAP certified laboratory (e.g. 
FoundationOne, UW OncoPlex, etc.). If archival tissue is not available, cell-free circulating tumor DNA 
(ctDNA) may be used. Patients may be screened for neo-antigen burden after consent before meeting all 
other eligibility criteria. 
6.1.2
TREATMENT
Following screening for eligibility and confirmation of genomic marker on screening, eligible patients 
will be assigned to the appropriate cohort (either A, B or C) and will receive durvalumab monotherapy for 
3 months followed by combination of durvalumab and olaparib for 3 months Cohort A and B), or 6 
months of combination therapy (Cohort C). Following the completion of the 6-month treatment period, 
patients will undergo monitoring for signs of PSA change, clinical and radiographic progression. Because 
observation is a reasonable option for prostate cancer patients with non-metastatic biochemical recurrence 
per NCCN guidelines, the study regimen will be given in the absence of androgen deprivation therapy.  
6.1.3
MONITORING
 Patients will be seen by research and oncology teams every 4 weeks while receiving durvalumab, and then 
every 3 months with PSA testing until completion of 24 months. Radiographic assessment (i.e., CT chest, 
abdomen and pelvis and bone scan) will be performed upon enrollment (within 6 weeks before study 
therapy start date) and then obtained as prompted by signs and symptoms of metastatic disease and/or at 
the time of PSA progression. Upon completion study visits (24 months from starting durvalumab) patients 
will continue to be followed as per standard of care. Clinical data after 24 months will be extracted from 
the clinical chart by the study team, as permitted by the patient. Patient will be followed passively through 
following clinical chart data up to 5 years total.  
6.1.4
PROGRESSION 
PSA progression will be defined as an increase in increase in PSA by 2 ng/ml and by 25% from baseline 
upon enrollment not earlier then 12 weeks after start of therapy, confirmed by repeat measurement at least 
2 weeks later.
Radiographic metastatic progression will be defined per RECIST criteria and Prostate Cancer Working 
Group 3 (PCWG3) criteria, respectively(56,57). No confirmatory scan is required as enrolled patients 
had no previous metastatic disease.
Lymph Nodes
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PCWG3 recommends that lymph nodes that were previously normal in size (< 1.0 cm) or 
pathologic in size must have grown by at least 5 mm in the short axis from baseline or nadir and be 
≥ 1.0 cm in the short axis to be considered to have progressed. If the node progresses to ≥ 1.5 cm 
in the short axis, it is pathologic and measurable. Nodes that have progressed to between 1.0 and 
less than 1.5 cm are pathologic subject to clinical discretion and are non-measurable. 
Visceral
The date of first metastasis is the date on which an unequivocal visceral lesion by iRECIST is 
determined. Visceral disease should be reported as being with or without other patterns of spread 
(node, bone).
Bone
Documentation of radiographic evidence of metastatic disease should include the time of the 
unequivocal development of new sites on bone scintigraphy. 
Use of Confirmatory Scans with Other Modalities
For patients who develop equivocal bone lesions while on study, PCWG3 discourages the use of 
other scanning modalities, including MRI, positron emission tomography, or other investigational 
scans that were not used to determine eligibility for the study. Supplemental scanning using 
imaging modalities with varied sensitivity that were selected by personal preference or regional 
practice may introduce bias.
 
6.1.5
ENDPOINTS 
Cohorts A, B and C will be analyzed separately for all endpoints, except safety. Quality of life 
assessments for Cohort C will be analyzed separately, while quality of life data will be assessed 
separately and combined for Cohorts A and B. 
Primary Endpoint(s):

Undetectable PSA1,2 (post-prostatectomy patients; including those that also received salvage 
radiation) or PSA <0.5 ng/ml1 (post-radiation patients) at 12-month timepoint after initiation 
(cycle 1, day 1) of therapy.
Secondary Endpoint(s): 

Adverse events during durvalumab monotherapy per CTCAE v5.0 guidelines

Adverse events during durvalumab and olaparib combination therapy per CTCAE v5.0 guidelines

PSA50 response1 (at least 50% decline in PSA from baseline at enrollment) at 3- and 6-month 
timepoints

Quality of life changes using:
a.
RANDSF-36 two- step 8-scale score (see Appendix IV for algorithm) and 
b.
IIEF surveys score in erectile function, orgasmic function, sexual desire, intercourse 
satisfaction and overall satisfaction (see Appendix VI for assessment details)
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36
1 confirmed by repeat measurement at least 2 weeks later
2 Undetectable PSA defined as PSA <0.1 ng/ml  
Exploratory Endpoint(s):

rPFS, defined as time from enrollment to date of first objective radiographic evidence of metastatic 
disease (soft tissue or bone lesion) or death; in the absence of an event, PFS will be censored at 
date of last disease assessment

PSA-PFS, defined as time from enrollment to PSA progression (increase in PSA by 2 ng/ml and 
by 25% from baseline/nadir), in the absence of an event, PSA-PFS will be censored at date of last 
disease assessment and/or visit documenting no next therapy.

EFS; defined as time from enrollment to initiation of next line of therapy, development of metastatic 
disease or death; in the absence of an event, EFS is censored at date of last disease assessment 
and/or visit documenting no next therapy.

Time to start of ADT; defined as time from enrollment to initiation of ADT; in the absence of an 
event, the endpoint is censored at date of last visit documenting no ADT initiation
Correlative Objectives and Endpoints:
1. Objective: identify favorable tumor microenvironment associated with response to durvalumab 
and olaparib
    Endpoint: CD8, CD4, FOXB3, PDL1 by IHC with quantitative output on archival prostate cancer 
tissue
2. Objective: identify genetic characteristics associated with response to durvalumab and olaparib
    Endpoint: number of somatic mutations, mutational signature, and DNA variants on whole exome 
or targeted gene sequencing of archival prostate cancer tissue
3. Objective: to evaluate tumor clonal evolution
    Endpoint: next generation sequencing of peripheral blood cell-free circulating tumor DNA 
(ctDNA) to evaluate mutational burden, and DNA variants in ctDNA at enrollment, at 6 months 
and at the time of progression 
4. Objective: evaluate systemic immune response at 3 and 6 months and at the time of progression
    Endpoint: on peripheral blood measure cytokines using Cytokine Human Magnetic 35-Plex Panel 
for the Luminex™ platform; T-cells population using flow cytometry and T-cell receptor 
sequencing. 
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37
6.2
STUDY SCHEMA
Figure 1. Study Schema 
7.
PATIENT SELECTION 
7.1
INCLUSION CRITERIA
For inclusion in the study patients must fulfill all of the following criteria: 

Histologic confirmation of adenocarcinoma of the prostate 

The patient must have received definitive local therapy for prostate cancer, consisting of either 
radiation therapy and/or prostatectomy (salvage or adjuvant radiation post-prostatectomy is not 
exclusionary).
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
PSA must be ≥2 ng/ml if received only prior definitive radiation (no PSA threshold required if 
prior prostatectomy was performed) with a PSA doubling time (PSADT) ≤10 months:
o
PSADT calculation must include all recorded PSA values >0.2 ng/ml over the past 6 
months prior to randomization, with a minimum of 3 values spaced at least 2 weeks apart, 
with each included value preferably measured at the same laboratory. PSA values obtained 
prior to localized therapy will be excluded. 
o
The calculation of PSADT is based on the natural log of PSA. 
o
The actual calculation of the PSADT can be obtained from the following online calculator: 
http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx

Prior salvage radiation or not a candidate for localized salvage radiation due to subject preference 
or clinical assessment based upon disease characteristics and/or subject co-morbidities

Prior hormonal therapy (i.e., androgen deprivation therapy, oral AR-signaling inhibitors) is 
allowed, provided this was stopped ≥ 6 months prior to starting treatment per protocol, testosterone 
is ≥150 ng/dl and patient did not demonstrate evidence of castration-resistance while on hormonal 
therapy (i.e., PSA was not rising on treatment). 

No evidence of metastatic disease on imaging by whole body bone scan and CT or MRI of the 
chest/abdomen/pelvis within 6 weeks before study therapy start day. PSMA PET or Fluciclovine 
scan within 6 weeks of start day may substitute other imaging studies.
o
Patients with oligometastatic disease (i.e., ≤3 sites) detectable on advanced imaging only 
(e.g., PSMA or Fluciclovine PET) are eligible. Note: Prior site directed radiation is 
allowed; however, PSA must be rising following radiation as indicated above.  
o
Abdominal or pelvic lymph nodes measuring ≤2 cm in short axis are allowed

Biomarker positive:
o
Biallelic CDK12 inactivating mutations as documented using a clinical grade sequencing 
assay performed in a CLIA/CAP certified laboratory
or
o
MMRd/MSI-high as documented using a clinical grade assay performed in a CLIA/CAP 
certified laboratory 
or
o
Loss of function mutations in homologous recombination genes (i.e., homologous 
recombination deficiency; HRD) as documented using a clinical grade sequencing assay 
performed in a CLIA/CAP certified laboratory. Homologous recombination genes include, 
but not limited to BRCA1, BRCA2, ATM, CHEK2, PALB2, RAD51D, NBN, GEN1, 
RAD51C, MRE11A, BRIP11A, FAM175A.
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Investigational Drug Substance:  , Olaparib (AZD2281)
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
Capable of giving signed informed consent which includes compliance with the requirements and 
restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent 
and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) 
obtained from the patient/legal representative prior to performing any protocol-related procedures, 
including screening evaluations.  

Age > 18 years at time of study entry.

Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 

Adequate normal organ and marrow function as defined below measured within 28 days prior to 
administration of study treatment as defined below: 
o
Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days  
o
Absolute neutrophil count (ANC) be ≥1.5 x 109/L
o
Platelet count ≥100 x 109/L 
o
Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to 
patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia 
that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), 
who will be allowed only in consultation with their physician.
o
AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver 
metastases are present, in which case it must be ≤5x ULN
o
Patient must have creatinine clearance (CL) ≥51 mL/min by the Cockcroft-Gault formula 
(Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine 
clearance:
Creatinine 
CL (mL/min)
Weight (kg) x (140 – Age)   
72 x serum creatinine (mg/dL)

Patient is willing and able to comply with the protocol for the duration of the study including 
undergoing treatment and scheduled visits and examinations including follow up.

Patients must have a life expectancy ≥ 16 weeks.

Body weight >30 kg

Male patients must use a condom during treatment and for 3 months after the last dose of olaparib 
when having sexual intercourse with a pregnant woman or with a woman of childbearing 
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potential.  Female partners of male patients should also use a highly effective form of 
contraception (Table10 for acceptable methods]) if they are of childbearing potential.
7.2
EXCLUSION CRITERIA

Prior chemotherapy for prostate cancer, unless done in the neoadjuvant setting, and if the last dose 
was >6 months prior to enrolment

Any prior treatment with a PD1 or PD-L1 inhibitor, including durvalumab

Any prior treatment with a PARP inhibitor, including olaparib

History of another primary malignancy except for
o
Malignancy treated with curative intent and with no known active disease ≥3 years before 
the first dose of durvalumab and of low potential risk for recurrence
o
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease
o
Adequately treated carcinoma in situ without evidence of disease

History of leptomeningeal carcinomatosis

Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the 
treating physician (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive 
heart failure, QTcF prolongation >470 ms, electrolyte disturbances, etc.), or patients with 
congenital long QT syndrome.

Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the 
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria 
o
Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician.
o
Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment 
with durvalumab or olaparib may be included only after consultation with the Study 
Physician. 

Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of 
MDS/AML.

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 
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Investigational Drug Substance:  , Olaparib (AZD2281)
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limited to, extensive bilateral lung disease on High Resolution Computed Tomography (HRCT) 
scan, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, 
uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava 
syndrome, interstitial lung disease, serious chronic gastrointestinal conditions associated with 
diarrhea or any psychiatric disorder that prohibits obtaining informed consent.

Patients unable to swallow orally administered medication and patients with gastrointestinal 
disorders likely to interfere with absorption of the study medication. 

Immunocompromised patients, e.g., patients with uncontrolled human immunodeficiency virus 
(HIV). HIV+ patients will be allowed on the study if on HAART and disease is controlled: 
CD4≥350cell/mcl, undetectable viral load, and no PPX antibiotics.
Note: HIV screening is not required to be eligible for this study.

Active infection including tuberculosis (TB testing only performed if deemed necessary per 
standard clinical practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), 
hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis 
B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C 
(HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

Active or prior documented autoimmune or inflammatory disorders (including inflammatory 
bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], 
systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis 
with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The 
following are exceptions to this criterion:
o
Patients with vitiligo or alopecia
o
Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone 
replacement 
o
Any chronic skin condition that does not require systemic therapy
o
Patients without active disease in the last 5 years may be included but only after 
consultation with the Investigator 
o
Patients with celiac disease controlled by diet alone

 Current or prior use of immunosuppressive medication within 14 days before the first dose of 
durvalumab. The following are exceptions to this criterion:
o
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection)
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Date: 11/25/2022 
42
o
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or 
its equivalent
o
Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: 
Patients, if enrolled, should not receive live vaccine whilst receiving durvalumab and up to 30 
days after the last dose of durvalumab.

Patients receiving any chemotherapy, immunotherapy, biologic, radiotherapy or hormonal 
therapy for cancer treatment concurrently or within 3 weeks of study treatment. Concurrent use of 
hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is 
acceptable.

Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation 
within 4 weeks of the first dose of study drug.

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 
study treatment is 2 weeks.

Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A 
inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting study 
treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.

Major surgery within 2 weeks of starting study treatment and patients must have recovered from 
any effects of any major surgery. 

Previous allogenic bone marrow transplant or double umbilical cord blood transplantation 
(dUCBT).

Participation in another clinical study with an investigational product administered in the last 3 
months

Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) 
or supportive care, while on the clinical study or during the follow-up period of this interventional 
study

Patients with a known hypersensitivity to olaparib or durvalumab or any of the excipients of the 
product.

Involvement in the planning and/or conduct of the study
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Investigational Drug Substance:  , Olaparib (AZD2281)
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7.3
WITHDRAWAL OF PATIENTS FROM STUDY TREATMENT AND/OR STUDY
7.3.1
PERMANENT DISCONTINUATION OF STUDY TREATMENT 
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 that, in the opinion of the Principal Investigator contraindicates further dosing

Severe non-compliance with the study protocol that, in the opinion of the Principal Investigator or 
Sponsor, warrants withdrawal (e.g., refusal to adhere to scheduled visits)

Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute myeloid leukemia 
(AML)

Subject is determined to have met one or more of the exclusion criteria for study participation at 
study entry and continuing investigational therapy might constitute a safety risk

Initiation of alternative anticancer therapy including another investigational agent

Study drug held for >4 weeks due to an AE
Patients who are permanently discontinued from further receipt of study treatment, regardless of the 
reason, will be identified as having permanently discontinued treatment. Patients who have permanently 
discontinued treatment will enter follow-up (Section 10.1.3), including the collection of any protocol-
specified blood specimens, unless consent is withdrawn, or the subject is lost to follow-up or enrolled in 
another clinical study.  All subjects will be followed for survival.  Subjects who decline to return to the 
site for evaluations will be offered follow-up by phone as an alternative.
If a patient decides to voluntary discontinue durvalumab or olaparib, the reason(s) for discontinuation will 
be documented. Ideally, the patient should continue attending subsequent study visits, and data collection 
should continue according to the study protocol. If the patient does not agree to continue in-person study 
visits, a modified follow-up must be arranged to ensure the collection of endpoints and safety 
information. This follow-up could be a telephone contact with the patient, a contact with a relative or 
treating physician, or information from medical records. The approach taken should be recorded in the 
medical records. A patient that agrees to modified follow-up is not considered to have withdrawn consent 
or to have withdrawn from the study.
Patients who permanently discontinue the study treatment for reasons other than evidence of PSA 
progression or metastatic disease on conventional imaging should continue to have PSA monitoring q3 
months for 24 months from the time of enrollment.  iRECIST scans should be performed if increase in 
PSA by 2 ng/ml and by 25% from baseline upon enrollment.
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If a patient is discontinued for iRECIST criteria, then the patient should have 1 additional follow-up scan 
performed preferably no less than 4 weeks after the prior assessment of disease.
Patients who decline to return to the site for evaluations should be contacted by telephone as an 
alternative. 
7.3.2
LOST TO FOLLOW-UP
Patients will be considered lost to follow-up only if no contact has been established by the time the study 
is completed, such that there is insufficient information to determine the patient’s status at that time. 
Patients who refuse to continue participation in the study, including telephone contact, should be 
documented as “withdrawal of consent” rather than “lost to follow-up.”  Treating physician and 
Investigators should document attempts to re-establish contact with missing patients throughout the study 
period. If contact with a missing patient is re-established, the patient should not be considered lost to 
follow-up and evaluations should resume according to the protocol.
In order to support key end points of PFS and OS analyses, the survival status of all patients in the full 
analysis and the safety analysis sets should be re-checked, this includes those patients who withdrew 
consent or are classified as “lost to follow up.”
Lost to Follow up – site personnel should check hospital records, the patients’ current 
physician, and a publicly available death registry (if available) to obtain a current survival 
status. (The applicable CRF modules will be updated.)
In the event that the patient has actively withdrawn consent to the processing of their personal 
data, the survival status of the patient can be obtained by site personnel from publicly 
available death registries (if available) where it is possible to do so under applicable local laws 
to obtain a current survival status. (The applicable CRF modules will be updated.)   
7.3.3
WITHDRAWAL OF CONSENT
Patients are free to withdraw from the study at any time (IP and assessments) without prejudice to further 
treatment.
Patients who withdraw consent for further participation in the study will not receive any further IP or 
further study observation, with the exception of follow-up for survival, which will continue until the end 
of the study unless the patient has expressly withdrawn their consent to survival follow-up. Note that the 
patient may be offered additional tests or tapering of treatment to withdraw safely.
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and the 
presence of any AE. The Investigator will follow up AEs outside of the clinical study. 
Biospecimens obtained as part of trial participation will be retained.
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Investigational Drug Substance:  , Olaparib (AZD2281)
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Edition Number V9
Date: 11/25/2022 
45
7.4
ADDITIONAL PATIENT ENDROLLEMENT
To ensure that each cohort includes at least 10 patients that receive combination therapy, an additional 
patient will be accrued for every participant that drops out prior to receiving at least one cycle of 
combination therapy (i.e., one infusion of durvalumab and 28 days of olaparib). Patients that drop out will 
still be included in our assessment of the primary endpoint.  
8.
INVESTIGATIONAL PRODUCT(S)
 Study drugs will be shipped from AstraZeneca to McKesson (Cary, NC), which will serve as central 
distributor to all study sites. The local investigational drug services (IDS) pharmacy will coordinate with 
the study investigator and/or research coordinator to order study drug shipments as needed. On treatment 
days, study drugs will be ordered per institutional SOPs and dispensed through IDS.
8.1
DURVALUMAB
8.1.1
DURVALUMAB FORMULATION/PACKAGING/STORAGE
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after dilution.  The 
solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine-hydrochloride, 275 mM trehalose 
dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; it has a pH of 6.0 and density of 1.054 
g/mL.  The nominal fill volume is 10.0 mL.  Investigational product vials are stored at 2°C to 8°C (36°F to 
46°F) and must not be frozen. Drug product should be kept in original packaging until use to prevent 
prolonged light exposure. 
8.1.2
DURVALUMAB DOSES AND TREATMENT REGIMENS
A durvalumab dose of 1500 mg (for patients >30 kg in weight) Q4W will be administered for total 6 cycles.
8.1.3
DURVALUMAB PREPARATION
Patients will receive 1500 mg durvalumab via IV infusion Q4W for 24 weeks (up to 6 doses/cycles) with 
the last administration on week 20, unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met. If a patient’s weight falls to 30 kg or below (≤30 kg) the patient should 
receive weight-based dosing equivalent to 20 mg/kg of durvalumab Q4W until the weight improves to >30 
kg, at which point the patient should start receiving the fixed dosing of durvalumab 1500 mg Q4W.
Preparation of durvalumab doses for administration with an IV bag
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s designated IP 
manager using aseptic technique.  Total time from needle puncture of the durvalumab vial to the start of 
administration should not exceed: 
24 hours at 2°C to 8°C (36°F to 46°F)
4 hours at room temperature
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A dose of 1500 mg (for patients >30 kg in weight) will be administered using an IV bag containing 0.9% 
(w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration ranging from 1 to 15 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm filter.  Add 30.0 mL (i.e., 1500 mg) of 
durvalumab to the IV bag. The IV bag size should be selected such that the final concentration is within 1 
to 15 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag.
If weight falls to ≤ 30 kg weight-based dosing at 20 mg/kg will be administered using an IV bag containing 
0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration ranging from 1 to 15mg/mL, 
and delivered through an IV administration set with a 0.2- or 0.22-μm filter.    
Standard infusion time 1 hour, however if there are interruptions during infusion, the total allowed infusion 
time should not exceed 8 hours at room temperature. 
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the infusion set 
used after the contents of the IV bag are fully administered or complete the infusion according to 
institutional policy to ensure the full dose is administered.  
If either preparation time or infusion time exceeds the time limits a new dose must be prepared from new 
vials.  Durvalumab does not contain preservatives, and any unused portion must be discarded. 
8.1.4
MONITORING OF DURVALUMAB DOSE ADMINISTRATION
Patients will be monitored before, during and after the infusion with assessment of vital signs at the times 
specified in the Schedule of Assessment. Patients are monitored (pulse rate, blood pressure) every 30 
minutes during the infusion period (including times where infusion rate is slowed or temporarily stopped).
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be decreased by 
50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial rate 
until completion of the infusion. For patients with a ≤Grade 2 infusion-related reaction, subsequent 
infusions may be administered at 50% of the initial rate. Acetaminophen and/or an antihistamine (e.g., 
diphenhydramine) or equivalent medications per institutional standard may be administered at the 
discretion of the investigator. If the infusion-related reaction is Grade 3 or higher in severity, study drug 
will be discontinued. The standard infusion time is one hour, however if there are interruptions during 
infusion, the total allowed time from infusion start to completion of infusion should not exceed 8 hours at 
room temperature. For management of patients who experience an infusion reaction, please refer to the 
toxicity and management guidelines in Appendix VIII.
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs and medical 
equipment to treat acute anaphylactic reactions must be immediately available, and study personnel must 
be trained to recognize and treat anaphylaxis. The study site must have immediate access to emergency 
resuscitation teams and equipment in addition to the ability to admit patients to an intensive care unit if 
necessary.
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Edition Number V9
Date: 11/25/2022 
47
8.2
OLAPARIB 
8.2.1
OLAPARIB FORMULATION/PACKAGING
The AstraZeneca Pharmaceutical Development R&D Supply Chain will supply olaparib to the 
investigator as round or oval green film coated tablet packed in high-density polyethylene (HDPE) bottles 
with child-resistant closures.
8.2.2
OLAPARIB LABELLING
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local regulatory 
guidelines. The labels will fulfil GMP Annex 13 requirements for labelling. Label text will be translated 
into local language. Each bottle of olaparib will have an investigational product label permanently affixed 
to the outside stating that the material is for clinical trial/investigational use only and should be kept out 
of reach of children. The label will include the dosing instructions and a space for the enrollment code (E-
code) to be completed at the time of dispensing. 
The label will include the following information: 
blank lines for quantity of tablets to be taken 
enrollment code (E-code) 
date of dispensing 
Instructions stating that the olaparib tablets should be taken at approximately the same time 
each morning and evening 
8.2.3
OLAPARIB STORAGE 
All study drugs should be kept in a secure place under appropriate storage conditions. For olaparib, the 
investigational product label on the bottle and the Investigator Brochure specifies the appropriate storage. 
8.2.4
OLAPARIB DOSES AND TREATMENT REGIMENS 
An olaparib dose 300 mgs bid continually will be administered for three 28-day cycles (Cycle 4-6 in 
Cohort A and B; cycle 1-6 in Cohort C)
Each olaparib dosing container will contain sufficient medication for at least 28 days plus overage. 
Olaparib will be dispensed to patients on Day 1 and every 28 days thereafter until the patient completes 
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Edition Number V9
Date: 11/25/2022 
48
the study, withdraws from the study or closure of the study. Study treatment is available as tablets 
containing 50mg of olaparib. Patients will be administered olaparib twice daily at 300 mgs bid 
continually. 300 mg olaparib 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.
8.2.5
OLAPARIB DOSE REDUCTION
In case a dose reduction is necessary (for reasons other than renal impairment or concomitant treatment 
with a moderate-strong CYP3A inhibitor), the Study treatment will be administered as follows: 
Table 1
Dose reductions for olaparib to manage adverse events
Initial Dose
Following re-challenge post 
interruption: Dose reduction 
1
Dose reduction 2
300 mg twice daily
(two x150 mg tablet 
twice daily)
250 mg twice daily
(one 150 mg tablet and one 
100 mg tablet twice daily)
200 mg twice daily
(two x 100 mg tablet 
twice daily)
Table 2
Dose reduction for olaparib if patient develops moderate renal impairment 
Initial Dose
Moderate renal impairment (calculated creatinine clearance by 
Cockcroft -Gault equation or based on a 24-hour urine test 
between 31 and 50 ml/min): Dose reduction 
300 mg twice daily
200 mg twice daily
Table 3
Dose reductions for study treatment if patient has to start taking a strong or 
moderate CYP3A inhibitor
Initial Dose
Strong CYP3A inhibitor
Moderate CYP3A inhibitor
300 mg twice daily
100 mg twice daily
150 mg twice daily
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49
8.2.6
OLAPARIB COMPLIANCE 
Patients will self-administer olaparib and record tablet administration in Pill Dairy (See Appendix VII). 
Study site staff will make tablet counts at regular intervals during treatment.  After the tablet count has 
been performed, the remaining tablets will not be returned to the patient but will be retained by the 
investigative site..  All patients must return their bottle(s) of olaparib at the appropriate scheduled visit, 
when a new bottle will be dispensed.  Patients will be instructed to notify study site personnel of missed 
doses.  
Any change from the dosing schedule, does interruptions, dose reductions, dose discontinuations should 
be recorded in eCRF.
The Investigational Product Storage Manager is responsible for managing the IMP from receipt by the 
study site until the destruction or return of all unused IMP.  The Investigator(s) is responsible for ensuring 
that the patient has returned all unused IMP.
9.
TOXICITY MANAGEMENT GUIDELINES 
9.1
DURVALUMAB TOXICITY GUIDELINES
AEs associated with durvalumab exposure may represent an immunologic etiology. These immune-related 
AEs (IMAEs) may occur shortly after the first dose or several months after the last dose of durvalumab 
treatment and may affect a single or multiple body systems simultaneously. Early recognition and 
management are critical to reduce complications. For suspected IMAEs, ensure adequate evaluation to 
confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, 
skin biopsy may be included as part of the evaluation. Based on the severity of IMAEs, withhold or 
permanently discontinue durvalumab and administer corticosteroids. Toxicity management guidelines, 
including when to withhold treatment are available from NCCN and ASCO and are recommended to be 
used to guide treatment decisions.(58,59) Specific trial guidelines are included in Appendix VII. 
9.2
MANAGEMENT OF OLAPARIB TOXICITY 
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. If the interruption is any longer, the study team must be informed. 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. Dose reduction below 200 mg twice daily will not be permitted. Once dose is reduced, escalation is 
not permitted. 
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9.2.1
Management of olaparib hematological toxicity
Management of anemia 
Table 4
Management of anemia
Hemoglobin
Action to be taken
Hb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2)
First occurrence:
Give appropriate supportive treatment and investigate causality. 
Treating physician judgement to continue olaparib with supportive 
treatment (eg transfusion) or interrupt dose for a maximum of 4 weeks. 
Study treatment can be restarted if Hb has recovered to > 9g/dl.
Subsequent occurrences:
If Hb< 10 but ≥ 9 g/dl  Treating physician judgement to continue olaparib 
with supportive treatment (e.g. transfusion) or dose interrupt (for max of 4 
weeks) and upon recovery dose reduction may be considered (to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second step).
If Hb< 9 but ≥ 8 g/dl, dose interrupt (for max of 4 weeks) until Hb ≥ 9 
g/dl and upon recovery dose reduction may be considered (to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second step). 
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 ≥ 9 
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 guidance later in this section for the management of this. 
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Management of neutropenia, leukopenia, and thrombocytopenia
Table 5
Management of neutropenia, leukopenia, and thrombocytopenia
Toxicity
Olaparib dose adjustment
CTCAE Grade 1-2
Treating physician 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 Treating 
physician 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 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 hospital 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 guidance later in this section for the management of this. 
Management of prolonged hematological toxicities while on olaparib treatment
If a patient develops prolonged hematological toxicity such as:
≥2 week interruption/delay in olaparib treatment due to CTC grade 3 or worse anemia and/or 
development of blood transfusion dependence
≥2 week interruption/delay in olaparib treatment due to CTC grade 3 or worse neutropenia (ANC < 1 x 
109/L)
≥2 week interruption/delay in olaparib 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 
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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.
9.2.2
Management of olaparib 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.
Olaparib can be dose reduced to 250 mg twice daily as a first step and to 200 mg twice daily 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.
9.2.3
Management of nausea and vomiting
Events of nausea and vomiting are known to be associated with olaparib treatment. From screening part 
onwards, should a patient develop nausea, vomiting and / or diarrhea, then these symptoms should be 
reported as AEs (see section 16.3) and appropriate treatment of the event given. 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 olaparib 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 (i.e., 2 pieces of toast or a couple of biscuits).
As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), generally a single 
agent antiemetic should be considered e.g., dopamine receptor antagonist, antihistamines or 
dexamethasone.
9.2.4
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 Investigator.
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF. 
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Olaparib treatment should be stopped at least 3 days prior to planned surgery. After surgery study 
treatment can be restarted when the wound has healed. No stoppage of study treatment is required for any 
needle biopsy procedure.
Olaparib treatment should be discontinued for a minimum of 3 days before a patient undergoes radiation 
treatment. Study treatment should be restarted within 4 weeks as long as any bone marrow toxicity has 
recovered.
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, patients should be 
advised to use caution while driving or using machinery if these symptoms occur. 
Table 6
Dose reductions for olaparib treatment
Initial Dose
Following re-challenge post 
interruption: Dose reduction 1
Dose reduction 2
300 mg twice daily
250 mg twice daily
200 mg twice daily
9.2.5
Management of 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 or based on a 24-hour urine test of between 31 and 50 
ml/min) for any reason during the course of the study: the dose of olaparib should be reduced to 200 mg 
twice daily.
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 Treating physician should use his or her discretion in determining 
whether a dose change or discontinuation of olaparib 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 is it recommended 
that olaparib be discontinued.
9.3
COMBINATION TREATMENT REGIMEN WITH TOXICITY MANAGEMENT 
GUIDELINES 
In addition to the individual toxicity management guidelines for durvalumab and olaparib described above, 
below outlined what actions are recommended for the management of any potential overlapping toxicities 
that may occur following treatment with this combination.
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Management of new or worsening pulmonary symptom
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities occur in the 
absence of a clear diagnosis, an interruption in both olaparib and durvalumab 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 durvalumab and olaparib study treatment can be restarted, if deemed appropriate by the Investigator. 
If significant pulmonary abnormalities are identified please follow durvalumab toxicity management 
protocol and continue holding both olaparib and durvalumab, discuss with the Investigator.
10.
STUDY PROCEDURES
10.1
SCHEDULE OF STUDY PROCEDURES
Before study entry, throughout the study, and following study drug discontinuation, various clinical and 
diagnostic laboratory evaluations are outlined. The purpose of obtaining these detailed measurements is to 
ensure adequate safety and tolerability assessments. Clinical evaluations and laboratory studies may be 
repeated more frequently if clinically indicated. The Schedules of Assessments during the screening and 
treatment period is provided in Appendix I.
10.1.1
SCREENING PHASE
Screening procedures will be performed up to 28 days before Day 1, unless otherwise specified. All patients 
must first read, understand, and sign the IRB-approved ICF before any study-specific screening procedures 
are performed. After signing the ICF, completing all screening procedures, and being deemed eligible for 
entry, patients will be enrolled in the study. Procedures that are performed prior to the signing of the ICF 
and are considered standard of care may be used as screening assessments if they fall within the 28-day 
screening window, except neo-antigen burden status (lfCDK12, MMRd/MSI-high, HRD) which can be 
determined at any point prior to enrolling on this trial, regardless of the date next-generation sequencing 
was performed or the date of tumor tissue acquisition used for this purpose. Patients may be screened for 
neo-antigen burden after consent before meeting all other eligibility criteria. 
The following procedures will be performed during the Screening phase:

Review of eligibility criteria

Informed consent

Medical history and demographics

Full physical exam 

ECOG Performance Status

Vitals signs, weight and height 

12-lead ECG (in triplicate if abnormal [2-5 minutes apart])

Review of prior/concomitant medications 
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
RANDSF-36 QOL survey

Calculate PSA doubling time

IIEF QOL survey

Review adverse events

CT chest, abdomen, pelvis (completed within 6 weeks before C1D1 date)1 
1 Brain MRI will be performed only necessary if clinically indicated.

Bone scan (completed within 6 weeks before C1D1 date)

CDK12, MMRd/MSI-high, HRD screening (clinical grade sequencing assay of archival tissue or 
ctDNA performed in a CLIA/CAP certified laboratory)

Clinical laboratory tests for:
o
Hematology (see Table 7)
o
Clinical chemistry (see Table 8)
o
TSH
o
Coagulation (PT, PTT, INR)
o
Creatinine Clearance
o
Hepatitis B and C serologies (HBsAg; anti–HCV antibody with reflexive an HCV RNA)
o
Testosterone
o
PSA
o
Urinalysis
o
Amylase 
o
Lipase
o
Cortisol
o
Fasting lipid
o
Study correlates blood
We will rely on past medical history and will not perform HIV screening for patients without 
known HIV infection. 
Table 7. Hematology Laboratory Tests a
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Basophils
Mean corpuscular volume
Eosinophils
Monocytes
Hematocrit
Neutrophils
Hemoglobin
Platelet count
Lymphocytes
Red blood cell count
Mean corpuscular hemoglobin
Total white cell count
Mean corpuscular hemoglobin 
concentration
Note: For coagulation parameters, activated partial thromboplastin time and international normalized ratio 
are to be assessed at baseline on Day 0 (unless all screening laboratory hematology assessments are 
performed within 3 days prior to Day 0), and as clinically indicated. Patients taking warfarin may 
participate in this study; however, it is recommended that INR be monitored carefully at least once per 
week for the first month, then monthly if the INR is stable. Each coagulation test result will be recorded 
in CRF.
a
Can be recorded as absolute counts or as percentages. Absolute counts will be calculated by DM if 
entered as percentage. Total white cell count therefore has to be provided.
Table 8. Clinical Chemistry (Serum or Plasma) Laboratory Tests
Albumin
Glucose
Alkaline phosphatase a
Lactate dehydrogenase (LDH)
Alanine aminotransferase a
Lipase b
Amylase b
Magnesium (Mg) c
Aspartate aminotransferase a
Potassium
Prostate specific antigen
Bicarbonate c
Sodium
Calcium 
Testosterone (total and free)
Chloride c
Thyroid function test e
Creatinine c d
Total bilirubina
Cortisol
Total protein
Fasting Lipidsf
Urea or blood urea nitrogen, depending on local practice
Gamma glutamyl transferase (GGT) c 
Uric acid
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a   Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed 
concurrently. If total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome) 
then fractionate into direct and indirect bilirubin. Hepatitis B and C serologies will be testing during 
screening phase. 
b
It is preferable that both amylase and lipase parameters are assessed. For sites where only 1 of these 
parameters is routinely measured then either lipase or amylase is acceptable.
c
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyl transferase, and 
magnesium testing are to be performed at baseline, on Cycle 1 Day 1 (unless all screening laboratory 
clinical chemistry assessments are performed within 3 days prior to Day 1), and if clinically indicated.
d           Creatinine Clearance will be calculated by data management using Cockcroft-Gault (using actual body                           
weight). 
e
If TSH is measured within 14 days prior to Cycle 1 Day 1, it does not need to be repeated at Cycle 1 
Day 1. Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion 
of an AE related to the endocrine system
 f   Fasting lipids include Cholesterol (Total), Triglycerides, HDL, LDL, Non-HDL Cholesterol, 
Cholesterol/HDL Ratio
Table 9. Urinalysis Testsa
Bilirubin
pH
Blood
Protein
Glucose
Specific gravity
Ketones
Colour and appearance
a Microscopy should be used as appropriate to investigate white blood cells and use the high-power field 
for red blood cells
If a patient shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN, refer to Section 9 for 
further instructions on cases of increases in liver biochemistry and evaluation of Hy’s Law. These cases 
should be reported as SAEs if, after evaluation, they meet the criteria for a Hy’s law case or if any of the 
individual liver test parameters fulfill any of the SAE criteria. 
All patients should have further chemistry profiles performed at 30 days (±3 days), 2 months (±1 week) and 
3 months (±1 week) after permanent discontinuation of study treatment.
Any clinically significant abnormal laboratory values should be repeated as clinically indicated and 
recorded on the eCRF. Situations in which laboratory safety results should be reported as AEs are described 
in Section 16.4.
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation from study 
therapy must have further tests performed until the laboratory values have returned to Grade 1 or 2, unless 
these values are not likely to improve because of the underlying disease.
Subject Registration
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Eligible patients will be entered on study centrally at the University of Washington by the Study 
Coordinator or Research Manager. To register a patient, the following documents should be completed 
and emailed to the Research Manager, Patrick Panlasigui at ppanlas2@seattlecca.org as well as the 
Study Coordinator Andrea Rivero at ariveroc@seattlecca.org at least 48 hours prior to any on study 
activities:

Date of Birth

Ethnicity and Race

Copy of pathology report and other source documents verifying eligibility 

Signed participant consent form 

HIPAA authorization form (if separate from ICF)

Completed eligibility checklist, signed by the local Investigator or Sub-Investigator
To complete the registration process, the Coordinating Site will: 

Review the registration packet and confirm eligibility

Assign a participant screening/enrollment study number to all participants

Send email confirmation regarding participant eligibility and registration status to the 
participating site
Signed ICFs must remain in each subject’s chart and must be available for verification by monitors or 
regulatory agencies at any time.
NOTE: Confirmation of enrollment must be provided by the Coordinating Site before on-study 
activities may begin.
10.1.2
TREATMENT PHASE 
Procedures to be conducted during the treatment phase of the study are presented in the Schedule of 
Assessments (Appendix I). Screening procedures performed within 72 hours of Cycle 1 Day 1 (C1D1) do 
not need to be repeated on C1D1.
Prior to each treatment cycle, enrolled eligible participants will undergo clinical assessment, medication 
review and toxicity screen with directed physical examination. Participants will also undergo laboratory 
assessment with CBC with differential, CMP, GGT, LDH, Mg and uric acid before each Day1 of each 4-
week cycle treatment administration. Provided no dose limiting toxicity is identified, participants will 
proceed to receive study drug treatment as per administration instructions.
Prior to treatment cycle 4 and after cycle 6 (at 12 weeks and 24 weeks from C1D1, respectively), additional 
laboratory testing, including PSA, TSH, amylase, lipase and cortisol will be tested. An additional blood 
sample will also be collected for study correlates at baseline (i.e. within 72 hours before C1D1), 12 weeks 
and 24 weeks from C1D1. At these same visits, patients will also complete QOL assessment with RANDSF-
36 and IIEF.
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10.1.3
POST-TREATMENT FOLLOW-UP VISIT
Upon completion of treatment with the study drugs, enrolled participants will undergo follow-up every 12 
weeks until 24 months from C1D1. Post-treatment visits will include clinical assessment, medication 
review, toxicity screen, directed physical examination, PSA testing and QOL assessment with RANDSF-
36 and IIEF. At 12-month visit we will assess primary endpoint: undetectable PSA (post-prostatectomy 
patients; including those that also received salvage radiation) or PSA <0.5 ng/m (post-radiation patients).
10.1.4
24-MONTH END OF STUDY VISIT
An end of study visit will be undertaken at 24 months from C1D1. This visit will include clinical 
assessment, medication review, toxicity screen, as well as a directed physical examination, PSA testing and 
QOL assessment with RANDSF-36 and IIEF.
Follow-up after end of study visit at 24-months will be recommended to continue at every 12-week schedule 
(per Section 10.1.3) but will be deferred to patient and clinician discretion. If regular follow-up with study 
site will not continue, request will be made for patient to be followed passively by study coordinator and if 
approved by patient, patient contact and locator information should be collected. Passive follow-up will be 
planned to continue until disease progression or for 10 years from enrollment.
10.1.5
 STUDY WITHDRAWAL VISIT
Patients withdrawing from the study prior to 24-months will undergo the procedures as follows depending 
on reason for withdrawal:

If withdrawal is related to PSA progression, patients will undergo repeat imaging with CT chest, 
abdomen, pelvis and bone scan and study treatment will be discontinued. Decision to start ADT or 
alternate therapy will be deferred to patient and oncologist as is clinically appropriate. If no further 
therapy is initiated, patients will be followed per post-treatment follow-up schedule (Section 
10.1.3). If ADT or alternate therapy is started, patient will be considered to not have achieved the 
primary endpoint at 12 months.

If withdrawal is related to metastatic progression or ADT initiation, patients will be considered to 
not have achieved the primary endpoint at 12 months.

If withdrawal is related to treatment toxicity, patients will be followed per post-treatment follow-
up schedule (Section 10.1.3) until alternate therapy is initiated or until 24-month end of study visit. 
If patient develops metastatic disease or alternate therapy is initiated prior to 12-month visit, 
patients will be considered to not have achieved the primary endpoint at 12 months.
Participants who withdraw consent from the study prior to scheduled end date will be offered a study 
withdrawal visit. This visit will include a clinical assessment, medication review, toxicity screen, as well 
as a directed physical examination and PSA testing.
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11.
RESTRICTIONS DURING THE STUDY AND CONCOMITANT TREATMENT(S)
11.1
RESTRICTIONS DURING THE STUDY
The following restrictions apply while the patient is receiving study treatment and for the specified times 
before and after:

Grapefruit juice. It is prohibited to consume grapefruit juice while on olaparib therapy.

Olaparib is regarded as a compound with medium/high fetal risk. Male patients with a female 
partner of childbearing potential
o
Non-sterilized male patients who are not abstinent and intend to be sexually active with a 
female partner of childbearing potential must use a male condom plus spermicide from the 
time of screening throughout the total duration of the drug treatment and the drug washout 
period (90 days after the last dose of durvalumab). However, periodic abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of contraception.  
Male patients should refrain from sperm donation throughout this period and for 3 months 
following the last dose of olaparib or durvalumab.
o
Female partners (of childbearing potential) of male patients must use two highly effective 
methods of contraception in combination throughout this period and for 3 months 
following the last dose of olaparib or durvalumab (see table 10 below)
N.B Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral 
salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.  
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Table 10. Highly Effective Methods of Contraception (<1% Failure Rate)
Non-hormonal Methods
Hormonal Methods

Total/True abstinence: When the patient 
refrains from any form of sexual intercourse 
and this is in line with their usual and/or 
preferred lifestyle; this must continue for the 
total duration of the trial and for at least for 3 
months after last dose. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, 
post-ovulation methods, or declaration of 
abstinence solely for the duration of a trial) 
and withdrawal are not acceptable methods of 
contraception 

Vasectomised 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

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
Blood donation
Patients should not donate blood for at least 90 days following the last infusion of durvalumab or until after 
4-5X the half-life of olaparib, whichever occurs longest.
11.2
CONCOMITANT TREATMENT(S)
The use of any natural/herbal products or other traditional remedies should be discouraged, but use of 
these products, as well as any medication or vaccine including over the counter or prescription medicines, 
vitamins, and/or herbal supplements that the patient is receiving at the time of enrolment or receives 
during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates
Dosage information including dose and frequency
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11.2.1
Permitted concomitant medications
Table 11. Supportive Medications
Supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(e.g., acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications identified 
as “prohibited,” as listed above 
To be administered as prescribed by the 
Treating physician
Best supportive care (including antibiotics, nutritional 
support, correction of metabolic disorders, optimal 
symptom control, and pain management (including 
palliative radiotherapy to non-target lesions, etc.)
Should be used, when necessary, for all 
patients
Inactivated viruses, such as those in the influenza 
vaccine
Permitted
11.2.2
Excluded concomitant medications
Table 12. Prohibited Concomitant Medications
Prohibited medication/class of drug:
Usage:
Any investigational anticancer therapy other 
than those under investigation in this study
Should not be given concomitantly whilst the patient 
is on study treatment
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study
Should not be given concomitantly whilst the patient 
is on study treatment
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those 
under investigation in this study
Should not be given concomitantly whilst the patient 
is on study treatment. (Concurrent use of hormones for 
non-cancer-related 
conditions 
[e.g., insulin 
for 
diabetes and hormone replacement therapy] is 
acceptable. 
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Prohibited medication/class of drug:
Usage:
Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers
Should not be given concomitantly or used for 
premedication prior to the I-O infusions. The 
following are allowed exceptions:

Use of immunosuppressive medications 
for the management of IP-related AEs, 

Use in patients with contrast allergies. 

In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted.
 A temporary period of steroids will be allowed if 
clinically indicated and considered to be 
essential for the management of non-
immunotherapy related events experienced by 
the patient (e.g., chronic obstructive pulmonary 
disease, radiation, nausea, etc.).
Live virus vaccines
Live bacterial vaccines
Not permitted while the patient is receiving olaparib 
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.
EGFR TKIs 
Should not be given concomitantly.
Should be used with caution in the 90 days post last 
dose of durvalumab.
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence of 
transaminase increases (with 1st generation EGFR 
TKIs) has been reported when durvalumab has been 
given concomitantly.
Live attenuated vaccines
Should not be given through 30 days after the last dose 
of IP (including SoC)
Herbal and natural remedies which may have 
immune-modulating effects
Should not be given concomitantly unless agreed by 
the sponsor
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11.2.1
Restricted concomitant medications
Table 13
Restricted concomitant medications
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which it’s allowed ):
Strong CYP3A inhibitors:
itraconazole, telithromycin, clarithromycin, 
boosted protease inhibitors, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir
Moderate CYP3A inhibitors:
ciprofloxacin, erythromycin, diltiazem, 
fluconazole, verapamil 
Strong or moderate CYP3A inhibitors 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 100 mg twice daily 
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 150 mg twice daily 
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.
Strong inducers:
phenobarbital, phenytoin, rifampicin, rifabutin, 
rifapentine, carbamazepine, nevirapine, 
enzalutamide and St John’s Wort
Moderate CYP3A inducers:
 bosentan, efavirenz and modafinil
Strong or moderate CYP3A inducers 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, then they must be monitored 
carefully for any change in efficacy of olaparib
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Table 13
Restricted concomitant medications
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which it’s allowed ):

CYP3A4 substrates: hormonal 
contraceptive, simvastatin, cisapride, 
cyclosporine, ergot alkaloids, fentanyl, 
pimozide, sirolimus, tacrolimus and 
quetiapine

CYP2B6 substrates: bupropion, 
efavirenz

OATP1B1substrates: bosentan, 
glibenclamide, repaglinide, statins and 
valsartan

OCT1, MATE1 and MATE2K 
substrates:  metformin

OCT2 substrates: serum creatinine

OAT3 substrates: furosemide, 
methotrexate
Effect of olaparib on other drugs
Based on limited in vitro data, olaparib may increase 
the exposure to substrates of CYP3A4, OATP1B1, 
OCT1, OCT2, OAT3, MATE1 and MATE2K.
 Based on limited in vitro data, olaparib may reduce 
the exposure to substrates of 2B6.
Caution should be observed if substrates of these 
isoenzymes or transporter proteins are co-
administered.
Anticoagulant therapy
Patients who are taking warfarin may participate in 
this trial; however, it is recommended that 
international normalized 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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12.
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION
12.1
STATISTICAL CONSIDERATION
This is a multicenter pilot phase 2, prospective, single-arm, three cohort, open-label trial that will 
investigate the clinical activity of durvalumab and olaparib in men with BCR prostate cancer. Patients in 
Cohort A and B will receive durvalumab monotherapy for 3 months followed by durvalumab plus 
olaparib for an additional 3 months. Patients in Cohort C will receive 6 months of durvalumab and 
olaparib combination therapy.
To ensure that each cohort includes at least 10 patients that receive combination therapy, an additional 
patient will be accrued for every participant that drops out prior to receiving at least one cycle of 
combination therapy (i.e. one infusion of durvalumab and 28 days of olaparib). Patients that drop out will 
still be included in our assessment of the primary endpoint.  
12.2
SAMPLE SIZE 
Ten patients will be enrolled in each cohort (total 30). Within a given cohort, a response1 rate of 30% or 
greater (response as defined in Section 6.1.5) would be a meaningful indicator of clinical activity and 
below 5% would be considered too low. The sample size was selected based on precision of a two-sided 
90% confidence interval (CI) for the response rate; the exact binomial CIs for 0 to 5 responses among 10 
patients are tabulated below. Observing 3 or more responses1 among 10 patients would provide a two-
sided 90% CI with lower confidence limit above 5%.   
N. responses1
0
1
2
3
4
5
Response1 rate
0%
10%
20%
30%
40%
50%
90% CI
0-25.9
0.5-39.4
3.7-50.7
8.7-60.7
15.0-69.7
22.2-77.8
1response as defined in Section 6.1.5
12.3
PRIMARY OBJECTIVES 
The primary response endpoint is defined in Section 6.1.5. Separately by cohort, the response rate will be 
estimated as the number of patients who achieve response divided by the number of patients who initiate 
study therapy. If a patient starts new off study prostate cancer therapy before assessment of primary 
endpoint or withdraws consent or does not have adequate data to assess response, the patient will be 
included in the denominator and considered as not having response. The response rate will be reported 
with exact binomial two-sided 90% CI. 
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12.4
SECONDARY AND EXPLORATORY OBJECTIVES 
Safety of durvalumab per CTCAE guidelines
Safety of durvalumab and olaparib combination per CTCAE guidelines
All patients who initiate study therapy will be evaluated for safety, combined across the three cohorts and 
separately for each cohort. Adverse events will be summarized as number (%) of patients by system organ 
class, CTCAE term and grade, where grade is the maximum across a patient’s treatment period. The 
summaries will be separated for the cycles during which durvalumab monotherapy is administered and 
those during with the combination is administered. Only subjects who received at least one dose of 
durvalumab will be included in the safety analysis of durvalumab.  Only subjects who received at least one 
dose of durvalumab and completed 2 weeks of olaparib will be included in the safety analysis of durvalumab 
and olaparib combination. The total sample size of 30 patients enrolled provides high probability of 
observing relatively rare AEs; there is 79% chance to observe at least one incidence of a specific AE if the 
true AE rate is 5%. 
PSA50 Response  
A descriptive summary (including the percentage and 90% CI) of PSA50 response rate (proportion of 
patients with a decline in PSA >50% from baseline) will be provided at 3- and 6-month timepoints. Subjects 
non-adherent to therapy will be followed to the end point at 3 and 6 - months per post treatment follow up. 
If a patient starts new off study prostate cancer therapy before assessment of endpoint or withdraws consent 
or does not have adequate data to assess response, the patient will be included in the denominator and 
considered as not having PSA50 response. The response rate will be reported with exact binomial two-
sided 90% CI. 
Quality of Life 
Quality of life will be assessed at the time of enrollment and then every three months for 24 months. We 
will use the RANDSF-36 and International Index of Erectile Function (IIEF) score calculation (see 
appendix III-VI). Scores at different times will be compared for individual patients, and each patient will 
have his enrollment survey scores as the comparison. Overall change in study patients’ QOL from time of 
enrollment to 6, 12, 18 and 24 months will be reported separately for Cohort C, while Cohorts A and B will 
report separately and combined. At the same time, for RANDSF-36, the mean, median, range and 95% CI 
of survey scores will be calculated every three months for enrolled patients. The trend of these means and 
90% CI will be plotted by time. 
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For IIEF, a summary table for every three months including enrolled patients on trial be given as below  
Function Domain
Max Score
Median Score
90% CI
A. Erectile Function (Q1,2,3,4,5,15)
B. Orgasmic Function (Q9,10) 
C. Sexual Desire (Q11,12)
D. Intercourse Satisfaction (Q6,7,8)
E. Overall Satisfaction (Q13,14) 
 
rPFS, PSA-PFS, EFS and time to start of ADT  
The endpoints are defined in Section 6.1.5. The distributions of each endpoint for each individual cohort 
will be estimated using Kaplan-Meier method.  The 24-month and median times to event will be reported 
with 90% CI.
12.5
CORRELATIVE OBJECTIVES 
Given our sample size no statistical test will be performed for correlative objectives. Association between 
tumor microenvironment (IHC score for CD8, CD4, FOXB3, PDL1) and primary endpoint will be 
described. We will also describe association between genetic characteristics (number of somatic 
mutations, mutational signature, and DNA variants) and primary endpoint will be described. We will 
describe immunologic response to treatments (level of cytokines in peripheral blood and % of T cell 
classes in peripheral blood and T-cell receptor sequencing) at baseline (i.e., within 72h of C1D1), 12 
weeks and 24 weeks from C1D1. We will describe tumor clonal evaluation by comparing sequencing 
results on archival prostate cancer tissue or ctDNA at the time of enrollment to ctDNA at 6 months and at 
the time of progression. 
12.6
 STUDY ARM ASSIGNMENT
Upon confirmation of eligibility, patients will be stratified into three cohorts: CDK12 mutations in Cohort 
A, MMRd/MSI-high in Cohort B and HRD in Cohort C. There are three single arms without 
randomization. Patients in Cohort A and B will receive durvalumab monotherapy for 3 months followed 
by durvalumab plus olaparib for an additional 3 months. Patients in Cohort C will receive 6 months of 
durvalumab and olaparib combination therapy.
12.7
 BLINDING
Since this is a three-cohort, single arm study, neither patients nor doctors will be blinded.
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13.
ASSESSMENT OF SAFETY
13.1
CLINICAL LABORATORY TESTS
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis will be taken 
at the times indicated in the assessment schedules and as clinically indicated (see the SoAs). 
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a licensed clinical 
laboratory according to local standard procedures. Sample tubes and sample sizes may vary depending on 
the laboratory method used and routine practice at the site. Abnormal clinically significant laboratory 
results should be repeated as soon as possible (preferably within 24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the Treating 
physician and investigator. The date, time of collection, and results (values, units, and reference ranges) 
will be recorded on the appropriate eCRF.
The laboratory variables to be measured are presented in Section 10.1.1, Table 7 (hematology), Table 8 
(clinical chemistry), and Table 9 (urinalysis).
Other safety tests to be performed at screening include assessment for hepatitis B surface antigen, 
hepatitis C antibodies.
13.2
PHYSICAL EXAMINATIONS
Physical examinations will be performed according to the assessment schedules (see the SoAs). Full 
physical examinations will include assessments of the head, eyes, ears, nose, and throat and the 
respiratory, cardiovascular, GI, urogenital, musculoskeletal, neurological, dermatological, 
hematologic/lymphatic, and endocrine systems. Height will be measured at screening only. Focused 
physical examinations are to be utilized by the Treating physician on the basis of clinical observations and 
symptomatology. Situations in which physical examination results should be reported as AEs are 
described in Section 16.3. 
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the study.  ECGs 
should be obtained after the patient has been in a supine position for 5 minutes and recorded while the 
patient remains in that position.
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 additional 12-lead 
ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding.  
Situations in which ECG results should be reported as AEs are described in Section 16.3.
At Screening, a single ECG will be obtained on which QTcF must be <470 ms. 
13.3
VITAL SIGNS
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated according to 
the SoAs. Body weight is also recorded at each visit along with vital signs.
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First durvalumab infusion
On the first infusion day, patients will be monitored, and vital signs collected/recorded in eCRF prior to, 
during and after infusion of IP as presented in the bulleted list below. 
BP and pulse will be collected from patients in the I-O arms before, during, and after each infusion at the 
following times (based on a 60-minute infusion):
Prior to the beginning of the infusion (measured once from approximately 30 minutes before up to 0 
minutes [i.e., the beginning of the infusion])
Approximately 30 minutes during the infusion (halfway through infusion) 
At the end of the infusion (approximately 60 minutes ±5 minutes)
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow the 
principles as described above or be taken more frequently if clinically indicated. A 1-hour observation 
period is recommended after the first infusion of durvalumab. 
Subsequent durvalumab infusions
BP, pulse and other vital signs should be measured, collected/recorded in eCRF prior to the start of the 
infusion. Patients should be carefully monitored, and BP and other vital signs should be measured during 
and post infusion as per institution standard and as clinically indicated. 
13.4
EARLY PATIENT REVIEW FOR SAFETY
It is recommended that patients are contacted 2 weeks after receiving every cycle of durvalumab (Cycle 1 
Day 14, Cycle 2 Day 14, Cycle 3 Day 14, Cycle 4 Day 14, Cycle 5 Day 14, Cycle 6 Day 14) of study 
drug(s) to ensure early identification and management of toxicities. 
13.5
ECOG PERFORMANCE STATUS
ECOG performance status will be assessed at the times specified in the assessment schedules (see the 
SoAs) based on the following:
0.
Fully active; able to carry out all usual activities without restrictions
1.
Restricted in strenuous activity, but ambulatory and able to carry out light work or work of a 
sedentary nature (e.g., light housework or office work)
2.
Ambulatory and capable of self-care, but unable to carry out any work activities; up and about 
more than 50% of waking hours.
3.
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours
4.
Completely disabled; unable to carry out any self-care and totally confined to bed or chair
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5.
Dead 
Any significant change from baseline or screening must be reported as an AE.
13.6
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 9.2.1. 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, olaparib 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.
13.7
OTHER SAFETY ASSESSMENTS
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality suggestive of 
pneumonitis/ILD is observed, toxicity management as described in detail in the Dosing Modification and 
Toxicity Management Guidelines (see Section 9.2) will be applied. The results of the full diagnostic 
workup (including high-resolution computed tomography [CT], blood and sputum culture, hematological 
parameters, etc.) will be captured in the eCRF. It is strongly recommended to perform a full diagnostic 
workup, to exclude alternative causes such as lymphangitic carcinomatosis, infection, allergy, cardiogenic 
edema, or pulmonary hemorrhage. In the presence of confirmatory HRCT scans where other causes of 
respiratory symptoms have been excluded, a diagnosis of pneumonitis (ILD) should be considered and the 
Dosing Modification and Toxicity Management Guidelines should be followed. 
The Investigator is responsible for ensuring that all staff involved in the study is familiar with the content 
of this section.
13.8
GENOMIC INSTABILITY STATUS 
All patients will undergo targeted next-generation sequencing in order to evaluate for the presence of a 
CDK12 mutations, MMRd/MSI-high, HRD and other gene alterations at baseline. This will be 
accomplished using the UW OncoPlex platform, which has been validated for use with tumor tissue 
derived DNA and cell free tumor DNA (ctDNA)(60) or other certified next-generation sequencing (NGS) 
assay performed in a CLIA/CAP laboratory. Archival prostate cancer tissue will be requested for NGS. If 
archival tissue not available, or if a patient has a PSA >20 ng/mL, a plasma sample may be used for 
ctDNA sequencing. 
Note: If prior to enrolling, a patient has already had their tumor sequenced using a next-generation 
sequencing assays performed in a CLIA/CAP certified laboratory (e.g., FoundationOne, Cans, etc.), these 
results may be used for determining of CDK12 mutations, MMRd/MSI-high, HRD mutational status.
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13.9
EXPLORATORY BIOMARKERS
 This study will incorporate a number of exploratory biomarkers. Given our rapidly evolving 
understanding of prostate cancer pathobiology and genetics, it is impossible to prospectively define all the 
relevant biomarkers for the patient population enrolled on this study. All samples will be collected at the 
timepoints indicated in Sections 10.1 of the protocol. Details regarding the collection, processing, 
shipping and storage of samples for exploratory research will be described in the Laboratory Manual. 
Examples of the studies to be conducted may include but will not be limited to those described below. 
Additional studies aimed at understanding response and resistance to the study drugs may be added as 
new information becomes available.
Protein expression studies 
Protein expression studies will be conducted on circulating tumor cells (CTCs) and/or tumor tissue using 
immunofluorescence (IF) and immunohistochemistry (IHC), respectively. Expression of CD4, CD8, 
FOXb3 and PDL-1 as well as potentially other proteins will be assessed. IHC will be performed using 
commercially available antibodies and standard lab techniques. Cytokine Human Magnetic 35-Plex Panel 
for the Luminex™ platform will be used to measure cytokine levels in peripheral blood. CTCs for protein 
studies will be isolated using the RareCyte platform, which involves density-based enrichment followed 
IF staining and digital microscopy. (61)
Transcript profiling studies 
Transcript profiling studies will be conducted on circulating tumor cells (CTCs) and/or tumor tissue. 
Transcript profiling on tumor tissue will be performed using RNA-seq, qRT-PCR or other gene 
expression profiling methods as appropriate (e.g., NanoString) and will follow standard lab techniques. 
AdnaTest will be used to isolate CTCs for transcript expression studies. AdnaTest isolates CTCs using 
antibody coated magnetic beads, which are designed to select populations of prostate cancer cells and is 
suitable for transcript profiling studies. Blood samples will be processed using AdnaTest and used for 
multiplexed qRT-PCR studies. 
Next generation sequencing
NGS to identify CDK12, MMRd/MSI or HRD is required for eligibility (see Section 13.8). Additionally, 
number of somatic mutations, mutational signature, and DNA variants will be explored on whole exome 
sequencing of archival prostate cancer tissue or NGS panel of ctDNA. T-cell receptor sequencing might 
be performed as well. For schedule of ctDNA collection, please see Section 10.1
Flow cytometry
Flow cytometry or peripheral blood will be performed (schedule in Section 10.1) to evaluate T-cell 
populations. 
13.10
PATIENT REPORTED OUTCOMES 
The RANDSF-35 and IIEF quality of life questionnaires will be administered periodically throughout the 
duration of the study (Appendix III-VI). Patients will be provided with blank questionnaires and 
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encouraged to complete these at home prior to scheduled clinic visits as outlined in Sections 10.1. These 
may also be completed in the clinic if preferred by the patient. If completed at home, questionnaires must 
be completed within the time windows indicated in Sections 10.1. 
14.
BIOLOGICAL SAMPLING PROCEDURES
14.1
VOLUME OF BLOOD
 Table 14 below provides an approximation of the amount of blood that will be drawn for the safety and 
biomarker assessments outlined in Sections 10.1. In general, these labs will not all be drawn at the same 
visit, and Table 14 provides an estimate for the upper limit of blood volume required from a patient at any 
given visit. The number of samples taken, as well as the volume required for each analysis, may be changed 
during the study as new data on the study treatment becomes available. The total volume of blood that will 
be drawn from each subject in this study is as follows: 
Table 14. Volume of Blood to be Drawn from Each Patients
Assessment
Sample volume 
(mL)
No of samples
Total volume 
(mL)
Clinical chemistry
5
1
5
Hematology
3
1
3
Coagulation
3
1
3
Safety1
Hepatitis panel
5
1
5
ctDNA studies
10
1
10
Cytokines
5
1
5
Flowcytometry
5
1
5
Exploratory 
biomarker 
research
Protein expression
5
1
5
Total
41
8
41
1 The sample volumes for safety assessments are approximate volumes that are subject to change. Additional 
blood samples may be needed depending on the results of these studies and if patients require follow up 
testing or undergo additional procedures (e.g., fresh metastatic biopsy).
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15.
HANDLING, STORAGE AND DESTRUCTION OF BIOLOGICAL SAMPLES 
Biospecimen samples will be stored for up to five years following the completion of this study. Samples 
will be stored at University of Washington and/or Fred Hutchinson Cancer Center (UW/FHCC). These 
samples may also be sent to our research partners participating in this study, including AstraZeneca. 
Specimens will not be used for reasons unrelated to this research study. All specimens will be kept in 
locked research laboratories at UW/FHCC. The use of these specimens will be supervised by the 
Investigator.
16.
STUDY OVERSIGHT FOR SAFETY EVALUATION
16.1.1
DEFINITION OF ADVERSE EVENTS 
The International Council on Harmonization (ICH) Guideline for Good Clinical Practice (GCP) E6(R1) 
defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
An AE includes but is not limited to any clinically significant worsening of a patient’s pre-existing 
condition. An abnormal laboratory finding (including ECG finding) that requires an action or intervention 
by the Treating physician, or a finding judged by the Treating physician to represent a change beyond the 
range of normal physiologic fluctuation, should be reported as an AE.
Adverse events may be treatment emergent (i.e., occurring after initial receipt of investigational product) 
or nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, disease, or other 
untoward medical event that begins after written informed consent has been obtained but before the patient 
has received investigational product. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the patient 
being enrolled into the study) for a documented pre-existing condition, that did not worsen from baseline, 
is not considered an AE (serious or nonserious). An untoward medical event occurring during the 
prescheduled elective procedure or routinely scheduled treatment should be recorded as an AE or SAE.
The term AE is used to include both serious and non-serious AEs.
16.1.2
DEFINITION OF SERIOUS ADVERSE EVENTS
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 fulfils one or more of the following criteria:

Results in death
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
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 in offspring of the patient

Is an important medical event that may jeopardize the patient or may require medical intervention 
to prevent one of the outcomes listed above.
Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalizations; or development of drug 
dependency or drug abuse.
Any new malignancy:
Adverse Events (AEs) for malignant tumors reported during a study should generally be assessed 
as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion 
should be used. In certain situations, however, medical judgement on an individual event basis 
should be applied to clarify that the malignant tumor event should be assessed and reported as a 
Non-Serious AE. For example, if the tumor is included as medical history and progression occurs 
during the study, but the progression does not change treatment and/or prognosis of the malignant 
tumor, the AE may not fulfill the attributes for being assessed as Serious, although reporting of 
the progression of the malignant tumor as an AE is valid and should occur. Also, some types of 
malignant tumors, which do not spread remotely after a routine treatment that does not require 
hospitalization, may be assessed as Non-Serious; examples include Stage 1 basal cell carcinoma 
and Stage 1A1 cervical cancer removed via cone biopsy.
The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (i.e., it is not the tumor for which entry into the study is a criterion and that is 
being treated by the IP under study and is not the development of new or progression of existing 
metastasis to the tumor under study). Malignant tumors that – as part of normal, if rare, 
progression – undergo transformation (e.g., Richter's transformation of B cell chronic 
lymphocytic leukemia into diffuse large B cell lymphoma) should not be considered a new 
malignant tumor.
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by the 
Investigator(s) and communicated to AstraZeneca.
16.1.3
DEFINITION OF ADVERSE EVENTS OF SPECIAL INTEREST (AESI)
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring. An AESI may be serious 
or non-serious. AESI are defined as AEs that include, but are not limited to, events with a potential 
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inflammatory or immune-mediated mechanism that may require more frequent monitoring and/or 
interventions such as corticosteroids, immunosuppressants, and/or endocrine therapy. 
If the Treating physician has any questions in regard to an event being an imAE, the Treating physician 
should promptly contact the Investigator.
AESIs observed with durvalumab include those listed below. Refer to the IB for complete details on the 
safety profile of durvalumab and incidence of observed AESI.

Diarrhea / Colitis, intestinal perforation, enterocolitis, and proctitis 

Pneumonitis / ILD

hepatitis / transaminase increases

Endocrinopathies (i.e., events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper- and 
hypothyroidism and type I diabetes mellitus)

Rash / Dermatitis

Nephritis / Blood creatinine increases

Pancreatitis / serum lipase and amylase increases  

Myocarditis

Myositis / Polymyositis

Immune thrombocytopenia 

Neuropathy / neuromuscular toxicity (e.g., Guillain-Barré, and myasthenia gravis)

Other inflammatory responses that are rare / less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and other events involving 
the eye skin, hematological and rheumatological events, vasculitis, non-infectious meningitis, non-
infectious encephalitis, and psoriasis. 
AESIs observed with durvalumab and olaparib combination include, but not limited to all of the above as 
well as:

Anemia

Leukopenia

Lymphopenia

Gastrointestinal disorders
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
Infection
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs.
Further information on these risks (e.g., presenting symptoms) can be found in the current version of the 
durvalumab and olaparib Investigator’s Brochure. More specific guidelines for their evaluation and 
treatment are described in detail in the Dosing Modification and Toxicity Management Guidelines (Section 
9). These guidelines have been prepared by the AZ to assist the Treating physician and Investigator in the 
exercise of his/her clinical judgment in treating these types of toxicities.  These guidelines apply to AEs 
considered causally related to the study drug/study regimen by the reporting investigator.
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality suggestive of 
pneumonitis/interstitial lung disease is observed, toxicity management as described in detail in the Dosing 
Modification and Toxicity Management Guidelines (Section 9) will be applied. The results of the full 
diagnostic workup (including high-resolution computed tomography (HRCT), blood and sputum culture, 
hematological parameters etc.) will be captured eCRF.
It is strongly recommended to perform a full diagnostic workup, to exclude alternative causes such as 
lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage. In the 
presence of confirmatory HRCT scans where other causes of respiratory symptoms have been excluded, a 
diagnosis of pneumonitis (ILD) should be considered and the Dosing Modification and Toxicity 
Management Guidelines should be followed. 
Pneumonitis (ILD) investigation
The following assessments, and additional assessments if required, will be performed to enhance the 
investigation and diagnosis of potential cases of pneumonitis. The results of the assessment will be 
collected.

Physical examination

Signs and symptoms (cough, shortness of breath and pyrexia, etc.) including auscultation 
for lung field will be assessed.

SpO2

Saturation of peripheral oxygen (SpO2)

Other items

When pneumonitis (ILD) is suspected during study treatment, the following markers should 
be measured where possible:
(i)
ILD Markers (KL-6, SP-D) and β-D-glucan
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(ii)
Tumor markers: Particular tumor markers which are related to disease 
progression. 
Additional Clinical chemistry: CRP, LDH
16.2
ASSESSMENT OF SAFETY PARAMETERS
16.2.1
ASSESSMENT OF SEVERITY
Assessment of severity is one of the responsibilities of the treating physician in the evaluation of
AEs and SAEs. Severity will be graded according to the NCI CTCAE v5.0.
The determination of severity for all other events not listed in the CTCAE should be made by
the treating physician based upon medical judgment and the severity categories of Grade 1 to 5 as
defined below.
Grade 1 (mild) 
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living.
Grade 2 (moderate) 
An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to 
the patient.
Grade 3 (severe) 
An event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the 
clinical status of the patient.
Grade 4 (life-threatening) 
An event, and/or its immediate sequelae, that is associated with an 
imminent risk of death or with physical or mental disabilities that affect 
or limit the ability of the patient to perform activities of daily living 
(eating, ambulation, toileting, etc.).
Grade 5 (fatal) 
Death (loss of life) as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 16.4. A Grade 3 AE need not 
necessarily be considered an SAE. For example, a Grade 3 headache that persists for several hours may 
not meet the regulatory definition of an SAE and would be considered a nonserious event, whereas a 
Grade 2 seizure resulting in a hospital admission would be considered an SAE.
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16.3
RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
AEs and SAEs will be collected from the time of the patient signing the informed consent form until the 
follow-up period is completed (90 days after the last dose of durvalumab or 30 days from last dose of 
olaparib, whatever comes later). If an event that starts post the defined safety, follow up period noted above 
is considered to be due to a late onset toxicity to study treatment then it should be reported as an AE or SAE 
as applicable.
During the course of the study, all AEs and SAEs should be proactively followed up for each patient for as 
long as the event is ongoing.  Every effort should be made to obtain a resolution for all events, even if the 
events continue after the patient has discontinued study drug or the study has completed.
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the treating 
physician for as long as medically indicated, but without further recording in eCRF.
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
The following variables will be collected for each AE:
In addition, the following variables will be collected for SAEs as applicable:

AE (verbatim)

The date when the AE started and stopped

The maximum CTCAE grade reported

Changes in CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the IPs (yes or no)

Action taken with regard to IPs

Administration of treatment for the AE

Outcome

In addition, the following variables will be collected for SAEs:

Date the AE met criteria for SAE

Date the Investigator became aware of the SAE

Seriousness criteria fulfilled
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
Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Whether an autopsy was performed

Causality assessment in relation to study procedure(s)

Causality assessment in relation to other medication, as explained in Section 16.3.2.16.3.2

Description of the SAE
The grading scales found in the NCI CTCAE version 5.0 will be utilized for all events with an assigned 
CTCAE grading. For those events without assigned CTCAE grades, the recommendation in the CTCAE 
criteria that converts mild, moderate, and severe events into CTCAE grades should be used. A copy of the 
CTCAE version 5.0 can be downloaded from the Cancer Therapy Evaluation Program website 
(http://ctep.cancer.gov).
16.3.1
STUDY RECORDING PERIOD AND FOLLOW-UP FOR ADVERSE 
EVENTS AND SERIOUS ADVERSE EVENTS
If a patient discontinues from treatment for reasons other than disease progression, and therefore 
continues to have tumor assessments, drug or procedure related SAEs must be captured until the patient is 
considered to have confirmed metastatic disease on conventional imaging and will have no further tumor 
assessments.
The treating physician is responsible for following all SAEs until resolution, until the patient returns to 
baseline status, or until the condition has stabilized with the expectation that it will remain chronic, even 
if this extends beyond study participation.
16.3.2
CAUSALITY COLLECTION
The treating physician will assess causal relationship between the IPs and each AE and answer “yes” or 
“no” to the question “Do you consider that there is a reasonable possibility that the event may have been 
caused by the investigational product?”
For SAEs causal relationship will also be assessed for other medication and study procedures. Note that for 
SAEs that could be associated with any study procedure, the causal relationship is implied as “yes.”
A guide to the interpretation of the causality question is found in Section 9.
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16.3.3
RELATIONSHIP TO PROTOCOL PROCEDURES
The treating physician is also required to provide an assessment of the relationship of SAEs to protocol 
procedures on the SAE report form. This includes both non-treatment–emergent (i.e., SAEs that occur prior 
to the administration of study treatment) and treatment-emergent SAEs. A protocol-related SAE may occur 
as a result of a procedure or intervention required during the study (e.g., blood collection). The following 
guidelines should be used by treating physician s to assess the relationship of SAEs to the protocol:

Protocol related: The event occurred due to a procedure or intervention that was described in the 
protocol for which there is no alternative etiology present in the patient’s medical record.

Not protocol related: The event is related to an etiology other than the procedure or intervention 
that was described in the protocol. The alternative etiology must be documented in the study 
patient’s medical record.
16.3.4
ADVERSE EVENTS BASED ON SIGNS AND SYMPTOMS
All AEs spontaneously reported by the patient or reported in response to the open question from the study 
personnel: “Have you had any health problems since the previous visit/you were last asked?” or revealed 
by observation will be collected and recorded in eCRF. When collecting AEs, the recording of diagnoses 
is preferred, when possible, to recording a list of signs and symptoms. However, if a diagnosis is known 
and there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis and each 
sign or symptom will be recorded separately.
16.3.5
ADVERSE EVENTS BASED ON EXAMINATIONS AND TESTS
The results from protocol-mandated laboratory tests and vital signs measurements will be summarized in 
the CSR. Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs 
should therefore only be reported as AEs if they fulfill any of the SAE criteria or are the reason for 
discontinuation of treatment with the IPs.
If deterioration in a laboratory value or vital sign is associated with clinical signs and symptoms, the sign 
or symptom will be reported as an AE and the associated laboratory result or vital sign will be considered 
as additional information. Whenever possible, the reporting treating physician should use the clinical rather 
than the laboratory term (e.g., anemia versus low hemoglobin value). In the absence of clinical signs or 
symptoms, clinically relevant deteriorations in non-mandated parameters should be reported as AEs.
Deterioration of a laboratory value that is unequivocally due to disease progression should not be reported 
as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as compared 
with the baseline assessment will be reported as an AE.
16.3.6
HY’S LAW
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need to be reported as 
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SAEs. Please refer to Section 9 for further instruction on cases of increases in liver biochemistry and 
evaluation of Hy’s law.
16.3.7
DISEASE PROGRESSION
Disease progression can be considered as a worsening of a patient’s condition attributable to the disease for 
which the study treatment 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 new metastasis on conventional 
imaging under study should be considered as disease progression and not an AE. Events that are 
unequivocally due to disease progression should not be reported as an AE during the study.
16.3.8
NEW CANCERS
The development of a new cancer should be regarded as an SAE. New primary cancers are those that are 
not the primary reason for the administration of the study treatment and have been identified after the 
patient’s inclusion in this study.
16.3.9
DEATHS
All deaths that occur during the study treatment period, or within the protocol-defined follow-up period 
after the administration of the last dose of study drug, must be reported as follows:

Death clearly resulting from disease progression should be reported to the Study Monitor/Physician 
at the next monitoring visit and should be documented in the eCRF in the Statement of Death page. 
It should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under study, the AE causing 
the death must be reported to the Study Monitor/Physician as an SAE within 24 hours. It should 
also be documented in the Statement of Death page in eCRF.

The report should contain a comment regarding the co involvement of PD, if appropriate, and 
should assign main and contributory causes of death.

Deaths with an unknown cause should always be reported as an SAE. It should also be documented 
in the Statement of Death page in eCRF.  

A postmortem may be helpful in the assessment of the cause of death, and if performed, a copy of 
the post-mortem results should be forwarded to AstraZeneca Patient Safety or its representative 
within the timeframes specified in Section 16.4
Deaths occurring after the protocol defined safety follow up period after the administration of the last dose 
of study drug should be documented in the Statement of Death page. If the death occurred as a result of an 
event that started after the defined safety follow up period and the event is considered to be due to a late 
onset toxicity to study drug, then it should also be reported as an SAE.
AstraZeneca/MedImmune retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
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16.3.10
FOLLOW-UP OF UNRESOLVED ADVERSE EVENTS
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the treating 
physician for as long as medically indicated, but without further recording in the eCRF.
 After 90 days, only patients with ongoing investigational product related SAEs will continue to be 
followed for safety.
AstraZeneca/MedImmune retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
16.3.11
POST-STUDY EVENTS
After the patient has been permanently withdrawn from the study, there is no obligation for the treating 
physician to actively report information on new AE or SAEs occurring in former study patients after the 
90-day since last durvalumab dose and 30-day since last olaparib dose. safety follow-up period.  
However, if a treating physician learns of any SAEs, including death, at any time after the patient has 
been permanently withdrawn from study, and he/she considers there is a reasonable possibility that the 
event is related to study treatment, the treating physician should notify Investigator and 
AstraZeneca/MedImmune Patient Safety.
16.4
REPORTING OF SERIOUS ADVERSE EVENTS
All SAEs will be reported whether or not considered causally related to the investigational product, or to 
the study procedure(s). The reporting period for SAEs is the period immediately following the time that 
written informed consent is obtained through 90 days after the last dose of durvalumab or 30 days after 
the last dose of olaparib or until the initiation of alternative anticancer therapy. The Investigator and/or 
treating physician are responsible for informing the Ethics Committee and/or the Regulatory Authority of 
the SAE as per local requirements.
For Pharmacovigilance purposes and characterization, any SAE of MDS/AML or new primary 
malignancy occurring after the 90 day follow up period should be reported to AstraZeneca Patient Safety 
regardless of investigator’s assessment of causality or knowledge of the treatment arm.  Investigators will 
be asked during the regular follow up for overall survival if the patient has developed MDS/AML or a 
new primary malignancy and prompted to report any such cases.  
At any time after a patient has completed the study, if an Investigator learns of any SAE including sudden 
death of unknown cause, and he/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 
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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 (90 days after the last dose of durvalumab or 30 days after 
the last dose of olaparib).
All serious, related and unexpected adverse events must be reported to AstraZeneca regardless of the 
country where the study is conducted.
For those events requiring expedited reporting to the regulatory authorities, the Investigator and/or 
treating physician must inform all applicable regulatory authorities (e.g., FDA), via a MedWatch/AdEERs 
or applicable required regulatory form (e.g., CIOMS), of any serious, related and unexpected adverse 
events in accordance with reporting obligations (e.g. FDA21 CFR 312.32) and will concurrently forward 
all such reports to AstraZeneca in English. A copy of the MedWatch/AdEERs report must be emailed to 
AstraZeneca at the time the event is reported to the regulatory authorities (e.g., FDA). It is the 
responsibility of the Investigator to compile all necessary information and ensure that the regulatory 
authorities receive a report according with the applicable reporting requirement timelines and to ensure 
that these reports are also submitted to AstraZeneca at the same time.
* A cover page should accompany the MedWatch/AdEERs form indicating the following:
“Notification from an Investigator Sponsored Study”
The investigator IND number assigned by the FDA
The investigator’s name and address
The trial name/title and AstraZeneca ISS reference number (ESR-19-14545)
* Investigator 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 
Investigator.
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s designated 
mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com
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 regulatory authorities still needs to 
be reported to AstraZeneca 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. 
Fred Hutch/UW is acting as the Coordinating Center for this multi-institutional study, therefore it is the 
responsibility of the Fred Hutch/UW Principal Investigator (or designee) to complete the Fred Hutch IRB 
Expedited Reporting Form for adverse events occurring at participating sites that meet the expedited 
reporting requirements. Expedited reporting includes all adverse events that are serious, related, and 
unexpected.
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Any external sites that participate in the trial will obtain independent IRB approval and will be subject to 
the adverse event reporting policies of their independent institution and IRB. Participating institutions 
must report the AEs to the Coordinating Center following the Cancer Consortium IRB adverse event (AE) 
reporting guidelines. The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and will be responsible for communicating to all participating investigators, any 
observations reportable under the Cancer Consortium IRB Reporting Requirements. Participating 
Investigators will review any distributed AE reports, and will send a copy to their IRB according to their 
local IRB’s policies and procedures, and file a copy with their regulatory documents.
16.4.1
REPORTING OF DEATHS TO ASTRAZENECA
All deaths must be recorded and reported as outlined in Section 16.4.  In addition, all SAEs resulting in 
death or death of unknown cause must be reported to AstraZeneca via 
AEMailboxClinicalTrialTCS@astrazeneca.com within 7 calendar days of awareness or sooner when 
required (See Section 16.4).
Participating institutions must report the SAEs to both AstraZeneca and the Coordinating Center 
following the reporting guidelines above. The Coordinating Center will maintain documentation of all 
Participating Institution Serious Adverse Event reports and will be responsible for communicating to all 
participating investigators, any observations reportable under the Cancer Consortium IRB Reporting 
Requirements. Participating Investigators will review any distributed SAE reports, and will send a copy to 
their IRB according to their local IRB’s policies and procedures, and file a copy with their regulatory 
documents. 
16.4.2
OTHER EVENTS REQUIRING REPORTING
16.4.3
OVERDOSE
An overdose is defined as a patient receiving a dose of durvalumab or olaparib in excess of that specified 
in the Investigator’s Brochure, unless otherwise specified in this protocol.
Any overdose of a study patient with durvalumab or olaparib, with or without associated AEs/SAEs, is 
required to be reported within 24 hours of knowledge of the event to the investigator. The investigator 
must report these to AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e-
mailbox (see Section 16.4 for contact information) within 7 calendar days or sooner when required (see 
Section 16.4). If the overdose results in an AE, the AE must also be recorded as an AE (see Section 16.4). 
Overdose does not automatically make an AE serious, but if the consequences of the overdose are serious, 
for example death or hospitalization, the event is serious and must be recorded and reported as an SAE 
(see Section 16.4). There is currently no specific treatment in the event of an overdose of durvalumab or 
olaparib.  There is currently no specific treatment in the event of overdose with durvalumab or olaparib 
and possible symptoms of overdose are not established. 
Olaparib and Durvalumab 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 
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should be reported as an overdose. The Maximum Tolerated Dose is 300 mg twice daily for olaparib 
(tablet) and 20 mg/kg Q4W for durvalumab (IV).
Adverse reactions associated with overdose should be treated symptomatically and should be managed 
appropriately. The treating physician will use clinical judgment to treat any overdose.
16.4.4
HEPATIC FUNCTION ABNORMALITY
Hepatic function abnormality that fulfills the biochemical criteria of a potential Hy’s Law case in a study 
patient, with or without associated clinical manifestations, is required to be reported as “hepatic function 
abnormal” within 24 hours of knowledge of the event to the investigator. The Investigator must report 
these events to AstraZeneca Patient Safety using the designated Safety e-mailbox (see Section 16.4 for 
contact information) within 7 calendar days or sooner when required, unless a definitive underlying 
diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to investigational 
product has been confirmed. The criteria for a potential Hy’s Law case are 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).

If the definitive underlying diagnosis for the abnormality has been established and is unrelated to 
investigational product, the decision to continue dosing of the study patient will be based on the 
clinical judgment of the treating physician.

If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
patient must be interrupted immediately. Follow-up investigations and inquiries must be initiated 
by the investigational site without delay.
Each reported event of hepatic function abnormality will be followed by the treating physician and 
evaluated by the investigator and AstraZeneca/MedImmune.  
16.4.5
PATERNAL EXPOSURE 
Male patients should refrain from fathering a child or donating sperm during the study and for 180 days 
after the last dose of durvalumab and at least for 90 days following the last dose of olaparib, whichever is 
the longer time period. 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) 
occurring from the date of the first dose until 180 days after the last dose of durvalumab and at least for 90 
days following the last dose of olaparib, whichever is the longer time period should, if possible, be followed 
up and documented. 
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the treating 
physician must obtain the consent of the patient’s partner. Therefore, the local study team should adopt the 
generic ICF template in line with local procedures and submit it to the relevant Ethics Committees 
(ECs)/Institutional Review Boards (IRBs) prior to use. 
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16.4.6
MEDICATION ERROR
For the purposes of this clinical study a medication error is an unintended failure or mistake in the treatment 
process for an AstraZeneca study drug that either causes harm to the patient or has the potential to cause 
harm to the patient. 
A medication error is not lack of efficacy of the drug, but rather a human or process related failure while 
the drug is in control of the study site staff or patient.
Medication error includes situations where an error 

Occurred

Was identified and intercepted before the patient received the drug

Did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error e.g., medication prepared incorrectly, even if it was not actually given to the 
patient

Drug not administered as indicated, for example, wrong route or wrong site of administration

Drug not taken as indicated e.g., tablet dissolved in water when it should be taken as a solid tablet 

Drug not stored as instructed e.g., kept in the fridge when it should be at room temperature 

Wrong patient received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to patient (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS - including those that lead to one of the above listed 
events that would otherwise have been a medication error 

Patient accidentally missed drug dose(s) e.g., forgot to take medication

Accidental overdose (will be captured as an overdose)

Patient failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in open label 
studies, even if an AZ product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the medication error. 
If a medication error occurs in the course of the study, then the treating physician or other site personnel 
informs investigator within 1 day i.e., immediately but no later than 24 hours of when he or she becomes 
aware of it.
The investigator works with the treating physician to ensure that all relevant information is completed 
within 1 or 5 calendar days. The investigator must report to AstraZeneca Patient Safety using the designated 
Safety e-mailbox (see Section 16.4 for contact information) within 7 calendar days or sooner when required 
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Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
88
(see Section 16.4) if there is an SAE associated with the medication error and within 30 days for all other 
medication errors. 
16.5
SAFETY MONITORING
Sequential boundaries will be used to monitor rate of dose limiting toxicity (see definition Section 16.5.1) 
throughout the treatment period. The accrual will be paused if excessive numbers of dose limiting toxicity 
events is equal to or exceeds bn out of n patients with full follow-up (see Table 15). This is a Pocock-type 
stopping boundary that yields the probability of crossing the boundary at most 20% when the rate of dose 
limiting toxicity events is equal to the acceptable rate 30%. All patients that received at least one dose of 
durvalumab will be evaluated for safety using Pocock-type stopping boundary. Number of dose limiting 
toxicity incidents will be counted from start of monotherapy with durvalumab till completion of 
combination therapy with durvalumab and olaparib. Because enrollment is expected to proceed slowly, 
stopping boundaries will be assessed after each dose limiting toxicity event. 
Table 15. Pocock-type stopping boundary for safety monitoring
Number of Patients, n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Boundary, bn
-
-
3 4 4 4 5 5 6 6 6 7 7 8 8 8 9 9 10 10
Number of Patients, n 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
Boundary, bn
10 11 11 11 12 12 12 13 13 14
16.5.1       DOSE LIMITING TOXICITY DEFINITION
Dose limited toxicity defined as:
Hematologic toxicity:

Grade ≥3 neutropenia complicated by fever >38.3°C

Grade 4 neutropenia (lasting more than 7 days)

Grade ≥3 thrombocytopenia with significant bleeding

Grade 4 thrombocytopenia (regardless of duration)

Grade 4 anemia (regardless of duration)

Myelodysplastic syndrome

Acute myeloid leukemia
Non-hematologic toxicity:

Any Grade 4 non-immune-mediated AE

Any Grade 4 immune-mediated AE, excluding endocrinopathies

Any Grade 3 non-immune mediated AE that does not resolve to ≤Grade 1 or baseline within 30 days 
with optimal medical management

Any Grade 3 immune-mediated AE – excluding diarrhea/colitis, pneumonitis, hepatitis, rash, 
neurotoxicity, myocarditis, myositis/polymyositis, endocrinopathies and nephritis – that does not 
resolve to ≤Grade 1 or baseline within 30 days after onset of the event despite optimal medical 
management including systemic corticosteroids

Grade 3 diarrhea or colitis that does not resolve to ≤Grade 1 within 14 days
[both immune- and non-immune-mediated indicated here; the same is the case if not specified in 
remaining bullet points below]
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Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
89

Grade 3 noninfectious pneumonitis

Grade 2 noninfectious pneumonitis that does not resolve to ≤Grade 1 within 3 days of the initiation of 
maximal supportive care

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3×ULN with concurrent 
increase in total bilirubin (TBL) ≥2×ULN without evidence of cholestasis or alternative explanations 
(e.g., viral hepatitis, disease progression in the liver; i.e., “Hy’s Law”)

ALT or AST >8×ULN or TBL>5×ULN

Grade 3 immune-mediated rash that does not resolve to ≤Grade 1 or baseline within 30 days

Grade 2 rash covering > 30% BSA that does not resolve to ≤Grade 1 or baseline within 30 days 

Any grade of immune-mediated rash with bullous formation

Grade 3 immune-mediated neurotoxicity (excluding Guillain-Barre and myasthenia gravis) that does 
not resolve to ≤Grade 1 within 30 days

Grade 2 or 3 immune-mediated peripheral neuromotor syndrome (such as Guillain-Barre and 
myasthenia gravis) that does not resolve to ≤Grade 1 within 30 days or that exhibits signs of 
respiratory insufficiency or autonomic instability

Grade 3 immune-mediated myocarditis

Any symptomatic immune-mediated myocarditis that does not become asymptomatic within 3 days 
of initiating optimal medical management including systemic corticosteroids

Grade 2 or 3 immune-mediated myositis/polymyositis that does not resolve to Grade ≤1 within 30 
days of initiating optimal medical management including systemic corticosteroids or that exhibits 
signs of respiratory insufficiency regardless of optimal medical management
Increase in creatinine >3×ULN, or >3×baseline for patients with a baseline creatinine elevated above 
ULN
17.
ETHICAL AND REGULATORY REQUIREMENTS
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 
Patient data protection.
This protocol and informed consent form(s) and any subsequent modifications — will be reviewed and 
approved by the Institutional Review Board Scientific Protocol Review Committee with respect to scientific 
content and compliance with applicable research and human subjects regulations. 
The protocol, site-specific informed consent form, participant education and recruitment materials, and 
other requested documents — and any subsequent modifications — also will be reviewed and approved by 
the ethical review bodies responsible for oversight of research conducted at the study site. 
Subsequent to initial review and approval, the responsible IRBs/Ecs will review the protocol at least 
annually. The Investigator will make safety and progress reports to the IRBs/Ecs at least annually, and 
within three months of study termination or completion. These reports will include the total number of 
participants enrolled in the study, the number of participants who completed the study, all changes in the 
research activity, and all unanticipated problems involving risks to human subjects or others.
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Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
90
17.1
INFORMED CONSENT
Written informed consent will be obtained from each study participant (or the parents or legal guardians of 
participants who cannot consent for themselves). Each study site is responsible for developing a study 
informed consent form for local use, based on the coordinating center approved ICF and site local templates 
(if applicable), that describes the purpose of the study, the procedures to be followed, and the risks and 
benefits of participation, in accordance with all applicable regulations. The study site also is responsible for 
translating the template form into local languages and verifying the accuracy of the translation by 
performing an independent back-translation.
Literate participants will document their provision of informed consent by signing their informed consent 
forms. Non-literate participants will be asked to document their informed consent by marking their 
informed consent forms (e.g., with an X, thumbprint, or other mark) in the presence of a literate third-party 
witness. Any other local IRB/EC requirements for obtaining informed consent from non-literate persons 
also will be followed. 
Participants (or their parents or legal guardians) will be provided with a copy of their informed consent 
forms if they are willing to receive them.
17.2
INCENTIVES
Participants will not be compensated for trial participation. No travel reimbursement is provided.
17.3
CONFIDENTIALITY
All study-related information will be stored securely at the study site. All participant information will be 
stored in locked file cabinets in areas with access limited to study staff. All laboratory specimens, reports, 
study data collection, process, and administrative forms will be identified by a coded number only to 
maintain participant confidentiality. All local databases will be secured with password-protected access 
systems. Forms, lists, logbooks, appointment books, and any other listings that link participant ID numbers 
to other identifying information will be stored in a separate, locked file in an area with limited access.
Participant’s study information will not be released without the written permission of the participant, except 
as necessary for monitoring by the investigators, AstraZeneca Pharmaceuticals and/or NIH. 
17.4
CHANGES TO THE PROTOCOL AND INFORMED CONSENT FORM
The protocol, the proposed informed consent and all forms of participant information related to the study 
(e.g., advertisements used to recruit participants) will be reviewed and approved by the Cancer 
Consortium IRB and Scientific Review Committee (SRC). Any changes made to the protocol will be 
submitted as a modification and will be approved by the IRB prior to implementation. 
Fred Hutch IRB
Approved 
8/16/2023

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
91
17.5
AUDITS AND INSPECTIONS
17.5.1
Documentation
Source documentation of clinical data will be stored at each participating site. The PI and study staff will 
maintain an electronic case report form (eCRF) database of all clinical data and additional study-related 
documentation will be maintained in a comprehensive and centralized filing system. Data entry into the 
eCRF will be performed at each participating site. These files will be suitable for inspection by 
AstraZeneca, the FDA, and/or other applicable regulatory agencies at any time. Documentation will 
consist of: subject files (complete medical records, laboratory data, supporting source documentation, and 
the Informed Consent); study files (the protocol with all amendments, copies of all pre-study 
documentation, and all correspondence between the FDA (as needed), IRB and sites; and drug 
accountability files, containing a complete account of the receipt and disposition of the study drug.
17.5.2
Access to Source Data
The PI will permit the Cancer Consortium representatives to monitor the study as frequently as deemed 
necessary to determine that protocol adherence and data recording are satisfactory. The eCRF and related 
source documents will be reviewed in detail at each site visit. Only original source documents are 
acceptable for review. Should the consortium or regulatory authorities select subjects at a participating 
site for review, said site will be required to provide electronic source documentation. This review includes 
inspection of data acquired as a requirement for participation in this study and other medical records as 
required to confirm information contained in the eCRF, such as past history, secondary diagnoses, and 
concomitant medications. Other study records, such as correspondence with the IRB, and other 
committees, as well as screening and drug accountability logs will also be inspected. All source data and 
study records must also be available for inspection by representatives of the FDA or other regulatory 
agencies.
18.
STUDY MANAGEMENT
18.1
TRAINING OF STUDY SITE PERSONNEL
Prior to opening this study for accrual, each participating site will be required to have a Site Initiation 
Visit (SIV). The SIV will involve a presentation by the Investigator to review the protocol in detail. The 
SIV should be attended (in person or virtually) by the Investigator, study coordinator, investigational drug 
services representative and any other sub-investigators. If any of the aforementioned personnel are unable 
to attend the SIV, the participating site will be responsible for distributing the protocol and SIV 
presentation for review. Training should be documented on delegation logs at each participating site.
Before initiation of the study, the coordinating center will review and discuss the following items with the 
Investigator and clinic staff: the protocol, study procedures, record keeping and administrative 
requirements, drug accountability, AE reporting, Good Clinical Practice guidelines, CRF/eCRF 
completion guidelines, monitoring requirements, and the ability of the site to satisfactorily complete the 
protocol. Additional documents with instructions for study compliance and CRF/eCRF completion will be 
provided.
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8/16/2023

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
92
The following documentation required by the coordinating center must be received prior to initiation of 
the trial: curricula vitae of the PI and all Sub-Investigators; signed Protocol Agreement; copy of the 
correspondence from the IRB indicating approval of the protocol and Informed Consent Forms, signed by 
the IRB chairperson or designee; an IRB roster of the IRB members; copy of the Informed Consent Forms 
that were reviewed and approved by the IRB.
18.2
MONITORING OF THE STUDY
Trial monitoring will be in accordance with the Fred Hutchinson Cancer Center (FHCC)/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan. Under the provisions of 
this plan, FHCC Clinical Research Support coordinates data and compliance monitoring conducted by 
consultants, contract research organizations, or FHCC 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), FHCC Scientific Review Committee (SRC) and the FHCC/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. 
Additionally, scheduled meetings will take place weekly and will include the Investigator (Michael 
Schweizer, MD), research nurse, data manager, and, when appropriate, the collaborators, sub-
investigators, and biostatistician involved with the conduct of the protocol. During these meetings the 
Sub-Investigators/ Investigator will discuss matters related to: safety of protocol participants, validity and 
integrity of the data, enrollment rate relative to expectation, characteristics of participants, retention of 
participants, adherence to protocol (potential or real protocol violations), data completeness, and progress 
of data for secondary objective.
18.3
SOURCE DATA
Source data will be maintained in study binders or electronically in secure servers as appropriate. Servers 
will be maintained at FHCC/UWMC and any hard copies of source data will be kept in a locked office or 
locked filling cabinets.
18.4
STUDY TIMETABLE AND END OF STUDY
The end of the study is defined as the last visit of the last patient undergoing the study. The study also 
may be discontinued at any time by AstraZeneca Pharmaceuticals, the investigators, and/or the US Food 
and Drug Administration, and/or site IRBs/Ecs.
Fred Hutch IRB
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Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
93
18.5
DATA MANAGEMENT
The Protocol Director, or her designees, will prepare and maintain adequate and accurate participant case 
histories with observations and other data pertinent to the study. Original source documents should be 
transcribed to Case Report Forms (CRFs) and used to analyze the study data. Source documents include 
hospital records, clinical charts, laboratory and pharmacy records, and recorded electronic data. 
All data required by the trial will be entered onto paper and electronic case report forms. Any corrections 
to data required into the paper case report forms must be made in such a way that the original entry is not 
obscured. Only designated study staff will enter data for study participants after study visits. Case report 
forms will be checked against source document data by study staff. 
Patient records will be kept in a secure location at the University of Washington accessible only to 
research authorized personnel. The patient identity will be kept as confidential as possible as required by 
law. Except as required by law, the patient will not be identified by name, social security number, 
address, telephone number, or any other direct personal identifier. Study subjects will be assigned an ID 
code. Information about the code will be kept in a secure location and access limited to research study 
personnel. The results of this research study may be presented at scientific or medical meetings or 
published in scientific journals. However, the patient identity will not be disclosed. The patient's personal 
data which may be included in the investigator's database shall be treated in compliance with all 
applicable laws and regulations. 
Trial oversight will be carried out by the protocol director, Dr. Michael Schweizer, and his research staff. 
They will meet monthly to review recently acquired data and adverse events. The data recorded within the 
research charts and protocol database is compared with the actual data that is available from the medical 
record and/or clinical histories. Data detailed in the research case report forms includes the nature and 
severity of all toxicities, which are also reported as described above. 
19.
STUDY GOVERNANCE AND OVERSIGHT 
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by AstraZeneca 
representatives in consultation with Patient Safety. Issues identified will be addressed; for instance, this 
could involve amendments to the study protocol and letters to Investigators.
Fred Hutch IRB
Approved 
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Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
94
20.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
20.1
IDENTITY OF INVESTIGATIONAL PRODUCT(S)
Table 16. List of Investigational Products for This Study
Investigational product
Dosage form and strength
Manufacturer
Durvalumab
50 mg/mL solution for infusion 
after dilution 
MedImmune/AstraZeneca
Olaparib
100 mg tablet
MedImmune/AstraZeneca
Olaparib
150 mg tablet
MedImmune/AstraZeneca
21.
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Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
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Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
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Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
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cancer (mCRPC). JCO. 2018 May 20;36(15_suppl):5007–5007. 
40. Meeting Library | Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) 
for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650). 
[Internet]. [cited 2019 May 18]. Available from: 
https://meetinglibrary.asco.org/record/169424/abstract
41. Robinson D, Van Allen EM, Wu Y-M, Schultz N, Lonigro RJ, Mosquera J-M, et al. Integrative 
clinical genomics of advanced prostate cancer. Cell. 2015 May 21;161(5):1215–28. 
42. Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, et al. Inherited DNA-Repair 
Gene Mutations in Men with Metastatic Prostate Cancer. New England Journal of Medicine. 2016 
Aug 4;375(5):443–53. 
43. Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-Repair Defects 
and Olaparib in Metastatic Prostate Cancer. New England Journal of Medicine. 2015 Oct 
29;373(18):1697–708. 
44. Karzai F, VanderWeele D, Madan RA, Owens H, Cordes LM, Hankin A, et al. Activity of 
durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without 
DNA damage repair mutations. J Immunother Cancer [Internet]. 2018 Dec 4 [cited 2019 May 2];6. 
Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280368/
45. Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer | NEJM [Internet]. [cited 
2019 May 18]. Available from: https://www.nejm.org/doi/full/10.1056/nejmoa1200690
46. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee J-L, Fong L, et al. Pembrolizumab as Second-Line 
Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017 16;376(11):1015–26. 
47. Lipson EJ, Forde PM, Hammers H-J, Emens LA, Taube JM, Topalian SL. Antagonists of PD-1 and 
PD-L1 in Cancer Treatment. Semin Oncol. 2015 Aug;42(4):587–600. 
48. Lim DM, Gulati R, Aleshin‐Guendel S, Gawne A, Wingate JT, Cheng HH, et al. Undetectable 
prostate-specific antigen after short-course androgen deprivation therapy for biochemically 
Fred Hutch IRB
Approved 
8/16/2023

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
98
recurrent patients correlates with metastasis-free survival and prostate cancer-specific survival. The 
Prostate. 2018;78(14):1077–83. 
49. Critz FA, Levinson AK, Williams WH, Holladay DA, Holladay CT. The PSA nadir that indicates 
potential cure after radiotherapy for prostate cancer. Urology. 1997 Mar;49(3):322–6. 
50. Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of 
therapeutic peptides and proteins in adults. J Clin Pharmacol. 2012 Jan;52(1):18–28. 
51. Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an investigational 
anti-interferon-α monoclonal antibody, in systemic lupus erythematosus. Clin Pharmacokinet. 2013 
Nov;52(11):1017–27. 
52. Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing of 
monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009 Sep;49(9):1012–24. 
53. Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab in 
cancer patients based on population pharmacokinetic analysis. Pharm Res. 2006 Jun;23(6):1275–84. 
54. Joaquin Mateo. TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase 
(PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA 
damage repair (DDR) alterations. J Clin Oncol 37, 2019 (suppl; abstr 5005). 
55. Abida W., et al. Preliminary Results from TRITON2: A Phase 2 Study of Rucaparib in Patients with 
Metastatic Castration-Resistant Prostate Cancer (mCRPC) Associated with Homologous 
Recombination Repair (HRR) Gene Alterations” (abstract 793PD), ESMO 2018. 
56. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: guidelines 
for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143–
52. 
57. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations 
From the Prostate Cancer Clinical Trials Working Grou... - PubMed - NCBI [Internet]. [cited 2019 
May 18]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26903579
58. National Comprehensive Cancer Network. NCCN IRAE guidelines [Internet]. Management of 
Immunotherapy-related toxicities. [cited 2019 May 20]. Available from: 
https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf
59. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of 
Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: 
American Society of Clinical Oncology Clinical Practice Guideline. JCO. 2018 Feb 
14;36(17):1714–68. 
60. Validation and implementation of targeted capture and sequencing for the detection of actionable 
mutation, copy number variation, and gene rearrang... - PubMed - NCBI [Internet]. [cited 2019 Aug 
1]. Available from: https://www-ncbi-nlm-nih-
gov.offcampus.lib.washington.edu/pubmed/24189654
Fred Hutch IRB
Approved 
8/16/2023

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Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
99
61. High-recovery visual identification and single-cell retrieval of circulating tumor cells for genomic 
analysis using a dual-technology platform inte... - PubMed - NCBI [Internet]. [cited 2019 Aug 1]. 
Available from: https://www-ncbi-nlm-nih-gov.offcampus.lib.washington.edu/pubmed/25944336
62. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of 
erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 
1997 Jun;49(6):822–30. 
Fred Hutch IRB
Approved 
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Date: 11/25/2022 
100
22. APPENDICES
I. SCHEDULE OF STUDY VISITS AND PROCEDURES
I. SCHEDULE OF STUDY VISITS AND PROCEDURES
Trial Period:
Screening
Treatment
Post-Treatment
Trial Phase/Cycle:
Pre-
treatment
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Follow-
up visits7
12-month 
follow-up
Post 12-month 
Follow-up visits7
24-month
follow-up12
Scheduling Window:
-28 to -1
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
Every 12 
weeks
(12 months 
from C1D1 
± 3 days)
Every 12 weeks
(24 months from 
C1D1 ± 3 days)
Study informed consent0
X
Inclusion/Exclusion criteria
X
Demographics and medical 
history
X2
Calculate PSA doubling time
X3
Prior and concomitant medication 
review
X
X
X
X
X
X
X
X
X
X
X
Review adverse events
X
X
X
X
X
X
X
X
X
X
X
RANDSF-36 QOL survey
X
X
X
X
X
X
IIEF QOL survey
X
X
X
X
X
X
Full physical examination
X
Targeted physical examination
X
X
X
X
X
X
X
X
X
X
Vital signs and weight
X
X
X
X
X
X
X
X
X
X
ECG8
X
As clinically indicated
ECOG performance status
X
X
X
X
X
X
X
X
X
X
CT chest, abdomen, pelvis
X4
Bone scan
X4
Repeat if increase in PSA by 2 ng/ml and by 25% from baseline not earlier then 12 weeks after start of 
therapy, confirmed by repeat measurement at least 2 weeks later
CDK12, MMRd/MSI-high, HRD 
screening1
X

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Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
101
I. SCHEDULE OF STUDY VISITS AND PROCEDURES
Trial Period:
Screening
Treatment
Post-Treatment
Trial Phase/Cycle:
Pre-
treatment
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Follow-
up visits7
12-month 
follow-up
Post 12-month 
Follow-up visits7
24-month
follow-up12
PSA5
X5
X
X
X
X
X
Testosterone (total and free)
X
PT/INR and aPTT10
X
CBC with differential
X
X
X
X
X
X
X
X
Comprehensive serum chemistry 
panel11
X
X
X
X
X
X
X
X
X
Lactate dehydrogenase 
X
X
X
X
X
X
X
X
Uric Acid
X
X
X
X
X
X
X
X
Magnesium
X
X
X
X
X
X
X
X
GGT
X
X
X
X
X
X
X
X
Urinalysis
X
TSH6
X
X
X6
X
Amylase and Lipase6
X
X
X6
X
Cortisol6
X
X
X6
X
Fasting lipid panel
X
Hepatitis B and C9
X
Study correlates blood
X
X
X
Archival tumor IHC for study 
correlates
X
Patient follow-up contact / Patient 
review for safety
Day 14 (+/- 3 days) of Cycles 1, 2, 3, 4, 
5, 6
Durvalumab administration
 
X
X
X
X
X
X
 
 
Cohort A & B
X
X
X
Olaparib 
dispensation
Cohort C
X
X
X
X
X
X
C-cycle
0 If laboratory or imaging procedures were performed for alternate reasons prior to signing consent, these can be used for screening purposes with consent of the patient. 
However, all screening laboratory and imaging results must have been obtained within 28 days of randomization. 

Clinical Study Protocol
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Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
102
1Screening specifications per Section 10.1.1
2 Record date of diagnosis, stage and primary treatment history
3 Can be obtained from following online calculator: http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx
4 Within 6 weeks before study therapy start day. For patients that don’t have imaging done before consent, it will be done on the study after confirmation of lfCDK12 or 
MMRd/MSI-high or HRD eligibility
5 Repeat PSA only if >28 days from screening PSA/most recent PSA. 
6 TSH, amylase, lipase and cortisol need only be checked at pre-treatment, 3, 6, 9 and 12 months (not necessary for every 12 weeks after 12 months)
7 First follow-up visit will be 2 weeks after last treatment dose for 24-week PSA and QOL survey
8 Any clinically significant abnormalities detected require triplicate ECG (electrocardiogram) results 
9 HBsAg; anti–HCV antibody with reflexive an HCV RNA
10 For patients on warfarin INR be monitored at least once per week for the first month, then monthly if the INR is stable 
11 Creatinine clearance will be measured by Cockcroft-Gault equation or based on a 24-hour urine test. 24 urine test could be added at any point CMP is performed at the 
discretion on Study Physician. 
12 Participants who withdraw consent from the study prior to scheduled end date will be offered a study withdrawal visit and will have all evaluations planned to be 
performed at 24-month follow up visit and also have CMP at 30 days (±3 days), 2 months (±1 week) and 3 months (±1 week) after permanent discontinuation of study 
treatment.

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Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
103
II. COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V5.0
CTCAE Terms
An Adverse Event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. An AE is a term that 
is a unique representation of a specific event used for medical documentation and scientific analyses. Each CTCAE v4.0 term is a MedDRA LLT 
(Lowest Level Term).
Grades
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this 
general guideline: 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL*. 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL**. 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
Grade 5 Death related to AE.
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.

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Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
104
III. RANDSF-36 SURVEY
SF-36 Survey
Date:
  /   /
Patient’s Name
Visit:
□ baseline
  3 month   □ 6 month     □ 9 month      □ 12 month
INSTRUCTIONS: Please answer every question. Some questions may look like others, but each one is different. Please take the time to read and 
answer each question carefully by circling the number that best represents your response.
1. In general, would you say your health is?
Excellent
(1)
Very 
Good
(2)
Good
(3)
Fair
(4)
Poor
(5)
2. Compared to one year ago, how would you rate your health in general now?
Much better now 
than one year ago
Somewhat better 
now 
than 
one 
year ago
About the same 
as one year ago
Somewhat worse 
now 
than 
one 
year ago
Much worse now 
than one year ago

Clinical Study Protocol
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Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
105
(1)
(2)
(3)
(4)
(5)
3. The following questions are about activities you might do during a typical day. Does your health now limit you in these activities? If so, how 
much: (circle one number on each line)
Yes, 
Limited A 
Lot
Yes, 
Limited A 
Little
No, 
Not 
Limited 
At All
A. Vigorous activities, such as running, lifting heavy 
objects participating in strenuous sports
1
2
3
B. Moderate activities, such as moving a table, pushing a 
vacuum cleaner, bowling, or playing golf
1
2
3
C. Lifting or carrying groceries 
1
2
3
D. Climbing several flights of stairs
1
2
3
E. Climbing one flight of stairs
1
2
3
F. Bending, kneeling, or stooping
1
2
3
G. Walking more than a mile
1
2
3
H. Walking several hundred yards
1
2
3
I. Walking one hundred yards
1
2
3
J. Bathing or dressing yourself
1
2
3

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
106
4. During the past 4 weeks, how much of the time have you had any of the following problems with your work or other regular daily activities 
as a result of your physical health? (Circle one number on each line) 
All the 
time
Most of 
the time
Some 
of 
the 
time
A little 
of 
the 
time
None 
of 
the 
time
A. Cut down on the amount of time you 
spend on work or other activities
1
2
3
4
5
B. Accomplished less than you would like
1
2
3
4
5
C. Were limited in the kind of work or other 
activities 
1
2
3
4
5
D. Had difficulty performing the work or 
other activities (for example, it took extra 
effort)
1
2
3
4
5
5. During the past 4 weeks, how much of the time have you had any of the following problems with your work or other regular daily activities 
as a result of any emotional problems (such as feeling depressed or anxious)? (Circle one number on each line)
All the 
time
Most of 
the time
Some 
of 
the 
time
A little 
of 
the 
time
None 
of 
the 
time

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
107
A. Cut down on the amount of time you 
spend on work or other activities
1
2
3
4
5
B. Accomplished less than you would like
1
2
3
4
5
C. Did work or activities less carefully than 
usual 
1
2
3
4
5
6. During the past 4 weeks, to what extent has your physical health or emotional problems interfered with your social activities with family, 
friends, neighbors, or groups? (Circle one)
Not at all
(1)
Slightly
(2)
Moderately
(3)
Quite 
a 
bit
(4)
Extremely 
(5)
7. How much bodily pain have you had during the past 4 weeks? (Circle one)
None
(1)
Very 
Mild
(2)
Mild
(3)
Moderate 
(4)
Severe
(5)
Very Severe 
(6)
8. During the past 4 weeks, how much did pain interfere with your normal work (including both work outside the home and housework)? 
(Circle one)

Clinical Study Protocol
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Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
108
Not at all
(1)
Slightly
(2)
Moderately
(3)
Quite 
a 
bit
(4)
Extremely 
(5)
9. These questions are about how you feel and how things have been with you during the past 4 weeks. For each question, please give the one 
answer that comes closest to the way you have been feeling. How much of the time during the past 4 weeks… (Circle one number on each line)
All the 
time
Most of 
the time
Some 
of 
the 
time
A little 
of 
the 
time
None 
of 
the 
time
A. did you feel full of life?
1
2
3
4
5
B. have you been very nervous?
1
2
3
4
5
C. have you felt so down in the dumps nothing 
could cheer you up?
1
2
3
4
5
D. have you felt calm and peaceful?
1
2
3
4
5
E. did you have a lot of energy?
1
2
3
4
5
F. have you felt downhearted and depressed?
1
2
3
4
5
G. did you feel worn out?
1
2
3
4
5
H. have you been happy?
1
2
3
4
5
I. did you feel tired?
1
2
3
4
5

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
109
10. During the past 4 weeks, how much of the time has your physical health or emotional problems interfered with your social activities (like 
visiting friends, relatives, etc.)?
All of the Time
(1)
Most of the Time
(2)
Some of the Time
(3)
A Little of the 
Time
(4)
None of the Time
(5)
11. How TRUE or FALSE is each of the following statements for you? (Circle one number on each line)
Definitely 
True
Mostly 
True
Don’t 
Know
Mostly 
False
Definitely 
False
A. I seem to get sick a little easier than other 
people
1
2
3
4
5
B. I am as healthy as anybody I know
1
2
3
4
5
C. I expect my health to get worse
1
2
3
4
5
D. My health is excellent
1
2
3
4
5
IV. RANDSF-36 SURVEY SCORING
Scoring the RAND 36-Item Health Survey is a two-step process. First, precoded numeric values are recoded per the scoring key given in Table 17. 
Note that all items are scored so that a high score defines a more favorable health state. In addition, each item is scored on a 0 to 100 range so that the 
lowest and highest possible scores are 0 and 100, respectively. Scores represent the percentage of total possible score achieved. In step 2, items in the 
same scale are averaged together to create the 8 scale scores. Table3 lists the items averaged together to create each scale. Items that are left blank 

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
110
(missing data) are not taken into account when calculating the scale scores. Hence, scale scores represent the average for all items in the scale that the 
respondent answered.
Example: Items 20 and 32 are used to score the measure of social functioning. Each of the two items has 5 response choices. However, a high score 
(response choice 5) on item 20 indicates the presence of limitations in social functioning, while a high score (response choice 5) on item 32 indicates 
the absence of limitations in social functioning. To score both items in the same direction, Table 17 shows that responses 1 through 5 for item 20 
should be recoded to values of 100, 75, 50, 25, and 0, respectively. Responses 1 through 5 for item 32 should be recoded to values of 0, 25, 50, 75, 
and 100, respectively. Table 18 shows that these two recoded items should be averaged together to form the social functioning scale. If the 
respondent is missing one of the two items, the person's score will be equal to that of the non-missing item.
Table 19 presents information on the reliability, central tendency, and variability of the scales scored using this method.
Table 17. Step 1: Recoding Items
Item numbers
Change original
response category *
To recoded
value of:
1, 2, 20, 22, 34, 36
1 →
100
2 →
75
3 →
50
4 →
25
5 →
0
3, 4, 5, 6, 7, 8, 9, 10, 11, 12
1 →
0
2 →
50
3 →
100

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
111
13, 14, 15, 16, 17, 18, 19
1 →
0
2 →
100
21, 23, 26, 27, 30
1 →
100
2 →
80
3 →
60
4 →
40
5 →
20
6 →
0
24, 25, 28, 29, 31
1 →
0
2 →
20
3 →
40
4 →
60
5 →
80
6 →
100
32, 33, 35
1 →
0
2 →
25

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
112
3 →
50
4 →
75
5 →
100
* Precoded response choices as printed in the questionnaire.
Table 18
Step 2: Averaging Items to Form Scales
Scale
Number of itemsAfter recoding per Table 1, 
average the following items
Physical functioning
10
3 4 5 6 7 8 9 10 11 12
Role limitations due to physical health
4
13 14 15 16
Role limitations due to emotional problems
3
17 18 19
Energy/fatigue
4
23 27 29 31
Emotional well-being
5
24 25 26 28 30
Social functioning
2
20 32
Pain
2
21 22

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Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
113
General health
5
1 33 34 35 36
Table 19
Reliability, Central Tendency, and Variability of Scales in the Medical Outcomes Study
Scale
ItemsAlphaMean SD
Physical functioning
10
0.93 70.61 27.42
Role functioning/physical
4
0.84 52.97 40.78
Role functioning/emotional
3
0.83 65.78 40.71
Energy/fatigue
4
0.86 52.15 22.39
Emotional well-being
5
0.90 70.38 21.97
Social functioning
2
0.85 78.77 25.43
Pain
2
0.78 70.77 25.46
General health
5
0.78 56.99 21.11
Health change
1
—
59.14 23.12

Cli nical St u d y Pr ot oc ol
I n vesti gati o nal Dr u g S u bsta nce:  , Ola pari b ( A Z D 2 2 8 1)
St u d y N u m ber E S R- 1 9- 1 4 5 4 5
E diti o n N u m ber V 9
Date: 1 1/ 2 5/ 2 0 2 2 
1 1 4
V. I N T E R N A TI O N A L I N D E X O F E R E C TI L E F U N C TI O N (II E F)
T hese q uesti o ns as k a b o ut t he effects t hat y o ur erecti o n pr o ble ms ha ve ha d o n y o ur se x life o ver t he last f o ur wee ks. Please tr y t o a ns wer t he q uesti o ns 
as h o nestl y a n d as clearl y as y o u are a ble. Y o ur a ns wers will hel p y o ur d oct or t o c h o ose t he m ost effecti ve treat me nt s uite d t o y o ur c o n diti o n. I n 
a ns weri n g t he q uesti o ns, t he f oll o wi n g defi niti o ns a p pl y: - se x ual acti vit y i ncl u des i nterc o urse, caressi n g, f ore pla y & mast ur bati o n - se x ual i nterc o urse 
is defi ne d as se x ual pe netrati o n of y o ur part ner - se x ual sti m ulati o n i ncl u des sit uati o n s uc h as f ore pla y, er otic pict ures etc. - ejac ulati o n is t he ejecti o n 
of se me n fr o m t he pe nis ( or t he feeli n g of t his) - or gas m is t he f ulfil me nt or cli ma x f oll o wi n g se x ual sti m ulati o n or i nterc o urse
O V E R T H E P A S T 4 W E E K S C H E C K O N E B O X O N L Y
 Q 1
H o w ofte n were y o u a ble t o get a n erecti o n d uri n g se x ual acti vit y?
0 N o se x ual acti vit y 
1 Al m ost ne ver or ne ver 
2 A fe w ti mes (less t ha n half t he ti me) 
3 S o meti mes (a b o ut half t he ti me) 
4 M ost ti mes ( m ore t ha n half t he ti me)
5 Al m ost al wa ys or al wa ys
 Q 2
W he n y o u ha d erecti o ns wit h se x ual sti m ulati o n, h o w ofte n were 
y o ur erecti o ns har d e n o u g h f or pe netrati o n?
0 N o se x ual acti vit y 
1 Al m ost ne ver or ne ver 
2 A fe w ti mes (less t ha n half t he ti me) 
3 S o meti mes (a b o ut half t he ti me) 
4 M ost ti mes ( m ore t ha n half t he ti me)
5 Al m ost al wa ys or al wa ys

Cli nical St u d y Pr ot oc ol
I n vesti gati o nal Dr u g S u bsta nce:  , Ola pari b ( A Z D 2 2 8 1)
St u d y N u m ber E S R- 1 9- 1 4 5 4 5
E diti o n N u m ber V 9
Date: 1 1/ 2 5/ 2 0 2 2 
1 1 5
 Q 3
W he n y o u atte m pte d i nterc o urse, h o w ofte n were y o u a ble t o 
pe netrate (e nter) y o ur part ner?
0 Di d n ot atte m pt i nterc o urse 
1 Al m ost ne ver or ne ver 
2 A fe w ti mes (less t ha n half t he ti me) 
3 S o meti mes (a b o ut half t he ti me) 
4 M ost ti mes ( m ore t ha n half t he ti me) 
5 Al m ost al wa ys or al wa ys
 Q 4
D uri n g se x ual i nterc o urse, h o w ofte n were y o u a ble t o mai ntai n 
y o ur erecti o n after y o u ha d pe netrate d (e ntere d) y o ur part ner?
0 Di d n ot atte m pt i nterc o urse 
1 Al m ost ne ver or ne ver 
2 A fe w ti mes (less t ha n half t he ti me) 
3 S o meti mes (a b o ut half t he ti me) 
4 M ost ti mes ( m ore t ha n half t he ti me) 
5 Al m ost al wa ys or al wa ys
 Q 5
D uri n g se x ual i nterc o urse, h o w diffic ult was it t o mai ntai n y o ur 
erecti o n t o c o m pleti o n of i nterc o urse?
0 Di d n ot atte m pt i nterc o urse 
1 Al m ost ne ver or ne ver 
2 A fe w ti mes (less t ha n half t he ti me) 
3 S o meti mes (a b o ut half t he ti me) 
4 M ost ti mes ( m ore t ha n half t he ti me) 

Cli nical St u d y Pr ot oc ol
I n vesti gati o nal Dr u g S u bsta nce:  , Ola pari b ( A Z D 2 2 8 1)
St u d y N u m ber E S R- 1 9- 1 4 5 4 5
E diti o n N u m ber V 9
Date: 1 1/ 2 5/ 2 0 2 2 
1 1 6
5 Al m ost al wa ys or al wa ys
 Q 6
H o w ma n y ti mes ha ve y o u atte m pte d se x ual i nterc o urse?
0 N o atte m pts 
1 O ne t o t w o atte m pts 
2 T hree t o f o ur atte m pts 
3 Fi ve t o si x atte m pts 
4 Se ve n t o te n atte m pts 
5 Ele ve n or m ore atte m pts
 Q 7
W he n y o u atte m pte d se x ual i nterc o urse, h o w ofte n 
was it 
satisfact or y f or y o u?
0 Di d n ot atte m pt i nterc o urse 
1 Al m ost ne ver or ne ver 
2 A fe w ti mes (less t ha n half t he ti me) 
3 S o meti mes (a b o ut half t he ti me) 
4 M ost ti mes ( m ore t ha n half t he ti me) 
5 Al m ost al wa ys or al wa ys
 Q 8
H o w m uc h ha ve y o u e nj o ye d se x ual i nterc o urse?
0 N o i nterc o urse 
1 N o e nj o y me nt at all 
2 N ot ver y e nj o ya ble 
3 Fairl y e nj o ya ble 

Cli nical St u d y Pr ot oc ol
I n vesti gati o nal Dr u g S u bsta nce:  , Ola pari b ( A Z D 2 2 8 1)
St u d y N u m ber E S R- 1 9- 1 4 5 4 5
E diti o n N u m ber V 9
Date: 1 1/ 2 5/ 2 0 2 2 
1 1 7
4 Hi g hl y e nj o ya ble 
5 Ver y hi g hl y e nj o ya ble
 Q 9
W he n y o u ha d se x ual sti m ulati o n or i nterc o urse, h o w ofte n di d 
y o u ejac ulate?
0 N o se x ual sti m ulati o n or i nterc o urse 
1 Al m ost ne ver or ne ver 
2 A fe w ti mes (less t ha n half t he ti me) 
3 S o meti mes (a b o ut half t he ti me) 
4 M ost ti mes ( m ore t ha n half t he ti me) 
5 Al m ost al wa ys or al wa ys
 Q 1 0
W he n y o u ha d se x ual sti m ulati o n or i nterc o urse, h o w ofte n di d 
y o u ha ve t he feeli n g of or gas m or cli ma x?
1 Al m ost ne ver or ne ver 
2 A fe w ti mes (less t ha n half t he ti me) 
3 S o meti mes (a b o ut half t he ti me) 
4 M ost ti mes ( m ore t ha n half t he ti me) 
5 Al m ost al wa ys or al wa ys
 Q 1 1
H o w ofte n ha ve y o u felt se x ual desire?
1 Al m ost ne ver or ne ver 
2 A fe w ti mes (less t ha n half t he ti me) 
3 S o meti mes (a b o ut half t he ti me) 
4 M ost ti mes ( m ore t ha n half t he ti me) 

Cli nical St u d y Pr ot oc ol
I n vesti gati o nal Dr u g S u bsta nce:  , Ola pari b ( A Z D 2 2 8 1)
St u d y N u m ber E S R- 1 9- 1 4 5 4 5
E diti o n N u m ber V 9
Date: 1 1/ 2 5/ 2 0 2 2 
1 1 8
5 Al m ost al wa ys or al wa ys
 Q 1 2
H o w w o ul d y o u rate y o ur le vel of se x ual desire?
1 Ver y l o w or n o ne at all 
2 L o w 
3 M o derate 
4 Hi g h 
5 Ver y hi g h
 Q 1 3
H o w satisfie d ha ve y o u bee n wit h y o ur o verall se x life?
1 Ver y dissatisfie d 
2 M o deratel y dissatisfie d 
3 E q uall y satisfie d & dissatisfie d 
4 M o deratel y satisfie d 
5 Ver y satisfie d
 Q 1 4
H o w satisfie d ha ve y o u bee n wit h y o ur se x ual relati o ns hi p wit h 
y o ur part ner?
1 Ver y dissatisfie d 
2 M o deratel y dissatisfie d 
3 E q uall y satisfie d & dissatisfie d 
4 M o deratel y satisfie d 
5 Ver y satisfie d

Cli nical St u d y Pr ot oc ol
I n vesti gati o nal Dr u g S u bsta nce:  , Ola pari b ( A Z D 2 2 8 1)
St u d y N u m ber E S R- 1 9- 1 4 5 4 5
E diti o n N u m ber V 9
Date: 1 1/ 2 5/ 2 0 2 2 
1 1 9
 Q 1 5
H o w d o y o u rate y o ur c o nfi de nce t hat y o u c o ul d get a n d kee p a n 
erecti o n?
1 Ver y l o w 
2 L o w 
3 M o derate 
4 Hi g h 
5 Ver y hi g h

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
120
VI. ASSESMENT OF INTERNATIONAL INDEX OF ERECTILE FUNCTION (IIEF)
The 15-question International Index of Erectile Function (IIEF) Questionnaire is a validated, multidimensional, self-administered investigation that 
has been found useful in the clinical assessment of erectile dysfunction and treatment outcomes in clinical trials. A score of 0-5 is awarded to each of 
the 15 questions that examine the 4 main domains of male sexual function: erectile function, orgasmic function, sexual desire and intercourse 
satisfaction. Scores are awarded according to the number 0-5 next to the answer, the higher the score the more distress patient is experiencing. 
In a study,(62) the IIEF Questionnaire was tested in a series of 111 men with sexual dysfunction and 109 age-matched, normal volunteers. The 
following mean scores were recorded: 

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
121
VII. PILL DIARY
 Durvalumab and Olaparib for treatment of biochemically recurrent prostate cancer in men predicted to have a high neoantigen load: a 
multicenter pilot phase 2 study 
Dates _______/________/________ to ________/________/________                                 Cycle #: _____
Subject ID: _____________________
      Patient Initials: ________________
PLEASE FILL OUT AND BRING THIS SHEET AT YOUR NEXT VISIT
Instructions for olaparib tablets:

should be taken at the dose of _______ twice a day orally 

should be taken at the same time each day, approximately 12 hours apart with one glass of water

should be swallowed whole and not chewed, crushed, dissolved or divided

can be taken with or without food

if vomiting occurs shortly after the olaparib tablets are swallowed, and all intact tablets can be seen and counted in the vomit, take the dose again 

if you miss a scheduled dose, you may 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 usual dose at the next scheduled time.
Please return all unused study medication to your research nurse.
Please complete this section for your current cycle.
Day
Date
Did you take your AM dose of agent 
(circle YES or NO)
Did you take your PM dose of agent (circle 
YES or NO)
Example
1/1/2016
YES / NO
YES / NO
1
YES / NO
YES / NO
2
YES / NO
YES / NO
3
YES / NO
YES / NO
4
YES / NO
YES / NO

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
122
5
YES / NO
YES / NO
6
YES / NO
YES / NO
7
YES / NO
YES / NO
8
YES / NO
YES / NO
9
YES / NO
YES / NO
10
YES / NO
YES / NO
11
YES / NO
YES / NO
12
YES / NO
YES / NO
13
YES / NO
YES / NO
14
YES / NO
YES / NO
15
YES / NO
YES / NO
16
YES / NO
YES / NO
17
YES / NO
YES / NO
18
YES / NO
YES / NO
19
YES / NO
YES / NO
20
YES / NO
YES / NO
21
YES / NO
YES / NO

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
123
22
YES / NO
YES / NO
23
YES / NO
YES / NO
24
YES / NO
YES / NO
25
YES / NO
YES / NO
26
YES / NO
YES / NO
27
YES / NO
YES / NO
28
YES / NO
YES / NO
Patient Signature: ________________________________________________________________   
Date: _____________________________
MD/RN Signature: ________________________________________________________________  
Date: _____________________________
Comments:_________________________________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________________________

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
124
VIII. DURVALUMAB TOXICITY MANAGEMENT GUIDELINE TABLES 
Dosing Modification and Toxicity Management Guidelines (TMGs) for Durvalumab Monotherapy, Durvalumab in 
Combination with other Products, or Tremelimumab Monotherapy – 28 October 2022
General Considerations regarding Immune-Mediated Reactions
These guidelines are provided as a recommendation to support investigators in the management of potential immune-mediated adverse events (imAEs).
Immune-mediated events can occur in nearly any organ or tissue, therefore, these guidelines may not include all the possible immune-mediated reactions. Investigators 
are advised to take into consideration the appropriate practice guidelines and other society guidelines (e.g., National Comprehensive Cancer Network (NCCN), European 
Society of Medical Oncology (ESMO)) in the management of these events. Refer to the section of the table titled “Other -Immune-Mediated Reactions” for general 
guidance on imAEs not noted in the “Specific Immune-Mediated Reactions” section.
Early identification and management of imAEs is essential to ensure safe use of the study drug. Monitor patients closely for symptoms and signs that may be clinical 
manifestations of underlying imAEs. Patients with suspected imAEs should be thoroughly evaluated to rule out any alternative etiologies (e.g., disease progression, 
concomitant medications, infections). In the absence of a clear alternative etiology, all such events should be managed as if they were immune-mediated. Institute 
medical management promptly, including specialty consultation as appropriate. In general, withhold study drug/study regimen for severe (Grade 3) imAEs. Permanently 
discontinue study drug/study regimen for life-threatening (Grade 4) imAEs, recurrent severe (Grade 3) imAEs that require systemic immunosuppressive treatment, or an 
inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.
Based on the severity of the imAE, durvalumab and/or tremelimumab should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, 
corticosteroid should be tapered over ≥ 28 days. More potent immunosuppressive agents should be considered for events not responding to systemic steroids. 
Alternative immunosuppressive agents not listed in this guideline may be considered at the discretion of the investigator based on clinical practice and relevant 
guidelines. With long- term steroid and other immunosuppressive use, consider the need for glucose monitoring. Dose modifications of study drug/study regimen should 
be based on severity of treatment-emergent toxicities graded per NCI CTCAE version in the applicable study protocol.
Considerations for Prophylaxis for Long Term use of Steroids for Patients Receiving Immune Checkpoint Inhibitor Immunotherapy

Infection Prophylaxis: Pneumocystis jirovecii pneumonia (PJP), antifungal and Herpes Zoster reactivation

Gastritis: Consider prophylaxis for patients at high risk of gastritis (e.g. NSAID use, anticoagulation) when the patient is taking steroid therapy

Osteoporosis: Consider measures for prevention and mitigation of osteoporosis .
Relevant Society Guidelines for Management of imAEs

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
125
These society guidelines are provided as references to serve in support of best clinical practice and the TMGs. Please note, these were the current versions of these guidelines at 
the time of updating TMGs. Please refer to the most up to date version of these guidelines.
1.
Brahmer JR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother 
Cancer 2021;9:e002435
2.
Brahmer JR, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical 
Oncology Clinical Practice Guideline. J Clin Oncol 2018;36(17):1714-1768.
3.
Haanen JBAG, et al. Management of toxicities for immunotherapy: European Society for Medical Oncology (ESMO) clinical practice guidelines for diagnosis, 
treatment, and follow-up. Annals Oncol 2017;28(Suppl4):i119-i1142.
4.
Sangro B, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol 2020;72(2):320-341.
5.
Thompson JA, et al. National Comprehensive Cancer Network Guidelines: Management of immunotherapy-related toxicities version 1.2022. Published February 
28, 2022.

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
126
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event (NCI CTCAE 
version 5.0)
Dose Modifications
Toxicity Management
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade:
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology with similar clinical presentation (e.g., 
infection, progressive disease)
−
Monitor patients for signs (e.g., tachypnoea) and symptoms of 
pneumonitis or ILD (new onset or worsening shortness of 
breath or cough). Evaluate Patients with imaging and 
pulmonary function tests, including other diagnostic procedures 
as described below.
−
Suspected pneumonitis should be confirmed with radiographic 
imaging and other infectious and disease-related etiologies  
excluded, and managed as described below.
−
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up (including clinically relevant culture 
specimens to rule out infection), and high- resolution computed 
tomography CT scan.
−
Consider Pulmonary and Infectious Diseases consults
Grade 1

No dose modifications required. 
However, consider holding study 
drug/study regimen dose as clinically 
appropriate and during diagnostic 
work-up for other etiologies.
For Grade 1:
−
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, pulse oximetry (resting and exertion), and 
laboratory work-up and then as clinically indicated.
Pneumonitis/Interstitial 
Lung Disease (ILD)
Grade 2

Hold study drug/study regimen dose 
until Grade 2 resolution to Grade ≤1.

If toxicity improves to Grade ≤1, 
then the decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper (<10 mg prednisone or 
equivalent).
For Grade 2:
−
Monitor symptoms daily and consider hospitalization, as 
clinically indicated. 
−
Consider Pulmonary and Infectious Diseases Consults; 
−
Promptly start systemic steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV equivalent).
−
Consider HRCT or chest CT with contrast, repeat imaging 
study as clinically indicated.

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
127
−
If no improvement within 2 to 3 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started
−
If no improvement within 2 to 3 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as tumor necrosis factor 
(TNF) inhibitors (e.g., infliximab at 5 mg/kg  IV once, may be 
repeated at 2 and 6 weeks after initial dose at the discretion of 
the treating provider or relevant practice guidelines ). Caution: 
It is important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. Consider, as 
necessary, discussing with Clinical Study Lead.
Grade 3 or 4

Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:
−
Hospitalize the patient. 
−
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent.
−
Obtain Pulmonary and Infectious Disease consults; consider 
discussing with Clinical Study Lead, as needed.
−
Consider starting anti-infective therapy if infection is still a 
consideration on the basis of other diagnostic testing despite 
negative culture results. 
−
Supportive care (e.g., oxygen).
−
If no improvement within 2 days, additional workup should be 
considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg IV, may be repeated at 2 and 6 
weeks after initial dose at the discretion of the treating provider 
or relevant practice guidelines). Caution: rule out sepsis and 
refer to infliximab label for general guidance before using 
infliximab.
Diarrhea/Colitis
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
General Guidance
For Any Grade:
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections), including testing for clostridium 
difficile toxin, etc.

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
128
defining the CTCAE 
grade/severity)
−
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes in 
bowel habits such as increased frequency over baseline or 
blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs, and ileus).
−
Consider further evaluation with imaging study with contrast.
−
Consult a gastrointestinal (GI) specialist for consideration of 
further workup.
-
When symptoms or evaluation indicate a perforation is 
suspected, consult a surgeon experienced in abdominal 
surgery immediately without any delay. 
-
PERMANENTLY DISCONTINUE STUDY DRUG FOR 
ANY GRADE OF INTESTINAL PERFORATION.
−
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order to 
prevent potential progression to higher grade event, including 
perforation. 
−
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis.
Grade 1

No dose modifications.
For Grade 1:
−
Monitor closely for worsening symptoms.
−
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), loperamide, and other 
supportive care measures. 
−
If symptoms persist, consider checking lactoferrin; if positive, 
treat as Grade 2 below. If negative and no infection, continue 
Grade 1 management
Grade 2

Hold study drug/study regimen until 
resolution to Grade ≤1

If toxicity improves to Grade ≤1, 
then study drug/study regimen can be 
resumed after completion of steroid 
taper (<10 mg prednisone, or 
equivalent).
For Grade 2:
−
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide.
−
Consider further evaluation with imaging study with contrast.
−
Consider consult of a gastrointestinal (GI) specialist for 
consideration of further workup.
−
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
129
−
If no improvement within 3 days despite therapy with 1 to 2 
mg/kg IV prednisone equivalent, reconsult GI specialist and, if 
indicated, promptly start additional immunosuppressant agent 
such as infliximab at 5 mg/kg IV, may be repeated at 2 and 6 
weeks after initial dose at the discretion of the treating provider 
or relevant practice guidelines Caution: it is important to rule 
out bowel perforation and refer to infliximab label for general 
guidance before using infliximab.
−
If perforation is suspected, consult a surgeon experienced in 
abdominal surgery immediately without any delay.
−
Consider, as necessary, discussing with Clinical Study Lead if 
no resolution to Grade ≤1 in 3 to 4 days.
Grade 3 or 4
Grade 3

For patients treated with durvalumab 
monotherapy, hold study drug/study 
regimen until resolution to Grade ≤1; 
study drug/study regimen can be 
resumed after completion of steroid 
taper (<10 mg prednisone per day, or 
equivalent 

For patients treated with durvalumab 
in combination with other products 
(not tremelimumab), decision to be 
made at the discretion of the study 
investigator, in discussion with 
AstraZeneca Clinical Study Lead.

For patients treated with durvalumab 
in combination with tremelimumab 
or tremelimumab monotherapy, 
Permanently discontinue both 
durvalumab and tremelimumab for 1) 
Grade 3 diarrhea colitis or 2) Any 
grade of intestinal perforation.
Grade 4
For Grade 3 or 4:
−
Urgent GI consult and imaging and/or colonoscopy as 
appropriate.
−
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent.
−
Monitor stool frequency and volume and maintain hydration.
−
If still no improvement within 2 days, continue steroids and 
promptly add further immunosuppressants. (e.g., infliximab at 
5 mg/kg IV, may be repeated at 2 and 6 weeks after initial dose 
at the discretion of the treating provider or relevant practice 
guidelines). Caution: Ensure GI consult to rule out bowel 
perforation and refer to infliximab label for general guidance 
before using infliximab. 
−
If perforation is suspected, consult a surgeon experienced in 
abdominal surgery immediately without any delay.

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
130

Permanently discontinue 
study drug/study regimen. 
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to rule out any 
alternative etiologies (e.g., viral hepatitis, disease progression, 
concomitant medications).
−
Monitor and evaluate transaminases (aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], 
alkaline phosphatase [ALP]), and total bilirubin. 
ALT or AST ≤ 3 x
ULN or total bilirubin
≤ 1.5 x ULN 

No dose modifications.

If it worsens, then consider holding 
therapy. 
                                  
−
Continue transaminase and total bilirubin  monitoring per 
protocol.
ALT or AST > 3 ≤ 5 x
ULN or total bilirubin
> 1.5 ≤ 3 x ULN

Hold study drug/study regimen dose 
until ALT or  AST  ≤  3 x ULN or 
total bilirubin  ≤ 1.5 x ULN. Resume 
study drug/study regimen after 
completion of steroid taper (<10 mg 
prednisone or equivalent).

Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law laboratory criteria 
(AST or ALT ≥3 × ULN AND 
bilirubin ≥2 × ULN without initial 
findings of cholestasis (i.e., elevated 
ALP) and in the absence of any 
alternative cause.
−
Regular and frequent checking of transaminases and total 
bilirubin  (e.g., every 1 to 2 days) until transaminases and total 
bilirubin elevations improving or resolve.
−
If no resolution to ALT or AST  ≤  3 x ULN or total bilirubin ≤ 
1.5 x ULN in 1 to 2 days, consider discussing with Clinical 
Study Lead, as needed.
−
If event is persistent (>2 to 3 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent.
Hepatitis 
Infliximab should not be 
used for management of 
immune-related hepatitis.
ALT or AST
> 5 ≤ 10 x ULN

Hold study drug/study regimen. 
Resume study drug/study regimen if 
elevations downgrade to ALT or 
AST ≤ 3 x ULN or total bilirubin ≤ 
1.5 x ULN after completion of 
−
Promptly initiate empiric IV methylprednisolone at 1 to 
2 mg/kg/day or equivalent.
−
Perform Hepatology consult, abdominal workup, and imaging 
as appropriate.
−
If still no improvement within 2 to 3 days despite 1 to 
2 mg/kg/day methylprednisolone IV or equivalent, promptly 
PLEASE SEE 
shaded area 
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in 
hepatocellular 
carcinoma (HCC) 
patients (or 
secondary tumour 
involvement of the 
liver with abnormal 
baseline values 
[BLV])

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
131
Concurrent ALT or
AST > 3 x ULN and
total bilirubin
> 2 x ULNd
ALT or AST
> 10 x ULN OR total
bilirubin > 3 x
ULN
steroid taper (<10 mg prednisone, or 
equivalent).

If in combination with 
tremelimumab, do not restart 
tremelimumab. 

Permanently discontinue study 
drug/study regimen.
start treatment with an additional immunosuppressive (e.g., 
mycophenolate mofetil 0.5 – 1 g every 12 hours then taper in 
consultation with hepatology consult or relevant practice 
guidelines). Discuss with Clinical Study Lead if mycophenolate 
is not available. Infliximab should NOT be used.
-
Promptly initiate empiric IV methylprednisolone at 1 to 2 
mg/kg/day or equivalent.
-
If still no improvement within 2 to 3 days despite 1 to 2 
mg/kg/day methylprednisolone IV or equivalent, promptly start 
treatment with an additional immunosuppressant.(e.g., 
mycophenolate mofetil 0.5 – 1 g every 12 hours then taper in 
consultation with hepatology consult or relevant practice 
guidelines). Discuss with Clinical Study Lead if mycophenolate 
is not available. Infliximab should NOT be used.

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
132
Any Elevations of 
AST, ALT, or T. Bili 
as Described Below
General Guidance
For Any Elevations Described:
−
Patients should be thoroughly evaluated to rule out any 
alternative etiologies (e.g., viral hepatitis, disease progression, 
concomitant medications, worsening of liver cirrhosis [e.g., 
portal vein thrombosis]).
−
Monitor and evaluate liver function test: AST, ALT, ALP, and 
T. Bili.
−
For hepatitis B (HBV)+ patients: evaluate quantitative HBV 
viral load, quantitative Hepatitis B surface antigen (HBsAg), or 
Hepatitis B envelope antigen (HBeAg).
−
For hepatitis C (HCV)+ patients: evaluate quantitative HCV 
viral load
−
Consider consulting hepatology or Infectious Disease 
specialists regarding changing or starting antiviral HBV 
medications if HBV viral load is >2000 IU/ml
−
Consider consulting hepatology or Infectious Disease 
specialists regarding changing or starting antiviral HCV 
medications if HCV viral load increased by ≥2-fold
−
For HCV+ with Hepatitis B core antibody (HBcAb) +: 
Evaluate for both HBV and HCV as above
Hepatitis 
(elevated transaminases 
and total bilirubin)
Infliximab should not be 
used for management of 
immune-related hepatitis. 
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any 
time) occurs in setting 
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation
THIS shaded area 
is guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients (or 
secondary tumour 
involvement of the 
liver with abnormal 
baseline values 
[BLV])

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
133
Isolated AST or ALT > 
ULN and ≤ 2. 5 x 
BLV.

No dose modifications. 

If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat 
as described for elevations in the 
row below. 

For all transaminase elevations, see 
instructions at bottom of shaded 
area if transaminase rise is not 
isolated but (at any time) occurs in 
setting of either increasing bilirubin 
or signs of BILI/Liver 
decompensation. 
 ALT or AST > 2.5 ≤ 5 
x BLV and ≤ 20×ULN

Hold study drug/study regimen 
dose until resolution to AST or 
ALT ≤2.5.0 x BLV. 

If toxicity worsens then treat as 
described for elevations in the rows 
below. If toxicity improves to AST 
or ALT ≤2.5.0×BLV, resume study 
drug/study regimen after 
completion of steroid taper (<10 
mg prednisone, or equivalent).
−
Regular and frequent checking of Transaminases and total 
bilirubin (e.g., every 1to 3 days) until elevations of these are 
improving or resolved.
−
Recommend consult hepatologist ; consider abdominal 
ultrasound, including Doppler assessment of liver perfusion.
−
Consider, as necessary, discussing with Clinical Study Lead.
−
If event is persistent ( > 2 to 3 days) or worsens, and 
investigator suspects toxicity to be an imAE, start prednisone 1 
to 2 mg/kg/day  PO or IV equivalent.
−
If still no improvement within 2 to 3 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional workup.  If still no improvement within 2 to 3 days 
despite 2mg/kg/day of IV methylprednisolone, consider 
additional abdominal workup (including liver biopsy) and 
imaging (i.e., liver ultrasound), and consider starting additional 
immunosuppressants (e.g., mycophenolate mofetil 0.5 – 1 g 
every 12 hours then taper in consultation with hepatology 
consult or relevant practice guidelines). Discuss Clinical  
Study Lead if mycophenolate mofetil is not available. 
Infliximab should NOT be used.

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
134
ALT or AST
>5-7X BLV and ≤ 20X
ULN OR concurrent
2.5-5X BLV and ≤
20XULN AND total
bilirubin > 1.5 - < 2 x
ULNd

Withhold durvalumab and 
permanently discontinue 
tremelimumab. 

Resume study drug/study 
regimen if elevations 
downgrade to AST or ALT 
≤2.5×BLV and after 
completion of steroid taper 
(<10 mg prednisone, or 
equivalent).

Permanently discontinue study 
drug/study regimen if the 
elevations do not downgrade 
to AST or ALT ≤2.5×BLV 
within 14 days.

Regular and frequent checking of LFTs (e.g., every 1-2 days) 
until elevations of these are improving or resolved.

Consult hepatologist (unless investigator is hepatologist); 
obtain abdominal ultrasound, including Doppler assessment of 
liver perfusion; and consider liver biopsy.

Consider discussing with Clinical Study Lead, as needed.

If investigator suspects toxicity to be immune-mediated, 
promptly initiate empiric IV methylprednisolone at 1 to 2 
mg/kg/day or equivalent.

If no improvement within 2 to 3 days despite 1 to 2 mg/kg/day 
methylprednisolone IV or equivalent, obtain liver biopsy (if it 
has not been done already) and promptly start treatment with 
an additional immunosuppressant. (e.g., mycophenolate 
mofetil 0.5 – 1 g every 12 hours then taper in consultation with 
a hepatologist or relevant practice guidelines). Discuss with 
Study Clinical Lead if mycophenolate is not available.

Infliximab should NOT be used.
ALT or AST
> 7 X BLV OR > 20
ULN whichever occurs
Permanently discontinue study drug/study regimen.                                     Same as above
first OR bilirubin >                                                                                                                                                                (except recommend obtaining liver biopsy early)
3ULN
Nephritis and/or renal 
dysfunction
Any Grade
(Refer to NCI CTCAE
applicable version in
study protocol for
defining the CTCAE
General Guidance
For Any Grade:
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, infections, 
recent IV contrast, medications, fluid status).
−
Consider consulting a nephrologist.
−
Consider imaging studies to rule out any alternative etiology.
−
Monitor for signs and symptoms that may be related to 
changes in renal function (e.g., routine urinalysis, elevated 
serum BUN and creatinine, decreased creatinine clearance, 
electrolyte imbalance, decrease in urine output, or proteinuria).

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
135
grade/severity)
−
Follow urine protein/creatinine ratio every 3-7 days.

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
136
Grade 1

No dose modifications.
For Grade 1:
−
Monitor serum creatinine weekly and any accompanying 
symptoms.

If creatinine returns to baseline, resume regular 
monitoring per study protocol.

If creatinine worsens, depending on the severity, 
treat as Grade 2, 3, or 4.
−
Consider hydration, electrolyte replacement, and diuretics, as 
clinically indicated.
−
Consider nephrologist consult if not resolved within 14 days, 
or earlier as clinically indicated.
Grade 2

Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 

If toxicity improves to Grade ≤1 or 
baseline, then resume study 
drug/study regimen after completion 
of steroid taper (<10 mg prednisone, 
or equivalent).
For Grade 2:
−
Consider including hydration, electrolyte replacement, and 
diuretics, as clinically indicated. 
−
Follow urine protein/creatinine ratio every 3-7 days.
−
Carefully monitor serum creatinine as clinically warranted.
−
Consult nephrologist and consider renal biopsy if clinically 
indicated.
−
Start prednisone 0.5 – 1 mg/kg/day if other causes are ruled 
out.
−
If event is persistent beyond 5 days or worsens, increase 
prednisone up to 2 mg/kg/day PO or IV equivalent.
−
If event is not responsive within 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, consider 
additional workup. When event returns to baseline, resume 
study drug/study regimen and routine serum creatinine 
monitoring per study protocol.
−
Grade 3 or 4

Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:
−
Carefully monitor serum creatinine on daily basis.
−
Follow urine protein/creatinine ratio every 3-7 days.
−
Consult nephrologist and consider renal biopsy if clinically 
indicated.
−
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
137
−
If event is not responsive within 3 to 5 days of steroids or 
worsens despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, consider additional workup and prompt treatment 
with an immunosuppressant.
Any Grade
(Refer to NCI CTCAE
applicable version in
study protocol for
definition of
severity/grade
depending on type of
skin rash) 
General Guidance
For Any Grade:
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology.
−
Monitor for signs and symptoms of dermatitis (rash and 
pruritus).
−
HOLD STUDY DRUG IF GRADE 3 PEMPHIGOID OR 
SEVERE CUTANEOUS ADVERSE REACTION 
(SCAR)1 IS SUSPECTED. 
−
PERMANENTLY DISCONTINUE STUDY DRUG IF 
SCAR OR GRADE 3 PEMPIGOID IS CONFIRMED.
Grade 1

No dose modifications.
For Grade 1:
−
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., emolient, lotion, or institutional standard).
Grade 2
For persistent (>1 weeks) Grade 2 
events, hold scheduled study drug/study 
regimen until resolution to Grade ≤1 or 
baseline.

If toxicity improves to Grade 
≤1 or baseline, then resume 
drug/study regimen after 
completion of steroid taper 
(<10 mg prednisone, or 
equivalent).
For Grade 2:
−
Consider dermatology consult and skin biopsy, as indicated.
−
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy.
−
Consider moderate-strength topical steroid.
−
If no improvement of rash/skin lesions occurs within 1 week 
or is worsening despite symptomatic treatment and/or use of 
moderate strength topical steroid, consider discussing with 
Clinical Study Lead, as needed, and promptly start systemic 
steroids such as prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.
Rash or Dermatitis
(Including Pemphigoid)
Grade 3 
For Grade 3:

Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline.
For Grade 3 
−
Reconsult a dermatologist. Consider skin biopsy (preferably 
more than 1) as clinically feasible.

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
138

If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of steroid 
taper (<10 mg prednisone, or 
equivalent).
−
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent.
−
Consider hospitalization.
−
Monitor the extent of rash [Rule of Nines].
−
Consider, as necessary, discussing with Clinical Study Lead.
Grade 4 
For Grade 4: 

Permanently discontinue study 
drug/study regimen.
For Grade 4
-
Reconsult a dermatologist. Consider skin biopsy (preferably 
more than 1) as clinically feasible. 
-
Promptly initiate empiric IV methylprednisolone 1 to 2 
mg/kg/day or equivalent.
-
Consider hospitalization.
-
Monitor the extent of rash [Rule of Nines].
-
Consider, as necessary, discussing with Clinical Study Lead.
Endocrinopathy
(e.g., hyperthyroidism, 
thyroiditis, 
hypothyroidism, Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency)
Any Grade
(Depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
applicable version in
study protocol for
defining the CTCAE
grade/severity) 
General Guidance
For Any Grade:
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including brain 
metastases, or infections).
−
Consider consulting an endocrinologist for endocrine events.
−
Consider discussing with Clinical Study Lead, as needed.
−
Monitor patients for signs and symptoms of endocrinopathies. 
(Non-specific symptoms include headache, fatigue, behavior 
changes, mental status changes, photophobia, visual field 
cuts, vertigo, abdominal pain, unusual bowel habits, 
polydipsia, polyuria, hypotension, and weakness.)
−
Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: thyroid stimulating hormone 
(TSH), free T3 and free T4 and other relevant endocrine and 
related labs (e.g., blood glucose and ketone levels,  
hemoglobin A1c (HgA1c)). If a patient experiences an AE 
that is thought to be possibly of autoimmune nature (e.g., 

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
139
thyroiditis, pancreatitis, hypophysitis, or diabetes insipidus), 
the investigator should send a blood sample for appropriate 
autoimmune antibody testing.
−
Investigators should ask subjects with endocrinopathies who 
may require prolonged or continued hormonal replacement, to 
consult their primary care physicians or endocrinologists 
about further monitoring and treatment after completion of 
the study. 
Grade 1

No dose modifications.
For Grade 1:
−
Monitor patient with appropriate endocrine function tests.
−
For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment of 
early-morning adrenocorticotropin hormone (ACTH), 
cortisol, TSH and free T4; also consider gonadotropins, sex 
hormones, and prolactin levels, as well as cosyntropin 
stimulation test (though it may not be useful in diagnosing 
early secondary adrenal insufficiency).
−
If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently out 
of range in 2 subsequent measurements, include free T4 at 
subsequent cycles as clinically indicated and consider 
consultation of an endocrinologist.
Grade 2, 3, or 4

For Grade 2-4 endocrinopathies 
other than hypothyroidism and Type 
1 diabetes mellitus (T1DM), 
consider holding study drug/study 
regimen dose until acute symptoms 
resolve.

Study drug/study regimen can be 
resumed once event stabilizes and 
after completion of steroid taper 
(<10 mg prednisone, or equivalent).

Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement (e.g., adrenal 
insufficiency) can be retreated with 
study drug/study regimen if the 
patient is clinically stable as per 
For Grade 2, 3, or 4
−
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan.
−
For all patients with abnormal endocrine work up, except 
those with isolated hypothyroidism or T1DM, and as guided 
by an endocrinologist, consider short-term corticosteroids 
(e.g., 1 to 2 mg/kg/day methylprednisolone or IV equivalent) 
and prompt initiation of treatment with relevant hormone 
replacement.
−
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids.
−
Isolated T1DM may be treated with appropriate diabetic 
therapy, and without corticosteroids. Only hold study 
drug/study regimen in setting of hyperglycemia when 
diagnostic workup is positive for diabetic ketoacidosis.

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
140
investigator or treating physician’s 
clinical judgement. 
−
For patients with normal endocrine workup (laboratory 
assessment or magnetic resonance imaging (MRI) scans), 
repeat laboratory assessments/MRI as clinically indicated.
Amylase/Lipase
increased
Any Grade
(Refer to NCI CTCAE
applicable version in
study protocol for
defining the CTCAE
grade/severity)
General Guidance
  
For Any Grade
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g. disease progression, viral 
infection, concomitant medications, substance abuse).
−
For modest asymptomatic elevations in serum amylase and 
lipase, corticosteroid treatment is not indicated as long as 
there are no other signs or symptoms of pancreatic 
inflammation.
−
Assess for signs/symptoms of pancreatitis
−
Consider appropriate diagnostic testing (e.g., abdominal 
CT with contrast, MRCP if clinical suspicion of 
pancreatitis and no radiologic evidence on CT)
−
If isolated elevation of enzymes without evidence of 
pancreatitis, continue immunotherapy. Consider other 
causes of elevated amylase/lipase
−
If evidence of pancreatitis, manage according to 
pancreatitis recommendations
Grade 1 
No dose modification 
Grade 2, 3, or 4
For Grade 2, 3, or 4

In consultation with relevant 
gastroenterology specialist. consider 
continuing study drug/study 
regimen if no clinical/radiologic 
evidence of pancreatitis ± 
improvement in amylase/lipase.
Acute Pancreatitis 
Any Grade
(Refer to NCI CTCAE
applicable version in
study protocol for
defining the CTCAE
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology.
−
Consider Gastroenterology referral

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
141
grade/severity)
Grade 2
Consider holding study drug/regimen
Grade 2
-
Consider IV hydration 
-
Consider Gastroenterology referral 
Grade 3 or 4
For Grade 3

Hold study drug/study regimen until 
resolution of elevated enzymes and 
no radiologic findings. If no 
elevation in enzymes or return to 
baseline values, then resume study 
drug/study regimen after completion 
of steroid taper (<10 mg prednisone, 
or equivalent).
For Grade 4

Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4
−
Promptly start systemic steroids prednisone 1 to 2 
mg/kg/day PO or IV equivalent.
−
IV hydration
Nervous System 
Disorders 
Aseptic Meningitis
Any Grade
( Refer to NCI CTCAE 
applicable version in
study protocol for
defining the CTCAE
grade/severity)
General Guidance
For Any Grade:
−
Consider Neurology consult. 
−
Consider MRI brain with and without contrast with pituitary 
protocol and a lumbar puncture for diagnosis.
−
Exclude bacterial and viral infections. (i.e. HSV).
−
Symptoms may include headache, photophobia, and neck 
stiffness, nausea/ vomiting which may resemble an infectious 
meningitis.
−
Patients may be febrile. 
−
Mental status should be normal. 
−
Consider IV acyclovir until polymerase chain reactions are 
available.

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
142
Any Grade 

Permanently discontinue study 
drug/study regimen. 
For Any Grade:
−
Consider neurology consult.
−
Consider MRI brain with and without contrast with pituitary 
protocol and a lumbar puncture for diagnosis.
−
Exclude bacterial and viral infections. (ie HSV).
−
Consider IV acyclovir until polymerase chain reactions are 
available.
−
Consider, as necessary, discussing with Clinical Study Lead.( 
Last bullet).
−
Consider hospitalization.
−
Once infection has been ruled out promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or equivalent.
Any Grade 
(Refer to NCI CTCAE
applicable version in
study protocol for
defining the CTCAE
grade/severity)

General Guidance 
For Any Grade:
-
Consider neurology consult. 
-
Consider testing including MRI of the brain with and without 
contrast, lumbar puncture, electroencephalogram (EEG) to 
evaluate for subclinical seizures, ESR, CRP, antineutrophil 
cytoplasmic antibody (ANCA) (if vasculitic process suspected), 
thyroid panel including TPO and thyroglobulin and additional 
autoantibodies to rule out paraneoplastic disorders.
-
Exclude bacterial and viral infections. (ie HSV).
-
Consider IV acyclovir until polymerase chain reactions are 
available.
-
Symptoms may include Confusion, altered behaviour, 
headaches, seizures, short-term memory loss, depressed level of 
consciousness, focal weakness, and speech abnormality.
Encephalitis 
Grade 2

Permanently discontinue study 
drug/study regimen.
For Grade 2:
−
Consider, as necessary, discussing with the Clinical Study 
Lead.
−
Once infection has been ruled out methylprednisone 1 to 
2 mg/kg/day. For progressive symptoms or if oligoclonal bands 

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
143
are present consider methylprednisone 1g IV daily for 3-5 days 
plus IVIG or plasmapheresis.
Grade 3 or 4
For Grade 3:

Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:
−
Consider, as necessary, discussing with study Clinical Study 
Lead.
−
Consider hospitalization.
−
Once infection is ruled out, start methylprednisolone 1 IV daily 
for 3-5 days for progressive symptoms. consider adding IVIG 
or plasmapheresis. 
Transverse Myelitis
Any Grade 
General Guidance 

Permanently 
discontinue 
immunotherapy. 

Consider MRI of the spine and 
brain. 

Once imaging is complete, 
consider lumbar puncture.

Consider testing to rule out 
additional 
aetiologies: 
B12, 
HIV, rapid plasma regain (RPR), 
ANA, anti-Ro/La antibodies, 
aquaporin-4 
IgG, 
myelin 
oligodendrocyte 
glycoprotein 
(MOG) 
IgG, 
paraneoplastic 
panel for anti-Hu and anti-
CRMP5/CV2
For Any Grade:
-
Consider neurology consult
-
Inpatient care
-
Consider prompt initiation of high methylprednisolone pulse 
dosing
-
Strongly consider IVIG or plasmapheresis
Peripheral neuropathy 
Any Grade
General Guidance
For Any Grade:

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
144
(Refer to NCI CTCAE
applicable version in
study protocol for
defining the CTCAE
grade/severity)
−
Patients should be evaluated to rule out any alternative etiology 
for neuropathy (e.g., disease progression, infections, metabolic 
syndromes or medications). It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in patients with 
underlying cancer, due to the multiple potential confounding 
effects of cancer (and its treatments) throughout the neuraxis. 
Given the importance of prompt and accurate diagnosis, it is 
essential to have a low threshold to obtain a Neurological 
consult.
−
Neurophysiologic diagnostic testing (e.g., electromyogram and 
nerve conduction investigations are routinely indicated upon 
suspicion of such conditions and may be best facilitated by 
means of a Neurology consultation.
Grade 1

No dose modifications.
For Grade 1:
−
Consider discussing with the study Clinical Study Lead, as 
needed.
−
Monitor symptoms for interference with ADLS, gait 
difficulties, imbalance, or autonomic dysfunction.
Grade 2

Hold study drug/study regimen dose 
until resolution to Grade ≤1.
For Grade 2:
−
Consult a neurologist.
−
Consider EMG/NCS
−
Consider discussing with the Clinical Study Lead, as needed.
−
Observation for additional sentinel symptoms or consider 
initiating prednisone 0.5–1 mg/kg orally .
−
If progression, initiate methylprednisolone 2–4 mg/kg/day and 
treat as GBS.
−
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine).
Grade 3 or 4
For Grade 3 or 4:

Permanently discontinue study 
drug/study regimen.
For Grade 3 or 4:
−
Consider discussing with Clinical Study Lead, as needed.
−
Recommend hospitalization.
−
Monitor symptoms and consult a neurologist.
−
Treat per Guillain-Barré Syndrome recommendations.

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
145
Guillain-Barré 
Syndrome (GBS)
General Guidance 
-
Recommend hospitalization
-
Obtain neurology consult
-
Obtain MRI of spine to rule out compression lesion
-
Obtain lumbar puncture
-
Antibody tests for GBS variants
-
Pulmonary function tests
-
Obtain electromyography (EMG) and nerve conduction studies
-
Frequently monitor pulmonary function tests and neurologic 
evaluations
-
Monitor for concurrent autonomic dysfunction
-
Initiate medication as needed for neuropathic pain
Grade 2-4
Grade 2-4 
Permanently discontinue 
-
Start IVIG or plasmapheresis in addition to methylprednisolone 
1 gram daily for 5 days, then taper over 4 weeks.
Myasthenia gravis
General Guidance 
-
Obtain neurology consult
-
Recommend hospitalization
-
Obtain pulmonary function tests
-
Obtain labs: ESR, CRP, creatine phosphokinase (CPK), aldolase 
and anti-striational antibodies
-
Consider 
cardiac 
exam, 
ECG, 
troponin, 
transthoracic 
echocardiogram for possible concomitant myocarditis
-
Obtain electromyography (EMG) and nerve conduction studies
-
Consider MRI of brain/spine to rule out CNS involvement by 
disease
-
Avoid medications that might exacerbate MG (e.g. beta 
blockers, some antibiotics, IV magnesium)

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
146
Grade 2 
Permanently discontinue  
-
Consider pyridostigmine 30mg three times daily and gradually 
increase based on symptoms (max dose 120mg four times daily)
-
Consider starting low dose prednisone 20mg daily and increase 
every 3-5 days. (Target dose 1mg/kg/day. Max dose 100mg 
daily)
Grade 3-4 
Permanently discontinue 
-
Start methylprednisolone 1-2mg/kg/day. Taper steroids 
based on symptom improvement
-
Start plasmapheresis or IVIG
-
Consider rituximab if refractory to plasmapheresis or IVIG
-
Frequent PFT assessments
-
Daily neurologic evaluations
Myocarditis
Any Grade
(Refer to NCI CTCAE
applicable version in
study protocol for
defining the CTCAE
grade/severity)
General Guidance

Discontinue drug permanently if 
biopsy-proven immune-mediated 
myocarditis.
For Any Grade:
−
Initial work-up should include clinical evaluation, B-type 
natriuretic peptide (BNP), cardiac enzymes, electrocardiogram 
(ECG), echocardiogram (ECHO), monitoring of oxygenation 
via pulse oximetry (resting and exertion), and additional 
laboratory work-up as indicated. Spiral CT or cardiac MRI can 
complement ECHO to assess wall motion abnormalities when 
needed.
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections)
−
The prompt diagnosis of immune-mediated myocarditis is 
important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function. 
−
Consider discussing with the Clinical Study Lead, as needed.
−
Monitor patients for signs and symptoms of myocarditis (new 
onset or worsening chest pain, arrhythmia, shortness of breath, 
peripheral edema). As some symptoms can overlap with lung 
toxicities, simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (e.g., pulmonary embolism, 
congestive heart failure, malignant pericardial effusion). 
Consult a cardiologist early, to promptly assess whether and 

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
147
when to complete a cardiac biopsy, including any other 
diagnostic procedures.
−
As indicated. Spiral CT or cardiac MRI can complement 
ECHO to assess wall motion abnormalities when needed.
Grade 2, 3 or 4
If Grade 2-4,  permanently 
discontinue study drug/study regimen.
For Grade 2-4:
−
Monitor symptoms daily, hospitalize.
−
Consider cardiology consultation and a prompt start of high 
dose/pulse corticosteroid therapy.
−
Supportive care (e.g., oxygen).
−
If no improvement consider additional immunosuppressive 
therapy such as TNF inhibitors (e.g., infliximab). IVIG or 
plasmapheresis or other therapies depending on the clincial 
condition of the patient, based on  the discretion of the 
treating specialist consultant or relevant practice guidelines). 
Caution: It is important to rule out sepsis and refer to 
infliximab label for general guidance before using 
infliximab. Infliximab is contraindicated for patients who 
have heart failure.
Myositis/Polymyositis 
(“Poly/myositis”)
Any Grade
(Refer to NCI CTCAE
applicable version in
study protocol for
defining the CTCAE
grade/severity)
General Guidance
For Any Grade:
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections).
−
Monitor patients for signs and symptoms of poly/myositis. 
Typically, muscle weakness/pain occurs in proximal muscles 
including upper arms, thighs, shoulders, hips, neck and back, 
and also difficulty breathing and/or trouble swallowing can 
occur and progress rapidly. Increased general feelings of 
tiredness and fatigue may occur, and there can be new-onset 
falling, difficulty getting up from a fall, and trouble climbing 
stairs, standing up from a seated position, and/or reaching up.
−
If poly/myositis is suspected, a Neurology consultation should 
be obtained early, with prompt guidance on diagnostic 
procedures. Myocarditis may co-occur with poly/myositis; 
refer to guidance under Myocarditis. Given breathing 
complications, refer to guidance under Pneumonitis/ILD. 

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
148
Given possibility of an existent (but previously unknown) 
autoimmune disorder, consider Rheumatology consultation.
−
Consider, as necessary, discussing with the Clinical Study 
Lead.
−
Initial work-up should include clinical evaluation, creatine 
kinase, aldolase, lactate dehydrogenase (LDH), blood urea 
nitrogen (BUN)/creatinine, erythrocyte sedimentation rate or 
C-reactive protein (CRP) level, urine myoglobin, and 
additional laboratory work-up as indicated, including a 
number of possible rheumatological/antibody tests (i.e., 
consider whether a rheumatologist consultation is indicated 
and could guide need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, antisynthetase [such as anti-Jo-
1], and/or signal-recognition particle antibodies). 
Confirmatory testing may include electromyography, nerve 
conduction studies, MRI of the muscles, and/or a muscle 
biopsy. Consider Barium swallow for evaluation of dysphagia 
or dysphonia.
Grade 1

No dose modifications.
For Grade 1:
−
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated.
−
Consider Neurology consult.
−
Consider, as necessary, discussing with the Clinical Study 
Lead.
Grade 2

Hold study drug/study regimen dose 
until resolution to Grade ≤1.

Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days 
or if there are signs of respiratory 
insufficiency.
For Grade 2:
−
Monitor symptoms daily and consider hospitalization.
−
Consider Rheumatology or Neurology consult, and initiate 
evaluation.
−
Consider, as necessary, discussing with the Clinical Study 
Lead.
−
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly 
start IV methylprednisolone 2 to 4 mg/kg/day systemic 
steroids along with receiving input from Neurology 
consultant 
−
If clinical course is not rapidly progressive, start systemic 
steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV 

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
149
1  SCAR terms include Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Erythema Multiforme, Acute Generalized
Exanthematous Pustulosis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Drug-induced hypersensitivity syndrome.
equivalent); if no improvement within 2 to 3 days, continue 
additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day
−
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 days, consider additional 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab). IVIG or plasmapheresis, or other therapies 
based on the discretion of the treating specialist consultant  or 
relevant practice guideline. Caution: It is important to rule 
out sepsis and refer to infliximab label for general 
guidance before using infliximab.
Grade 3 
For Grade 3:

Hold study drug/study regimen dose 
until resolution to Grade ≤1.

Permanently discontinue study 
drug/study regimen if Grade 3 
imAE does not resolve to Grade ≤1 
within 30 days or if there are signs 
of respiratory insufficiency.
For Grade 3 
−
Monitor symptoms closely; recommend hospitalization.
-
Consider Rheumatology and/or Neurology consult.
−
Consider discussing with the Clinical Study Lead, as needed.
−
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from Neurology 
consultant.
−
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 2 to 3 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg IV, may be repeated at 2 and 6 
weeks after initial dose at the discretion of the treating 
provider or relevant practice guidelines). Caution: It is 
important to rule out sepsis and refer to infliximab label 
for general guidance before using infliximab.
−
Consider whether patient may require IV IG, plasmapheresis.

Clinical Study Protocol
Investigational Drug Substance:  , Olaparib (AZD2281)
Study Number ESR-19-14545
Edition Number V9
Date: 11/25/2022 
150
Other–Immune-Mediated Reactions
Severity Grade of the Event
(Refer to NCI CTCAE applicable 
version in study protocol for defining 
the CTCAE grade/severity)
Dose Modifications
Toxicity Management
Any Grade
Note: It is possible that events with an inflammatory or
immune mediated mechanism could occur in nearly all 
organs, some of them are not noted specifically in these 
guidelines (e.g., immune thrombocytopenia, haemolytic 
anaemia, uveitis, vasculitis).
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections).
−
The Clinical Study Lead may be contacted for immune- 
mediated reactions not listed in the “specific immune- 
mediated reactions” section
−
Consultation with relevant specialist
−
Treat accordingly, as per institutional standard.
Grade 1
No dose modifications.
Monitor as clinically indicated
Grade 2

Hold study drug/study regimen until resolution to
≤Grade 1 or baseline.

If toxicity worsens, then treat as Grade 3 or Grade 4.

Study drug/study regimen can be resumed once event 
stabilizes to Grade ≤1 after completion of steroid 
taper.

Consider whether study drug/study regimen should be 
permanently discontinued in Grade 2 events with high 
likelihood for morbidity and/or mortality when they 
do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper
Grade 3
Hold study drug/study regimen
Grade 4
Permanently discontinue study drug/study regimen
Note: As applicable, for early phase studies, the following sentence may be added: “Any event 
greater than or equal to Grade 2, please discuss with Clinical Study Lead.”
For Grade 2, 3, or 4
Treat accordingly, as per institutional standard, appropriate 
clinical practice guidelines, and society guidelines. (See 
page 4

Clinical Study Protocol
Drug Substance 
Study Number ESR-19-14545
Edition Number V9
Date 11/25/2022
151
Infusion-Related Reactions
Severity Grade of the 
Event
(Refer to NCI CTCAE
applicable version in 
study
protocol for defining the 
CTCAE grade/severity)
Dose Modifications
Toxicity Management
Any Grade
General Guidance
For Any Grade:
−
Manage per institutional standard at the discretion of investigator.
−
Monitor patients for signs and symptoms of infusion-related 
reactions (e.g., fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (e.g., generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia).
Grade 1 or 2
For Grade 1:

The infusion rate of study drug/study regimen may be 
decreased by 50% or temporarily interrupted until 
resolution of the event.
For Grade 2:

The infusion rate of study drug/study regimen may be 
decreased 50% or temporarily interrupted until resolution 
of the event.

Subsequent infusions may be given at 50% of the initial 
infusion rate.
For Grade 1 or 2:
−
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator.
−
Consider premedication per institutional standard prior to 
subsequent doses.
−
Steroids should not be used for routine premedication of Grade ≤2 
infusion reactions.
Grade 3 or 4
For Grade 3 or 4:

Permanently discontinue study drug/study regimen.
For Grade 3 or 4:
−
Manage severe infusion-related reactions per institutional standard, 
appropriate clinical practice guidelines, and society guidelines. 

Clinical Study Protocol
Drug Substance 
Study Number ESR-19-14545
Edition Number V9
Date 11/25/2022
152
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Clinical Study Lead.”
Non–Immune-Mediated Reactions
Severity Grade of the Event
(Refer to NCI CTCAE
applicable version in study
protocol for defining the
CTCAE grade/severity)
Dose Modifications
Toxicity Management
Any Grade
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant.
Treat accordingly, as per institutional standard.
Grade 1
No dose modifications.
Treat accordingly, as per institutional standard.
Grade 2-3
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline.
Treat accordingly, as per institutional standard.
Grade 4
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the Sponsor.).
Treat accordingly, as per institutional standard.

Clinical Study Protocol
Drug Substance 
Study Number ESR-19-14545
Edition Number V9
Date 11/25/2022
153
List of Abbreviations 
AChE
Acetylcholinesterase
ILD
Interstitial lung disease
ACTH
Adrenocorticotropic hormone
imAE(s)
Immune-mediated adverse event(s)
ALT
Alanine aminotransferase
INR
International normalized ratio
ASCO
American Society of Clinical Oncology
IU
International units
AST
Aspartate aminotransferase
IV
Intravenous
(T) Bili
(Total) Bilirubin
IVIG
Intravenous immunoglobulin
BNP
B-type natriuretic peptide
LDH
Lactate dehydrogenase
BUN
Blood urea nitrogen
LFTs
Liver function tests
CRP
C-reactive protein
LLN
Lower limit of normal
CSP
Clinical Study Protocol
MRCP
Magnetic resonance cholangiopancreatography
CT
Computed tomography 
MRI
Magnetic resonance imaging
CTCAE 
Common Terminology Criteria for Adverse Events 
NCCN
National Comprehensive Cancer Network
CTLA-4
Cytotoxic T-Lymphocyte antigen 4
NCI
National Cancer Institute
DILI
Drug-induced liver injury 
PD-L1
Programmed cell death ligand-1
ECG
Electrocardiogram 
PJP
Pneumocystis jjrovecii pneumonia
ECHO
Echocardiogram
PO
By mouth
ESMO
European Society of Medical Oncology
SCAR
Severe cutaneous adverse reaction
GI
Gastrointestinal 
SITC
Society for Immunotherapy of Cancer
HBcAb 
Hepatitis B core antibody
SJS
Stephen Johnson Syndrome
HBeAg
Hepatitis B envelope antigen
T1DM
Type 1 diabetes mellitus
HBsAg
Hepatitis B surface antigen 
T3
Triiodothyronine
HBV
Hepatitis B virus
T4
Thyroxine
HCC
Hepatocellular cancer 
TEN
Toxic Epidermal Necrolysis
HCV
Hepatitis C virus 
TMG(s)
Toxicity management guideline(s)
HgA1c
Hemoglobin A1C
TSH
Thyroid stimulating hormone
ICI(s)
Immune checkpoint inhibitor(s)
ULN
Upper limit of normal