Clinical trial NCT04951492
Conditions: Castration-Resistant Prostate Carcinoma Prostate Adenocarcinoma
Sponsor: University of Washington
Start date: 2022-11-09; Completion date: 2023-10-15
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial investigates the effect of olaparib in treating patients with castration resistant prostate adenocarcinoma. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
OUTLINE:

Patients receive olaparib orally (PO) twice daily (BID). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up to 1 year.

Arms: arm 1: Patients receive olaparib orally (PO) twice daily (BID). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Olaparib
Intervention descriptions: intervention 1: Given PO

Protocol documents:
ICF_000.pdf: 
 
 
Official Title: 
Olaparib in Prostate Cancer Patients with Evidence of 
Homologous Recombination Deficiency as Assessed Using 
an Integrated Genomic Signature  
NCT Number: 
NCT04951492 
Document Type:  
Informed Consent Form 
Date of the 
Document: 
10/26/2022 
 
 
 


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Fred Hutchinson Cancer Center 
University of Washington 
Consent to take part in a research study: 
Olaparib in Prostate Cancer Patients with Evidence of Homologous 
Recombination Deficiency as Assessed Using an Integrated Genomic Signature 
Principal Investigator: Michael T. Schweizer, MD.  
University of Washington; Fred Hutchinson Cancer Center 
206-606-6252
Funding Source: 
 AstraZeneca 
Emergency number (24 hours): 206-598-6190 
Request the on-call Oncology Fellow 
Important things to know about this study. 
You are invited to participate in a research study. The purpose of this research is to 
determine the clinical effect of olaparib in men with metastatic prostate cancer that has 
become resistant to standard hormonal therapies (also known as castration-resistant 
prostate cancer) and whose tumors show genetic changes that we predict may respond well 
to olaparib.   
People who agree to join the study will be required to take olaparib twice daily. You will 
also be asked to provide blood samples and undergo imaging procedures (bone scans and 
CAT scans) at regular intervals.  
We do not know if olaparib will help treat this subtype of prostate cancer. Olaparib could 
cause side effects such as those described below in this form.  
You do not have to join this study; you can choose to receive standard methods to treat 
prostate cancer instead. We will give you details about the purpose, procedures, risks and 
possible benefits related to this study. We will explain other choices that you have. We will 
also give you any other information that you need to make an informed decision about 
joining this study.  
The following is a detailed description of this study. Please read this description carefully. 
You can ask any questions you want to help you decide whether to join the study. If you 
join this study, we will give you a signed copy of this form to keep for future reference.  
We invite you to join this research study. 
We invite you to join this research study because you have prostate cancer that has become 
resistant to standard hormonal therapies (also known as castration-resistant prostate cancer) 
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and your tumor showed genetic changes that we predict may respond well to olaparib. Up 
to 30 men with castration-resistant prostate cancer who have these genetic changes will 
join this study. 
Research is not the same as treatment or medical care. The purpose of a research study is 
to answer scientific questions.  
You do not have to be in the study. You are free to say “yes” or “no”, or withdraw after 
joining. If you say “no,” you will have no penalty or loss of benefits and your regular 
medical care will not change.  
What is the purpose of this study? 
We are doing this study to examine the clinical effects of olaparib in men with prostate 
cancer that has become resistant to hormonal therapies and has specific changes on tumor 
genetic sequencing. We want to know if men with prostate cancer who have these changes 
and whose cancer is getting worse after treatment with hormone therapy will experience a 
Prostate Specific Antigen (PSA) decline following treatment with olaparib. 
In this study, we want to learn what effects, good or bad, olaparib has on men with prostate 
cancer with certain genetic changes in their cancer. If you join this study, we will give you 
olaparib and watch carefully for any side effects. 
What research tests, procedures, and treatments are done in this study? 
 
STUDY PROCEDURES 
 
Screening Visit (Up to 30 days prior to starting study drugs) 
If you decide to take part, your study doctor will first talk with you and give you a physical 
exam, to see if you are able to join the study. At this visit, your doctor will: 
• Ask questions about your medical history, your current health, if you suffer 
from pain or other problems, and if you are taking any other medications or 
have recently been on any other research studies. You are asked to give as 
complete and accurate answers as possible. 
• Record your vital signs such as temperature, blood pressure, pulse, height, and 
weight. 
• Obtain an EKG (to check for any possible heart conditions). 
• Collect a blood sample for standard tests (approximately 2 tablespoons of 
blood). 
• CT scan of the chest, abdomen, and pelvis: a CT scan uses special x-ray 
equipment to take pictures of the body to identify and/or measure any tumors 
that may be present at the beginning of the study. This scan will be needed prior 
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to taking the study drug. Your first scan should be done within 8 weeks prior to 
starting the study drug. If you have already had a chest, abdomen and pelvis CT 
scan done according to the study requirements and the results can be used for 
this study, they do not need to be repeated. You will continue to have CT scans 
of your chest, abdomen and pelvis every three months throughout your 
participation in the study. 
• Bone scan: a bone scan is done to identify abnormal processes involving the 
bone such as tumor, infection, or fracture. A bone scan uses bone-seeking 
radioactive material that is injected into a vein so that it travels through the 
bloodstream. The radiation is detected by a camera that slowly scans your body 
and takes pictures of how much the radioactive material collects in the bones. 
This scan will be needed prior to your receiving the study drugs. The first bone 
scan should be done within 8 weeks prior to starting the study drug. If you have 
already had a bone scan done according to the study requirements and the 
results can be used for this study, they do not need to be repeated. You will 
continue to have a bone scan every three months throughout your participation 
in the study. 
 
• Biopsy: A bone or tissue biopsy will be taken from an area of your body where 
the cancer has spread. A biopsy is a procedure in which a small sample of tissue 
or bone is taken from the body.  
 
You may not have to undergo a biopsy if leftover tissue or bone is available 
from a past biopsy done as part of your cancer care. If the previous biopsy 
sample is available and appropriate for genetic testing, the researchers will use 
these samples instead of asking you to have a biopsy. Samples that are stored 
at another hospital from previous biopsies will be requested by the researchers 
if appropriate. You may be asked to undergo another biopsy if the first biopsy 
could not be used to evaluate the genetic profile of your cancer. You do not 
have to agree to another biopsy. Your decision to have or not have the biopsy 
will not affect your medical care and you will not lose any benefits to which 
you are entitled.   
•  Additional PET/CT or MRI scans may be used as initial screening assessments. 
 
Treatment Period 
If you are enrolled into the study, you will start the study medication, olaparib. You 
will take two 150mg tablets of olaparib (300mg total) twice daily. A 4-week supply of 
the oral drugs will be provided at the beginning of each month of the trial. You will be 
given a diary to record your study drug dosing. Study staff will instruct you on how to 
fill out your diary. 
Certain drugs may interact with the olaparib. You need to tell your study doctor of all 
medications and supplements (e.g., herbs, vitamins) you take.  
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Olaparib must be taken only by you. It must also be kept out of the reach of children or 
persons of limited capacity to understand.  
You will be evaluated for side effects and asked about all medications you are taking 
throughout the study. Below are time points and the tests and procedures that will be 
done during these time points. The study doctor may perform more tests and procedures 
if they feel it is necessary to monitor your safety and evaluate your cancer. 
If you can join the study, at this visit your doctor/research nurse will: 
 
Cycle 1 Study Visits 
• Day 1 visit 
o A 28-day supply of olaparib will be provided. 
o Ask questions about your medical history, your current health, if you 
suffer from pain or other problems. Ask if you have recently started any 
new medications or supplements. 
o Record your vital signs such as temperature, blood pressure, pulse, and 
weight. 
o Give you a physical exam. 
o Blood will be collected for standard labs (less than 2 tablespoons). 
o Blood will be collected for research purposes (approximately 2 
tablespoons).  
Cycle 2 and 3 Visits 
• Day 1 visit 
o A 28-day supply of olaparib will be provided. 
o Any unused olaparib from the prior 28 days will be collected. 
o Ask questions about your medical history, your current health, if you 
suffer from pain or other problems. Ask if you have recently started any 
new medications or supplements. 
o Record your vital signs such as temperature, blood pressure, pulse, and 
weight. 
o Give you a physical exam. 
o Blood will be collected for standard labs (less than 2 tablespoons). 
Cycle 4 Study Visits 
• Day 1 visit 
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o Any unused olaparib from the prior 28 days will be collected. 
o Scans: Undergo a bone scan and CT scan of the chest, abdomen, and 
pelvis. 
o A 28-day supply of olaparib will be provided as long as there is no 
evidence that your cancer is worsening. 
o Ask questions about your medical history, your current health, if you 
suffer from pain or other problems. Ask if you have recently started any 
new medications or supplements. 
o Record your vital signs such as temperature, blood pressure, pulse and 
weight. 
o Give you a physical exam. 
o Blood will be collected for standard labs (less than 2 tablespoons). 
o Blood will be collected for research purposes (approximately 2 
tablespoons).  
Cycle 5 and on Study Visits 
• Day 1 visit 
o Any unused  from the prior 28 days will be collected. 
o Undergo bone, CT scan chest, abdomen, and pelvis scans every 3 
cycles: Cycle 7, Cycle 10, Cycle 14, etc. 
o A 28-day supply of olaparib will be provided if there is no evidence that 
your cancer is worsening. 
o Record your vital signs such as temperature, blood pressure, pulse, and 
weight. 
o Give you a physical exam. 
o Blood will be collected for standard labs (less than 2 tablespoons). 
End of Study Visit (Within 14 days of stopping all study drug) 
Once your participation in the study is completed, you will have a final visit for the 
study. The following items must be completed within 30 days of stopping study drugs: 
• Collect any unused olaparib from the prior 28 days.  
• Ask questions about your medical history, your current health, if you suffer from 
pain or other problems. Ask if you have recently started any new medications 
or supplements. 
• Record your vital signs such as temperature, blood pressure, pulse, and weight. 
• Give you a physical exam. 
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• Blood will be collected for standard labs (less than 2 tablespoons). 
• Blood will be collected for research purposes (approximately 2 tablespoons). 
• Optional biopsy: This will be performed as described under the ‘Screening visit’ 
section above. 
 
Long-term Follow-up (approximately every 6 months for up to 2 years) 
• You will not have to come to clinic for these visits. A study coordinator or nurse 
will contact you via telephone, mail, or email to ask you questions about your 
prostate cancer. In the event of your passing, we will contact your next of kin. 
How long would you stay in this study? 
If you join this study, you will stay in this study as long as you appear to be benefitting 
from treatment. After stopping treatment, you will remain in the study for an additional 
2-years. 
You will receive olaparib as long you appear to be benefitting from treatment. After 
that, you would have follow-up exams in the office once within 14 days of stopping 
treatment. Additional follow up will be performed by phone, email or postal for up to 
2-years after your last dose of study drugs. 
Doctors could take you out of this study at any time. This would happen if: 
• 
They think it is in your best interest not to continue in the study. 
• 
You are not able or willing to follow study procedures. 
• 
The whole study is stopped.   
If you withdraw from the study for any reason, previously collected information would 
remain in the study records and would be included in the analysis of results. This 
information could not be removed from the study records.  
Long-term follow-up means keeping track of someone’s medical condition for a long 
time. If you join this study, we will contact you approximately every 6 months by 
phone, email, or postal mail to see how you are doing. We will also ask your doctor to 
send a copy of your medical records. This information will help us learn about the long-
term effects of olaparib.  
You do not have to be in long-term follow-up. You can say “yes” or “no”. Either way, 
you can still join this study. If you drop out of the study, you will be asked if we can 
contact you every 6 months by phone, email, or postal mail to see how you are doing. 
If you choose not to join long-term follow-up, you will not be contacted regularly, and 
we will not ask your doctor to send medical records, but we might still need to contact 
you for some other reason. 
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What are the side effects (risks)? 
In this part of the consent form, we describe the side effects we expect from the tests 
and treatments in this study. Olaparib could cause side effects we do not know about 
yet. We carefully watch everyone in the study for side effects.   
If you join this study, we will tell you if we discover new side effects that could affect 
you.  
Side effects may be mild or very serious. Medicines could be given to help lessen side 
effects. Many side effects go away soon after you stop taking olaparib. In some cases, 
side effects can last a long time or never go away.  
Risks of Olaparib: 
Very common side effects (more than 10% of patients): 
• Nausea 
• Vomiting 
• Tiredness/weakness/fatigue 
• Indigestion/heartburn (dyspepsia) 
• Difficulty breathing (Dyspnea) 
• Loss of appetite 
• Headache 
• Change in taste of foods (dysgeusia) 
• Dizziness 
• Diarrhea. Your doctor may prescribe a medicine to treat this. If it gets severe, tell 
your doctor straight away. 
• Cough 
• Decrease in the number of red blood cells (anemia), which can be associated with 
symptoms of shortness of breath, fatigue, pale skin or fast heartbeat 
• Decrease in the number of platelets in blood (thrombocytopenia) which can be 
associated with symptoms of bruising or bleeding for longer if injured 
• Decrease in the total number of white blood cells (leukopenia) and in certain 
white blood cells (neutropenia) that protect from infection, which can be 
associated with symptoms of fever 
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Common side effects: (1 to 10% of patients) 
• Sore mouth (stomatitis) 
• Pain in the stomach area under the ribs (upper abdominal pain) 
• Rash 
• Decrease in the number of white blood cells that support the immune system 
(lymphopenia) which can be associated with increased susceptibility to infection 
• Increase in blood creatinine seen from a laboratory test showing how your 
kidneys are working. 
Uncommon (up to 1% of patients) side effects that may occur are: 
• Increase in size of red blood cells: This will be monitored by the laboratory safety 
tests that will be done in this study because this doesn’t normally have any 
symptoms.  
• Allergic reactions (Hypersensitivity) 
• Itchy rash on swollen, reddened skin (dermatitis) 
• Swelling under the skin (Angioedema) 
• Myelodysplastic syndrome: a pre-cancerous condition where the bone marrow 
isn’t as good at producing blood cells as it was before (red blood cells and/or 
white blood cells and/or platelets). This condition has the potential to transform 
into acute myeloid leukemia.  
• Acute myeloid leukemia: a cancer of the bone marrow where many abnormal and 
immature white blood cells (blast cells) are made while normal functioning 
blood cells are not made. 
 
Driving and using machines 
The study drug may affect your ability to drive or use machines. If you feel dizzy, weak, 
or tired while taking your study treatment, avoid when driving or using tools or 
machines. 
 
Other potential risks of olaparib: 
Other side effects have been seen in previous studies, but it is not yet known if these 
were related to olaparib, or if they were unrelated events possibly due to the patient’s 
cancer or other cause. Assessing the full range of side effects of olaparib is an important 
part of this study. 
 
Pneumonitis: (lung inflammation) has been reported in a small number of patients 
treated with olaparib in previous studies, and some patients have died. It is not known 
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if olaparib caused the pneumonitis in these patients as they had other possible causes 
such as lung cancer and/or metastases in the lungs, pre-existing lung disease, were 
smokers, or had been treated previously with chemotherapy or radiotherapy. Notify 
your study doctor as soon you experience worsening of symptoms of shortness of 
breath, cough and fever. 
 
The Study Doctor may decide to interrupt, reduce or permanently stop your olaparib 
dose if you experience certain side effects. If your dose is reduced, you will be given a 
new bottle of tablets.  
Risks of Blood Draw:  
You may feel some discomfort when the needle is placed in your vein to draw blood 
for testing. Sometimes a bruise may develop where the blood was drawn or the needle 
was placed, and occasionally infection or bleeding may develop at the puncture site. 
Light-headedness and/or fainting may occur during blood collection. 
Radiation Exposure: 
While you are in this research study, CT scans, Bone Scans, and x-rays may be used to 
evaluate your disease and expose you to radiation. The frequency of these exams is no 
greater than what you would receive as standard care. Everyone receives a small 
amount of radiation every day called “background radiation”. This radiation is natural 
and comes from space, air, water, soil, and the food you eat. Each year you are exposed 
to about 3 milliSieverts (mSv) of this background radiation. A milliSievert is a unit of 
radiation dose. For comparison, the estimated radiation dose from each of these tests is 
listed below. The risk to your health from this level of radiation exposure is too low to 
be detectable and may be nonexistent. 
• CT chest: 7 mSv 
• CT abdomen: 8 mSv 
• CT pelvis: 6 mSv 
• Bone Scan: 6.3 mSv 
In the long term, over many years, there is a very low risk of developing a new cancer 
because of the radiological evaluation and treatment for your cancer. 
Risks Associated with Contrast Agents Used During Scans: 
There is a small risk with using a contrast agent that is injected into a vein during the 
CT scan. The contrast agent is a special dye that highlights organs, blood vessels or 
tissue to make them more visible. Depending on the type of contrast agent that is used, 
it may cause decreased kidney function or worsen kidney function in people who 
already have decreased kidney function. Therefore, we will monitor your kidney 
function closely while you participate in this study. If there is any change in your kidney 
function, we may have to remove you from the study. 
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Rarely, some people have allergic reactions (such as hives and itching) to the contrast 
agent. Serious reactions (for example, drop in blood pressure, difficulty breathing or 
severe allergic reaction and death) are rare.   
 
Reproductive risks: 
If you join this study, you will have to use condoms from the time this form is signed 
until at least 3 months after the last dose of olaparib when having sexual intercourse 
with a female partner, even if they are pregnant. Your female partner must also use a 
suitable method of contraception either hormonal or non-hormonal.  
Suitable methods of contraception for you and your female partner include: 
 
• 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 3 months after the last 
dose of study drug. 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.   
• Vasectomized participant PLUS male condom.  With participant assurance that 
they 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  
 
You must not donate sperm while taking study treatment and for 3 months after the last 
dose of study treatment. Tell your study doctor immediately if your partner becomes 
pregnant while taking study treatment or within 3 months of your last dose of study 
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treatment.  
 
Non-physical risks: 
 
In addition to the physical risks/discomforts associated with this study, there may be 
psychological, emotional, financial, social, and legal risks that might result. If you join 
this study, non-physical risks are: 
• You may get tired or bored when we are asking you questions. You do not have 
to answer any question you do not want to answer. 
• There is risk that information about you may become known to people outside 
this study. 
• You might not be able to work. 
• Results of genetic tests might be released by accident. This risk is very low, 
because we keep personal information private. If these results became known, 
you could have problems with family members or insurance. 
What are the potential benefits? 
We do not know if this study would help you. We are testing olaparib to see its effects 
on people with prostate cancer that has become resistant to hormonal treatments and 
whose tumors show genetic changes that we predict may respond well to olaparib.  You 
might get better if you receive olaparib, but your condition could stay the same or even 
get worse. We hope the information from this study will help other people with prostate 
cancer in the future. 
You have other choices besides this study. 
You do not have to join this study. You are free to say “yes” or “no”. Your regular 
medical care would not change if you decide to say “no”.  
You have other choices for treatment.  Each of these choices has risks and benefits. 
You should talk to your doctor or healthcare provider about these choices.   
Other choices include: other hormonal therapies (Zytiga, Xtandi, ketoconazole) or 
chemotherapy (docetaxel, cabazitaxel), radiation (Xofigo), vaccine therapy 
(Provenge), other research studies or palliative care (treatment of symptoms such as 
pain when they occur, but no specific therapy for your cancer). 
Enrollment in this study may exclude you from other research studies.  
Protecting Privacy as an Individual and the Confidentiality of Personal Information  
If you join this study, some people or organizations might need to look at your medical 
records and research records for quality assurance or data analysis. They include: 
• 
AstraZeneca (the manufacturers of olaparib) and their agents.  
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• 
Institutional Review Boards (IRB), including the Fred Hutchinson Cancer 
Center IRB. An IRB is a group that reviews the study to protect the rights and 
welfare of research participants. 
• 
Fred Hutchinson Cancer Center, University of Washington. 
• 
US National Institutes of Health, National Cancer Institute, Office for Human 
Research Protections, Food and Drug Administration, and other regulatory 
agencies as required. 
We will do our best to keep personal information confidential. But we cannot guarantee 
total confidentiality.  Personal information may be given out if required by law.  For 
example, workplace safety rules may require health workers to contact you about lab 
tests. Or a court may order study information to be disclosed. Such cases are rare. 
We will not use personal information in any reports about this study, such as journal 
articles or presentations at scientific meetings. 
 
If you join this study, information about your participation would be made part of your 
permanent medical record. This information would include a copy of this consent form. If 
an insurance company or employer or anyone else were authorized to see your medical 
record, they would see a copy of this consent form.  
 
This research is covered by a Certificate of Confidentiality from the U.S. government. 
This Certificate helps protect the confidentiality of information about people who join 
this study. If you join the study, the Certificate means that generally we would not have 
to give out identifying information about you even if we were asked to by a court of 
law. We would use the Certificate to resist any demands for identifying information.  
We could not use the Certificate to withhold research information if you give written 
consent to give it to an insurer, employer, or other person.   
This protection has some limits. We would voluntarily provide the information:  
• To a member of the federal government who needs it in order to audit or evaluate 
the research.  
• To the funding agency and groups involved in the research, if they need the 
information to make sure the research is being done correctly.  
• To the federal Food and Drug Administration (FDA), if required by the FDA.  
• To someone who is accused of a crime, if he or she believes that our research 
records could be used for defense.  
• To authorities, if we learn of child abuse, elder abuse, or if participants might 
harm themselves or others.  
How is my genetic information protected? 
 
A federal law called the Genetic Information Nondiscrimination Act (GINA) helps 
protect genetic information about people who join research studies.  
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GINA restricts access to genetic information so that it cannot be used for health 
insurance coverage decisions. GINA prevents health insurance companies or group 
health plans from:  
 
• Asking for genetic information obtained in research studies, or 
• Using genetic information when making decisions regarding your eligibility or 
premiums  
GINA does not help or protect against genetic discrimination by companies that sell 
life, disability, or long-term care insurance.  
 
How long will my samples be stored? 
 
Your samples will be used for the purposes of this study and may be stored for up to five 
years following the completion of this study. Samples will be stored at University of 
Washington and/or Fred Hutchinson Cancer Center for research purposes only. Your 
samples will be destroyed after use for the purposes of this study. Researchers will not 
report their results to you or your doctor. Your specimens will not be used for reasons 
unrelated to this research study. All specimens will be kept in locked research laboratories 
at University of Washington and/or Fred Hutchinson Cancer Center. The use of these 
specimens will be supervised by the primary investigators at University of Washington 
(Michael Schweizer, MD) and his designees. These samples will not contain your name or 
other identifiable information. Analyses will be conducted at the University of Washington, 
Fred Hutchinson Cancer Center and/or their research partners.  
 
Would we pay you if you join this study? 
There is no payment for being in this study. 
 
Would you have extra costs if you join this study?  
If you join this study, you will have some extra costs. Your insurance company may 
pay these costs, but some insurance policies do not cover these costs. We can help you 
find out whether your insurance company would cover these costs. 
The extra costs are: 
• 
Cost of staff and equipment to give study drugs olaparib). There is no charge 
for the olaparib itself. 
• 
Cost of standard doctor visits and lab tests. 
• 
Cost of extra tests that are given outside of standard care.  
If you join this study, you or your insurance company would have to pay for the costs 
of standard treatment in this study. 
You would not be billed for: 
• 
Olaparib (study drug) 
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• 
Research bone marrow procedure or testing. 
 
What if you get sick or hurt after you join this study? 
 
For a life threatening problem, call 911 right away or seek help immediately.  Contact 
your study doctor when the medical emergency is over or as soon as you can.    
 
For all other medical problems or illness related to this research, immediately contact 
study staff via the 24-hour emergency number on the first page of this form .  They will 
treat you or refer you for treatment.  You or your health insurance will have to pay for 
the treatment. There are no funds to pay you for a research-related injury, added 
medical costs, loss of a job, or other costs to you or your family.  State or national law 
may give you rights to seek payment for some of these expenses.  You do not waive 
any right to seek payment by signing this consent form. 
 
You or your insurer will be billed for treatment of problems or complications that result 
from your condition or from standard clinical care. 
You will not lose any legal right to seek payment for treatment if you sign this form. 
What will my information and/or tissue samples be used for? 
Your information and tissue samples (such as blood and tumor cells) will be used for 
the purposes of this study. 
Your tissue samples might help researchers develop new products. This research could 
be done by for-profit companies. You will not receive any revenue generated from 
products developed using your tissue samples. 
During this study, if the researchers learn new information that may be important to 
your general health or to your disease or condition, they will share that information 
with you. This study is not specifically designed to identify inherited genetic conditions 
that lead to risk of cancer. During this study, however, we may find information about 
genetic conditions you may have been born with and we will attempt to share these 
with you.  
Your tissue contains DNA. DNA makes up the genes that serve as the "instruction 
book" for the cells in our bodies. By studying genes, researchers can learn more about 
diseases such as cancer. There are many different types of genetic tests. The testing on 
your tissue samples will include genetic testing called whole genome sequencing. 
Whole genome sequencing looks at all the genetic information in your cells. This type 
of testing can provide useful information to researchers. It can also present risks if the 
test results became known to others, for example you could have problems with family 
members or insurance companies. There is also a risk that these test results could be 
combined with other information to identify you.  
FHCRC IRB Approval  
10/26/2022 
Document Released Date


 
057IRBform_ModelConsentClin / Version 15.00 / 10-21-2022 / Page 15 of 17  
Your rights 
• 
You do not have to join this study. You are free to say “yes” or “no”.  
• 
If you get sick or hurt in this study, you do not lose any of your legal rights to 
seek payment by signing this form. 
• 
During the study, we might learn new information that you need to know. For 
example, some information may affect your health or well-being. Other 
information might make you change your mind about being in this study. If we 
learn these kinds of information, we will tell you. 
• 
If you join this study, you will not have to stay in it. You can stop at any time 
(even before you start). Your regular medical care would not change. You 
would have no penalty for stopping, but it would be better not to join the study 
if you think that you would change your mind later.   
• 
If you decide to drop out, we will want you to tell the study doctor. The doctor 
could tell you about the effects of stopping olaparib. You and the doctor could 
talk about the follow-up care and testing that would help the most 
• 
Before you leave the study, the doctor might ask you to continue in the long-
term follow-up part of the study.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This Web site will not include information that can identify 
you. At most, the Web site will include a summary of the results. You can search this 
website at any time.  
Your responsibilities 
If you join this study, you will have some responsibilities:  
• 
Follow the schedule of study visits and procedures. 
• 
Take study medications as directed.  
• 
Prevent pregnancy. 
• 
Tell us about side effects.  
 
For more information 
If you have questions or concerns about this study, you can talk to your doctor anytime. 
Other people you could talk to are listed below. 
If you have questions about: 
 
Call: 
This study (including complaints and 
requests for information) 
 
206-606-6252 (Dr. Michael Schweizer) 
206-606-7486 (Zoya Bauer, research Manager)  
If you get sick or hurt in this study 
 
206-606-6252 (Dr. Michael Schweizer) 
FHCRC IRB Approval  
10/26/2022 
Document Released Date


 
057IRBform_ModelConsentClin / Version 15.00 / 10-21-2022 / Page 16 of 17  
 
Optional Procedures: 
 
Please read each question and think about your choice. When you decide on each question, 
please circle YES or NO. 
 
Do you agree to undergo biopsy at the End of Study? 
(circle one) 
YES  
NO  
 
 
Your rights as a research participant 
 
206-667-5900 or email irodirector@fredhutch.org (Director of 
Institutional Review Office, Fred Hutchinson Cancer Center) 
206-543-0098 (Human Subjects Division, University of 
Washington) 
Your bills and health insurance 
coverage 
 
206-598-8260 (UWMC Patient Financial Services) 
206-606-1091 (Fred Hutchinson Cancer Center Patient 
Financial Clearance) 
FHCRC IRB Approval  
10/26/2022 
Document Released Date


 
057IRBform_ModelConsentClin / Version 15.00 / 10-21-2022 / Page 17 of 17  
Signatures 
Please sign below if you:  
• have read this form (or had it read to you); 
• had the opportunity to ask any questions you have; 
• had the opportunity to discuss the research with the person obtaining consent; 
and  
• agree to participate in this study. 
 
Participant: 
 
 
 
 
 
Printed Name 
 
Signature 
 
Date 
 
 
 
If you served as an interpreter or impartial witness during the consent process, sign below 
to indicate you attest to the accuracy of the presentation and the participant’s apparent 
understanding of and willingness to participate in the research. 
 
Impartial Witness or Interpreter: 
 
 
 
 
 
Printed Name 
 
Signature 
 
Date 
 
Researcher’s statement 
I have discussed the research study, including procedures and risks, with the person 
signing above. A copy of the signed consent form will be given to the participant. 
 
Person obtaining consent signature: 
 
 
 
 
 
Printed Name 
 
Signature 
 
Date 
 
 
Protocol: Version 14.0 
Current consent version date: 10/25/2021 
Previous consent version date: N/A 
Copies to: Patient, Sponsor and Regulatory Binder 
FHCRC IRB Approval  
10/26/2022 
Document Released Date

Prot_SAP_002.pdf: 
 
 
Official Title: 
Olaparib in Prostate Cancer Patients With Evidence of 
Homologous Recombination Deficiency As Assessed Using 
an Integrated Genomic Signature 
NCT Number: 
NCT04951492 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
10/26/2022 
 
 


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Clinical Study Protocol 
Drug 
Substance: 
Olaparib 
Study Code: 
ESR-20-20693 
Version: 
3.0 
Date: 
October 21, 2022 
Olaparib in Prostate Cancer Patients With Evidence of Homologous 
Recombination Deficiency As Assessed Using an Integrated Genomic 
Signature
Sponsor-Investigator / Primary Investigator: Michael Schweizer, MD 
Statistician: Roman Gulati, MS 
Bioinformatics: Navonil De Sarkar, PhD 
Financial/ Drug Support: AstraZeneca 
IRO REC'D OCT 21 2022
FHCRC IRB Approval  
10/26/2022 
Document Released Date


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VERSION HISTORY 
Version 1.0, April 8, 2021 
Version 2.0, April 22, 2021 
Version 3.0, October 21, 2022 
 


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TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................... 1 
VERSION HISTORY .............................................................................................. 2 
TABLE OF CONTENTS ......................................................................................... 3 
1.0 
PROTOCOL SUMMARY ....................................................................................... 7 
1.1 
Schedule of Activities (SoA) ................................................................................... 7 
1.2 
Synopsis ................................................................................................................... 9 
1.2.1 
Inclusion Criteria & Exclusion Criteria  ................................................................ 11 
1.3 
Schema ................................................................................................................... 15 
2.0 
INTRODUCTION ................................................................................................. 16 
2.1 
Background and Study Rationale ........................................................................... 16 
2.2 
Benefit/Risk Assessment ....................................................................................... 20 
3.0 
OBJECTIVES AND ENDPOINTS ....................................................................... 21 
3.1 
PRIMARY OBJECTIVE: ...................................................................................... 21 
3.2 
SECONDARY OBJECTIVES: ............................................................................. 21 
3.3 
EXPLORATORY OBJECTIVES: ......................................................................... 21 
3.4 
PRIMARY ENDPOINT: ....................................................................................... 22 
3.5 
SECONDARY ENDPOINTS: ............................................................................... 22 
4.0 
STUDY DESIGN ................................................................................................... 22 
4.1 
Overall Design ....................................................................................................... 22 
4.2 
Scientific Rationale for Study Design .................................................................... 23 
4.3 
Justification for Dose ............................................................................................. 23 
4.4 
End of Study Definition ......................................................................................... 24 
5.0 
STUDY POPULATION ........................................................................................ 24 
5.1 
Inclusion Criteria ................................................................................................... 24 
5.2 
Exclusion Criteria .................................................................................................. 25 
5.3 
Lifestyle Restrictions ............................................................................................. 27 
5.3.1 
Meals and Dietary Restrictions .............................................................................. 27 
5.3.2 
Activity .................................................................................................................. 27 
5.4 
Screen Failures ....................................................................................................... 28 
5.5 
Study Treatments ................................................................................................... 28 
5.5.1 
Investigational Products ......................................................................................... 28 


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5.6 
Preparation/Handling/Storage/Accountability ....................................................... 29 
5.7 
Treatment Compliance ........................................................................................... 29 
5.8 
Concomitant Therapy ............................................................................................. 29 
5.8.1 
Background Medication ......................................................................................... 33 
5.8.2 
Other Concomitant Treatment ............................................................................... 33 
5.9 
Dose Modification ................................................................................................. 33 
5.10 
Treatment After The End of The Study ................................................................. 34 
5.11 
Discontinuation of Study Treatment ...................................................................... 35 
5.11.1 
Procedures for Discontinuation of Study Treatment ............................................. 35 
5.12 
Lost to Follow-Up .................................................................................................. 36 
5.13 
Withdrawal From The Study ................................................................................. 36 
6.0 
STUDY ASSESSMENTS AND PROCEDURES ................................................. 36 
6.1 
Assessment of HRD ............................................................................................... 37 
6.1.1 
LOH Score ............................................................................................................. 37 
6.1.2 
iHRD Status ........................................................................................................... 37 
6.2 
Efficacy Assessments ............................................................................................. 37 
6.2.1 
Primary Objective .................................................................................................. 37 
6.2.2 
Secondary and Exploratory Objectives .................................................................. 37 
6.3 
Safety Assessments ................................................................................................ 38 
6.3.1 
Clinical Safety Laboratory Assessments................................................................ 38 
 
Coagulation ............................................................................................................ 39 
 
Bone Marrow or Blood Cytogenetic Samples ....................................................... 39 
6.3.2 
Physical Examinations ........................................................................................... 39 
6.3.3 
Vital Signs .............................................................................................................. 39 
6.3.4 
Electrocardiograms ................................................................................................ 39 
6.4 
Data Monitoring and Collection of Adverse Events .............................................. 39 
6.4.1 
Method of Detecting AEs and SAEs...................................................................... 40 
6.4.2 
Time period and Frequency for Collecting AE and SAE Information .................. 40 
 
Adverse Events After the End of Treatment Visit ................................................. 41 
6.4.3 
Follow-up of AEs and SAEs .................................................................................. 41 
6.4.4 
Adverse Event Data Collection .............................................................................. 42 
6.4.5 
Causality Collection ............................................................................................... 43 
6.4.6 
Adverse Events Based on Signs and Symptoms .................................................... 43 
6.4.7 
Adverse Events Based on Examinations and Tests ............................................... 43 
6.4.8 
Hy’s Law ................................................................................................................ 44 
6.4.9 
Disease Progression ............................................................................................... 44 
6.4.10 
New Cancers .......................................................................................................... 44 
6.4.11 
Lack of Efficacy ..................................................................................................... 45 
6.4.12 
Deaths .................................................................................................................... 45 
6.4.13 
Olaparib Adverse Events of Special Interest ......................................................... 45 


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6.5 
Safety Reporting and Medical Management .......................................................... 45 
6.5.1 
Reporting of Serious Adverse Events .................................................................... 45 
6.5.2 
Pregnancy/Paternal Exposure ................................................................................ 46 
6.5.3 
Overdose ................................................................................................................ 46 
6.5.4 
Medication Error .................................................................................................... 47 
6.5.5 
Management of Adverse Events ............................................................................ 47 
 
Management of Hematological Toxicity ............................................................... 47 
 
Management of Anemia ......................................................................................... 47 
 
Management of Neutropenia, Leukopenia and Thrombocytopenia....................... 48 
 
Management of Prolonged Hematological Toxicities While On Study 
Treatment ............................................................................................................... 49 
 
Management of Non-Hematological Toxicity ....................................................... 49 
 
Management of New or Worsening Pulmonary Symptom .................................... 49 
 
Management of Nausea and Vomiting................................................................... 50 
 
Interruptions for Intercurrent Non-Toxicity Related Events.................................. 50 
 
Renal impairment ................................................................................................... 51 
6.6 
Genetics .................................................................................................................. 51 
6.6.1 
Collection of Mandatory Genetic Samples ............................................................ 51 
6.7 
Biomarkers ............................................................................................................. 51 
6.7.1 
Storage, Re-Use and Destruction of Biomarker Samples ...................................... 52 
6.8 
Sample Size Determination .................................................................................... 52 
6.9 
Statistical Analyses ................................................................................................ 52 
6.9.1 
Efficacy Analyses .................................................................................................. 52 
6.9.2 
Safety Analyses ...................................................................................................... 53 
7.0 
REFERENCES ...................................................................................................... 54 
 
 
 


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LIST OF TABLES 
Table 1 
Schedule of Activities ................................................................................. 7 
Table 2 
Study Treatments ...................................................................................... 28 
Table 4 
Prohibited Medications ............................................................................. 30 
Table 5 
Restricted Concomitant Medications........................................................ 31 
Table 6 
Dose Reductions For Olaparib To Manage Adverse Events .................... 34 
Table 7 
Dose reduction For Olaparib If Patient Develops Moderate Renal 
Impairment ............................................................................................... 34 
Table 8 
Dose Reductions For Olaparib If Patient Has To Start Taking A 
Strong Or Moderate CYP3A Inhibitor ..................................................... 34 
Table 9 
Laboratory Safety Variables ..................................................................... 38 
Table 10 
Management of Anemia ........................................................................... 47 
Table 11 
Management of Neutropenia, Leukopenia and Thrombocytopenia ......... 48 
Table 12 
Dose Reductions For Study Treatment ..................................................... 50 
 
LIST OF FIGURES 
Figure 1 Study Design ......................................................................................................... 15 
Figure 2. iHRD Accurately Predicts Time On Olaparib Treatment ....................................... 18 
Figure 3. iHRD Distribution Across HR Mutant Subgroups. ................................................ 19 
 
LIST OF APPENDICES 
Appendix A Actions Required In Cases Of Increases In Liver Biochemistry And 
Evaluation Of Hy’s Law ........................................................................... 56 
Appendix B Adverse Event Definitions And Additional Safety Information .................... 60 
Appendix C Acceptable Birth Control Methods ................................................................ 64 
Appendix D Pill Diary Template ........................................................................................ 65 
Appendix E Recommendations From Prostate Cancer Clinical Trials Working 
Group 3 (PCWG3)16 ................................................................................. 67 
 
 


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1.0 PROTOCOL SUMMARY 
1.1 
Schedule of Activities (SoA) 
Table 1 
Schedule of Activities 
 
Pre-
Screening 
Screening 
Treatment Cyclesa 
End of 
Treatment 
Treatment Cycle 
Pre-
Screening 
Screening 
Cycle 
1g 
Cycle 
2 
Cycle 
3 
Cycle 
4 
After 
Cycle 
4 
Discontinueh 
Cycle Day 
 
Day -30 to 0 
Day 1 
+/- 7 
days 
Day 1 
+/- 7 
days 
Day 1 
+/- 7 
days 
Day 1 
+/- 7 
days 
Day 1 
+/- 7 
days 
Within 30 days 
Administrative 
Procedures 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
 
X 
 
 
 
 
 
 
Demographics and 
Medical History 
 
X 
 
 
 
 
 
 
Prior and Concomitant 
Medication Review 
 
X 
X 
X 
X 
X 
Q1C 
X 
Olaparib Dispensation 
 
 
X 
X 
X 
X 
Q1C 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
Review Adverse 
Events 
 
 
X 
X 
X 
X 
Q1C 
X 
ECOG Performance 
Status 
 
X 
X 
X 
X 
X 
Q1C 
X 
Vital Signs and Weight 
 
X 
X 
X 
X 
X 
Q1C 
X 
Physical Examinationb 
 
X 
X 
X 
X 
X 
Q1C 
X 


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EKG 
 
X 
 
 
 
 
 
 
Laboratory 
Assessments 
 
 
 
 
 
 
 
 
LOH Assessment 
Xd 
 
 
 
 
 
 
 
iHRD Analysis/Whole 
Exome Sequencing 
 
X 
 
 
 
 
 
 
PSA 
 
X 
X 
 
 
X 
Q3C 
X 
Testosterone Level 
 
X 
 
 
 
 
 
 
CBC with Differential 
 
X 
X 
X 
X 
X 
Q1C 
X 
Comprehensive Serum 
Chemistry Panel 
 
X 
X 
X 
X 
X 
Q1C 
X 
PT/INR and PTT 
 
X 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
Correlative Studies 
Blood Collectionc 
 
 
X 
 
 
X 
 
X 
Research Biopsye 
 
X 
 
 
 
 
 
X 
Radiographic 
Assessmentsf 
 
Xi 
 
 
 
X 
Q3C 
 
A. One treatment cycle is equal to 28 days 
B. Full physical exam is required at screening. Subsequent physical exams may be targeted. 
C. Refer to Laboratory Manual for details on correlative blood sample processing. 
D. Pathologic assessment to evaluate LOH score is a pre-screening requirement and will be performed 
on archival tissue or ctDNA. Sufficient tissue must also be available for whole exome sequencing in 
order to determine iHRD status.  
E. If archival metastatic tissue previously obtained is already available and suitable for 
research 
assessments, another metastatic biopsy will not be mandated. Research biopsy will only occur if 
considered safe and feasible by the treatment team. CBC with Differential, PT/INR and PTT will only 
be obtained in the pre-screening period if metastatic biopsy is planned. 
F. Radiographic assessments should include a CT chest/abdomen/pelvis and bone scan. PET/CT or MRI 
may be used as initial screening assessments.  
G. Assessments done during the screening period do not need to be repeated if within 7 days. 
H. Assessments do not need to be repeated if within 7 days 
I. Radiographic assessments do not need to be repeated if within 8 weeks 
 


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1.2 
Synopsis 
Protocol Title: Olaparib in Prostate Cancer Patients With Evidence of Homologous 
Recombination Deficiency As Assessed Using an Integrated Genomic Signature 
Short Title: Novel Genomic Signature and Olaparib Response 
Rationale: 
Homologous recombination repair (HRR) is a key pathway involved in resolving double-stranded 
DNA (dsDNA) breaks. Inactivating mutations in homologous recombination (HR) genes have 
been associated with improved outcomes to PARP inhibitors (PARPi) in men with mCRPC. Our 
group has developed an integrated approach to calling HRD signatures (iHRD - integrated 
Homologous Recombination Deficiency) with the goal of predicting sensitivity to DNA damaging 
therapeutics such as PARPi. This signature is a multiparametric classification that was defined 
using 418 patient samples from the Stand Up 2 Cancer (SU2C) repository and was subsequently 
validated on a set of 139 tumors from our UW rapid autopsy program. Importantly, this assay 
allows us to identify 11-12% of mCRPC patients who do not have mutations in HR genes but who 
we would predict to have functional loss of HR and therefore stand to benefit from PARP 
inhibition.  Based on these observations, we hypothesize that iHRD signature analysis will allow 
us to identify more men who are likely to benefit from PARP inhibitors, including those (11-12% 
of mCRPC population) who are otherwise excluded from clinical trials evaluating these agents. 
We therefore plan to conduct a Phase II study to evaluate the utility of using iHRD signature 
analysis to select patients for treatment with olaparib. 
Objectives and Endpoints:  
Primary Objective: 
Determine the percent of patients achieving a ≥50% reduction in PSA (PSA50 response) 
following at least 12 weeks of treatment with olaparib 300mg twice daily in men with metastatic 
castration-resistant prostate cancer (mCRPC) who are iHRD+ and who have progressed on a 
second generation hormonal agent (e.g. abiraterone or enzalutamide).  
Secondary Objectives: 
1. Determine the percent of iHRD+ mCRPC patients achieving radiographic response per 
RECIST 1.1 criteria following treatment with olaparib. 
 
2. Determine the radiographic progression free survival (PFS) in iHRD+ mCRPC patients 
treated with olaparib. 
 
3. Determine the PSA PFS according to PCWG3 criteria in iHRD+ mCRPC patients treated 
with olaparib. 
 
4. Determine the overall survival in iHRD+ mCRPC patients treated with olaparib. 
 


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5. Assess the incidence and severity of adverse events according to the National Cancer 
Institute- Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
 
Exploratory Objectives: 
Correlative work will be conducted to assess differences in clinical outcomes in those with vs. 
without iHRD positivity. This work will also allow us to further understand the biology 
underlying these differences. Serial blood samples and metastatic tissue will be obtained at 
baseline and upon progression. Examples of studies to be conducted may include, but are not 
limited to:  
1. 
Evaluate for differences in radiographic/PSA response and PFS in patients who are 
iHRD+ compared to patients who are iHRD-. 
2. 
Evaluate for differences in radiographic/PSA response and PFS by specific HR gene 
involvement.  
3. 
Compare iHRD signature to other functional methods of predicting HRD including large 
scale state transition (LST) score and COSMIC signature 3/8 status, Telomeric allelic imbalance 
(TAI) score. 
4. 
Optimize iHRD signature based on the results of this trial and develop a pipeline for 
calling iHRD from targeted exome panels.  
5. 
Conduct transcript profiling studies on metastatic tissue.  
Primary Endpoint: 
Lowest on-treatment PSA, following at least 12 weeks of olaparib in men with mCRPC who are 
iHRD+ 
Secondary Endpoints: 
The following endpoints will be assessed in men with iHRD+ mCRPC treated with olaparib: 
1. Radiographic response rate per RECIST 1.1 criteria  
 
2. Radiographic progression free survival (PFS)  
 
3. PSA PFS according to PCWG3 criteria 
 
4. Overall survival 
 
5. Incidence and severity of adverse events according to the National Cancer Institute- 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
 


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Study Design 
This will be a single arm, Phase II study designed to evaluate the clinical activity of olaparib in 
mCRPC patients with evidence of HRR deficiency as determined using iHRD signature analysis. 
Patients will initially be screened for eligibility on the basis of a loss of heterozygosity (LOH) 
score optimized for UW OncoPlex, a clinical grade targeted sequencing assay. Eligible LOH 
score positive subjects will then enroll and receive treatment with olaparib 300 mg by mouth 
twice daily. One treatment cycle will be defined as 28-days, and consist of continuous daily 
dosing of olaparib. All patients will then undergo germline and somatic whole exome sequencing 
(WES) to assess iHRD status. Only those found to be iHRD+ will be used for the purpose of 
assessing the primary endpoint (i.e. best PSA response). Those patients that are LOH score-
positive/iHRD-negative will be allowed to continue on treatment, however, and will be used in 
assessment of exploratory objectives. All patients will continue on androgen deprivation therapy 
(ADT) (i.e. surgical or medical castration), and should have a two-week washout from their most 
recent mCRPC therapy and weaned from steroids prior to enrolment. 
PSA will be measured on day 1 of every third cycle. Radiographic assessment with bone and CT 
scans will occur every 12 weeks. The primary endpoint will be lowest on-treatment PSA and 
primary objective is to determine the PSA50 rate. Patients will be permitted to continue until 
disease progression by radiographic (per RECIST 1.1), PSA (per PWCG3 criteria) or clinical 
criteria (e.g. increasing pain), whichever comes first. Prior to completing 3 cycles of treatment, 
patients should not discontinue treatment for PSA progression alone. Patients will come off study 
at time of clinical, radiographic, or PSA progression. Secondary objectives will include 
assessment of radiographic PFS, PSA PFS, overall survival, and adverse events.  
1.2.1 Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following inclusion criteria and 
none of the exclusion criteria apply: 
1. 
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. 
2. 
Subject must be > 18 years of age at the time of signing the informed consent form. 
3. 
Individuals who have documented histologically confirmed adenocarcinoma of the 
prostate. 
4. 
Subject must have evidence of castration resistant prostate cancer as evidenced by 
PSA progression (per Prostate Cancer Working Group 3 [PCWG3] criteria) and a 
castrate serum testosterone level (i.e. < 50 mg/dL)1. 
5. 
PSA must be at least 2 ng/mL and rising on two successive measurements at least two 
weeks apart.  
6. 
At least one lesion (measurable and/or non-measurable) that can be accurately 
assessed at baseline by CT scan, MRI, or PET and is suitable for repeated assessment.  


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7. 
Must have progressed on abiraterone and/or a second generation AR antagonist (i.e. 
enzalutamide, apalutamide, or darolutamide). If these were given in the hormone 
sensitive setting, patients must also have progressed on at least one prior approved 
therapy for CRPC. 
8. 
Must have archival tissue available or be willing to undergo metastatic biopsy in order 
to perform next-generation DNA sequencing and undergo whole exome sequencing.  
9. 
Patient must have a positive LOH score on prior UW OncoPlex testing 
10. 
Patients must have normal organ and bone marrow function measured within 28 days 
prior to administration of study treatment as defined below: 
− 
Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days   
− 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
− 
Platelet count ≥ 100 x 109/L 
− 
Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) 
− 
Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase 
(SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate 
Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver 
metastases are present in which case they must be ≤ 5x ULN 
− 
Patients must have creatinine clearance estimated of ≥51 mL/min using the 
Cockcroft-Gault equation or based on a 24 hour urine test : 
Estimated creatinine clearance = 
(140-age [years]) x weight (kg)    
 
 
 
 
 
serum creatinine (mg/dL) x 72 
11. 
Eastern Cooperative Oncology Group (ECOG) performance status ≤2  
12. 
Patients must have an estimated life expectancy ≥ 16 weeks. 
13. 
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 ([see appendix C for acceptable methods]) if they are 
of childbearing potential 
Exclusion Criteria  
1. As judged by the investigator, any evidence of serious and/or unstable pre-existing medical 
or psychiatric condition which in the investigator’s opinion makes it undesirable for the 
patient to participate in the trial. 


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2. Other malignancy unless curatively treated with no evidence of disease for ≥5 years  except: 
adequately treated non-melanoma skin cancer and non-muscle invasive bladder cancer. 
3. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by 
the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive 
heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with 
congenital long QT syndrome. 
4. Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2) 
caused by previous cancer therapy, excluding alopecia. 
5. Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive 
of MDS/AML. 
6. Patients with symptomatic uncontrolled brain metastases.  A scan to confirm the absence of 
brain metastases is not required. The patient can receive a stable dose of corticosteroids 
before and during the study as long as these were started at least 4 weeks prior to treatment.  
Patients with spinal cord compression unless considered to have received definitive treatment 
for this and evidence of clinically stable disease for 28 days. 
7. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-
malignant systemic disease or active, uncontrolled infection.  Examples include, but are not 
limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial 
infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior 
vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution 
Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining 
informed consent. 
8. Patients unable to swallow orally administered medication and patients with gastrointestinal 
disorders likely to interfere with absorption of the study medication.  
9. Immunocompromised patients, e.g., patients who are known to be serologically positive for 
human immunodeficiency virus (HIV) and are not receiving active treatment or who have a 
detectable viral load. 
10. Patients with known active hepatitis (i.e. Hepatitis B or C).  
− 
Active hepatitis B virus (HBV) is defined by a known positive HBV surface 
antigen (HBsAg) result.  Patients with a past or resolved HBV infection 
(defined as the presence of hepatitis B core antibody and absence of 
HBsAg) are eligible. 
− 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. 
11. Any previous treatment with PARP inhibitor, including Olaparib. 


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12. Any previous treatment with platinum chemotherapy in the metastatic castration-resistant 
setting. 
13. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) 
within 3 weeks prior to study treatment.  
14. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, 
nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, 
erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to 
starting olaparib is 2 weeks. 
15. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort ) or moderate CYP3A 
inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting 
olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. 
16. Major surgery within 2 weeks of starting study treatment and patients must have recovered 
from any effects of any major surgery. 
17. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation 
(dUCBT). 
18. Patients with a known hypersensitivity to olaparib or any of the excipients of the product. 
19. Involvement in the planning and/or conduct of the study. 
20. Judgment by the investigator that the patient should not participate in the study if the patient 
is unlikely to comply with study procedures, restrictions and requirements. 
Statistical Methods 
Based on the PROFOUND study, we estimate a response rate of 20% (H0) in patients with any 
HR mutations (e.g. BRCA2, ATM, CDK12, CHEK2, etc).2 We will require a 50% (H1) response 
rate in iHRD positive patients to justify further development of this approach for selecting 
patients for olaparib treatment. Therefore, assuming we enroll 20 iHRD positive patients, this 
study would provide 87% power at a one-sided alpha of 0.03 to detect a 50% response rate 
compared to the null rate of 20%. Given that prior experience has shown that ~75% of patients 
with a positive LOH score will also have evidence of iHRD positivity, we will enroll a total of 
30 patients to identify at least 22 iHRD positive subjects. This should allow for a drop out rate of 
10% to ensure that at least 20 iHRD positive subjects are able to reach 12 weeks of treatment for 
the primary endpoint analysis. 
The primary objective is to determine the percentage of patients who are iHRD+ that achieve a 
PSA50 response (i.e. ≥50% decline in PSA from baseline). The lowest on treatment PSA will be 
defined as the lowest value following at least 12 weeks of treatment (i.e. the beginning of Cycle 
4). The PSA50 response rate will be calculated along with 90% confidence intervals (CI). PSA 
changes will be presented as waterfall plots per PCWG3 recommendations. If a patient drops out 


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of the study prior to assessing best PSA response he will be considered as not having had a 
PSA50 response. However, an additional study subject will be enrolled to ensure an adequate 
number of subjects are available to estimate the PSA50 response rate. 
1.3 
Schema 
The general study design is summarized in Figure 1. 
Figure 1 
Study Design 
 
LOH loss of heterozygosity; iHRD integrated homologous recombination deficiency 
LOH 
High 
(n=30)  
Assess iHRD: 
Whole Exome 
Sequencing 
+ 
Paired Germline 
Sequencing 
iHRD+ 
(n=20) 
iHRD- 
(n=10) 
Olaparib 
Olaparib 
Screening 
Enrollment 
Progression 


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2. 
INTRODUCTION 
2.1 
Background and Study Rationale 
METASTATIC CASTRATION RESISTANT PROSTATE CANCER: 
Prostate cancer remains the second leading cause of cancer death among American men despite 
significant treatment advances in the past decade.3 Advanced prostate cancer is an androgen-
dependent malignancy, and the mainstay of treatment is androgen deprivation therapy and other 
hormonally targeted agents. However, resistance to these therapies inevitably develop, leading to 
the late and inevitably fatal disease state known as metastatic castration resistant prostate cancer 
(mCRPC).  Resistance is thought to be conferred by various mechanisms, including increased 
intratumoral steroidogenesis, increased androgen receptor expression, and constitutively active 
androgen receptor splice variants.  In addition there are several somatic genomic alterations that 
are associated with aggressive disease, including TP53 mutations or deletions, PTEN loss, and 
defects in DNA-repair genes.4 While recent approvals have expanded the treatment toolbox for 
patients with certain genetic alterations, the continued lethality of this disease highlights the need 
for additional therapeutic options.  
HOMOLOGOUS RECOMBINATION DEFICIENCY AND RESPONSE TO PARP 
INHIBITORS: 
Inactivating mutations in homologous recombination (HR) genes have been associated with 
improved responses to PARP inhibitors (PARPi) in men with mCRPC, likely through the 
induction of synthetic lethality. The TOPARP-A trial observed a response rate to the PARPi 
olaparib of 88% in men with homozygous deletions or deleterious mutations in DNA-repair 
genes compared to 6% in men without these alterations.5 Further work has shown that response 
rates to PARP inhibitors vary dramatically depending on the affected gene.6,7 83.3% of men with 
BRCA 1/2 alterations responded to olaparib (50% decline in PSA or RECIST 1.1 objective 
response) in the TOPARP-B trial compared to 10.5% with ATM mutations and 0% with CDK12 
mutations.7 The finding of heterogeneous clinical outcomes based on affected gene has been 
recapitulated in both the TRITON2 and PROfound studies.2,6  This variability in response 
underscores the problem with relying on 3-15 gene panels to define homologous recombination 
deficiency (HRD) for the purpose of selecting patients for treatment with PARPi. Furthermore, 
there is also a subset of patients without known deleterious mutations who still respond to 
treatment with a PARPi.5 Taken together, these observations suggest that defects in DNA-repair 
genes are an imperfect biomarker to predict response to PARP inhibition and highlight the need 
for development of novel predictive strategies.  
Differences in response to PARPi by affected gene may partially be explained by the fact that not 
all genes have the same biologic significance in terms of their role in mediating homologous 
recombination repair. In addition, next generation sequencing (NGS) assays looking for mutation 
defects in specific genes will miss epigenetic and cryptic events that result in HRD. Therefore, 
functional measures of HRD should provide a more reliable means for selecting patients who 
would benefit from treatment with a PARP inhibitor. 


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PREDICTING HOMOLOGOUS RECOMBINATION DEFICIENCY:  
Homologous recombination repair (HRR) is a key pathway involved in resolving double-
stranded DNA (dsDNA) breaks. HRR utilizes the undamaged sister chromatid as a template in 
order to produce error-free repair of the dsDNA damage.8 When functional defects occur in this 
pathway by germline and/or somatic events, characteristic genome wide alterations occur, which 
result in predictable tumor signatures that can be called using bioinformatic tools. This HR 
deficiency signature calling has the potential to complement existing genomic biomarkers being 
developed to identify those likely to benefit from PARPi treatment.9  
Several scores have been developed in an attempt to identify functional loss of HR activity, 
however, there are important limitations to the most widely used approaches10-13. An LOH-based 
score has been validated in epithelial ovarian cancer to strongly associate with functional defects 
in BRCA1 and BRCA2 as well as methylation of the promoter region of RAD51C, another gene 
in the HR pathway.10 Although this score may capture an additional subset of patients who have 
HRD tumors than those captured by NGS alone, it is impacted by tumor ploidy and cellularity 
and thus may lack specificity.  The COSMIC 3 signature has been developed based on unique 
genomic alterations associated with the loss of BRCA1/BRCA2.14,15 However, this signature does 
not appear to reliably discriminate between responder/non-responders to olaparib (Figure 2). 
To address these shortcomings, our group has developed an integrated approach to calling HRD 
signatures (iHRD - integrated Homologous Recombination Deficiency), with the goal of more 
reliably defining prostate cancer tumors that will be sensitive to DNA damaging therapeutics 
such as PARPi. This signature is a multiparametric classification that was defined using 418 
patient samples from the Stand Up 2 Cancer (SU2C) repository and was subsequently validated 
on a set of cases from our UW rapid autopsy program. iHRD was more closely associated with 
improved clinical outcomes in patients receiving olaparib on the TOPARP-B study (Figure 2)5. 
Importantly, iHRD also allows us to identify 11-12% of mCRPC patients who do not have 
mutations in HR genes but who we would predict to have functional loss of HR and therefore 
stand to benefit from PARP inhibition (Figure 3).  


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Figure 2. iHRD accurately predicts time on olaparib treatment. Data from 22 clinical cases of men with 
mutations in HRR genes treated with olaparib was re-analyzed, with time on olaparib treatment stratified by HRD 
mutational status, COSMIC3 signature and iHRD status. iHRD was more closely associated with time on olaparib 
than other approaches. iHRD correlated with time on olaparib treatment (top). Kaplan-Meier estimates showed a 
significant association between time on olaparib treatment and iHRD positivity; however, neither HR-biallelic loss 
nor COSMIC3 signature was associated with longer time on treatment. 
 
 
 


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Figure 3. iHRD distribution across HR mutant subgroups. Spectrum of iHRD distribution across homologous 
recombination (HR) and putative HR associated gene mutant subgroups. Bi-allelic BRCA1, BRCA2, ATM, and 
PALB2 as biomarkers would potentially miss 65 of 107 iHRD+ mCRPC.  
 
OLAPARIB BACKGROUND 
Investigators should be familiar with the current olaparib (AZD2281) Investigator Brochure (IB). 
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. 
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 prostate 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. 
Olaparib is currently FDA approved for men with metastatic castration resistant prostate cancer 
who have germline or somatic defects in any one of 14 HRR genes and who have progressed 
following treatment with enzalutamide or abiraterone. This approval was granted on the basis of 
the PROfound study – a Phase III randomized, open-label, multi-center trial16. Patients were 
eligible to enroll if they had mCRPC and had previously received either enzalutamide or 


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abiraterone and who had HRR gene alterations. Men received either olaparib 300mg twice daily 
or investigator’s choice of either abiraterone or enzalutamide. The primary endpoint was 
progression free survival (PFS) in the group with BRCA1, BRCA2 and/or ATM mutations (Cohort 
A). A second cohort consisted of patients with mutations in other HR repair-associated genes 
(Cohort B). Secondary endpoints were analyzed in a hierarchical fashion to control for trial-wide 
type 1 error associated with multiple testing, which occurred in the following order: objective 
response rate (Cohort A), PFS (combined Cohorts A and B), time to pain progression (Cohort 
A), and overall survival (Cohort A).  
The primary endpoint of PROfound was met, with a PFS of 7.4 months vs. 3.6 months (P<0.001) 
in the olaparib vs. control groups for Cohort A. Secondary endpoints also favored the olaparib 
group, with an objective response rate in Cohort A of 33% vs. 2% in control group (P<0.001), 
median PFS of 5.8 months vs. 3.5 months for combined Cohorts A and B (P<0.001), median 
overall survival of 18.5 months vs. 15.1 months for Cohort A (P=0.02) and median overall 
survival of 17.5 months vs. 14.3 months for combined Cohorts A and B (P=0.0063). These 
results led the FDA to approve olaparib for a broad group of mCRPC patients with somatic or 
germline alterations in BRCA1, BRCA2 or any of 12 additional HR repair pathway genes. 
It should be noted that data supporting the use of olaparib in patients with non-BRCA mutations 
is sparse. There was no clear difference in PFS observed in either ATM (N=86) or CDK12-
mutated (N=89) (Figure 2B and Supplemental Figure S5) patients enrolled on PROfound.  In 
addition, the reported PSA and radiographic response rates for ATM (5.3% and 8.3%, 
respectively) and CDK12-mutated mCRPC (0% for both) was also low in TOPARP-B7. These 
results highlight the need for refinement of HRD biomarkers.  
HYPOTHESIS: 
Based on these observations, we hypothesize that iHRD signature analysis will allow us to 
identify more men who are likely to benefit from PARP inhibitors, including those (11-12% of 
mCRPC population) who are otherwise excluded from clinical trials evaluating these agents. We 
therefore plan to conduct a Phase II study to evaluate the utility of using iHRD signature analysis 
to select patients for treatment with olaparib. 
2.2 
Benefit/Risk Assessment 
Olaparib is an FDA approved therapy for men with mCRPC and mutations in genes associated 
with homologous recombination repair based on improved progression free survival compared to 
novel hormonal agents (i.e. abiraterone or enzalutamide)17. This trial will include men with 
mCRPC and evidence of HRD based on a novel integrated genomic signature (iHRD). Based on 
the aforementioned rationale, we anticipate that olaparib will be effective in this patient 
population.  One benefit of this study is access to a potentially efficacious antineoplastic 
medication that would not otherwise be available for a subset of men with mCRPC. Further, men 
in this study will have already progressed on at least one approved therapy for mCRPC, and 
effective treatment options remain somewhat limited for this patient population. 
Risks of participating in this study are the known toxicities of olaparib, including hematologic 
toxicities, infections associated with myelosuppression, gastrointestinal toxicity, venous 


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thromboembolic events and risk of secondary leukemias/myelodysplastic syndrome17. For 
information on all identified and potential risks with olaparib refer to the current version of the 
IB. Overall, the investigators feel that the benefits of participating in this study outweigh the 
risks of participation.  
3. 
OBJECTIVES AND ENDPOINTS 
3.1 
PRIMARY OBJECTIVE: 
Determine the percent of patients achieving a ≥50% reduction in PSA (PSA50 response) 
following at least 12 weeks of treatment with olaparib 300mg twice daily in men with metastatic 
castration-resistant prostate cancer (mCRPC) who are iHRD+ and who have progressed on a 
second generation hormonal agent (e.g. abiraterone or enzalutamide).  
3.2 
SECONDARY OBJECTIVES: 
6. Determine the percent of iHRD+ mCRPC patients achieving radiographic response per 
RECIST 1.1 criteria following treatment with olaparib. 
 
7. Determine the radiographic progression free survival (PFS) in iHRD+ mCRPC patients 
treated with olaparib. 
 
8. Determine the PSA PFS according to PCWG3 criteria in iHRD+ mCRPC patients treated 
with olaparib. 
 
9. Determine the overall survival in iHRD+ mCRPC patients treated with olaparib. 
 
10. Assess the incidence and severity of adverse events according to the National Cancer 
Institute- Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
 
3.3 
EXPLORATORY OBJECTIVES: 
Correlative work will be conducted to assess differences in clinical outcomes in those with vs. 
without iHRD positivity. This work will also allow us to further understand the biology 
underlying these differences. Serial blood samples and metastatic tissue will be obtained at 
baseline and upon progression. Examples of studies to be conducted may include, but are not 
limited to:  
1. 
Evaluate for differences in radiographic/PSA response and PFS in patients who are 
iHRD+ compared to patients who are iHRD-. 
2. 
Evaluate for differences in radiographic/PSA response and PFS by specific HR gene 
involvement.  


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3. 
Compare iHRD signature to other functional methods of predicting HRD including large 
scale state transition (LST) score and COSMIC signature 3/8 status, Telomeric allelic imbalance 
(TAI) score, and presence of underlying HRR mutation. 
4. 
Optimize iHRD signature based on the results of this trial and develop a pipeline for 
calling iHRD from targeted exome panels.  
5. 
Conduct transcript profiling studies on metastatic tissue.  
3.4 
PRIMARY ENDPOINT: 
Lowest on-treatment PSA, following at least 12 weeks of olaparib in men with mCRPC who are 
iHRD+ 
3.5 
SECONDARY ENDPOINTS: 
The following endpoints will be assessed in men with iHRD+ mCRPC treated with olaparib: 
1. Radiographic response rate per RECIST 1.1 criteria  
 
2. Radiographic progression free survival (PFS)  
 
3. PSA PFS according to PCWG3 criteria 
 
4. Overall survival 
 
5. Incidence and severity of adverse events according to the National Cancer Institute- 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
4. 
STUDY DESIGN 
4.1 
Overall Design 
This will be a single arm, Phase II study designed to evaluate the clinical activity of olaparib in 
mCRPC patients with evidence of HRR deficiency as determined using iHRD signature analysis. 
Patients will initially be screened for eligibility on the basis of a loss of heterozygosity (LOH) 
score optimized for UW OncoPlex, a clinical grade targeted sequencing assay. Eligible LOH 
score positive subjects will then enroll and receive treatment with olaparib 300 mg by mouth 
twice daily. One treatment cycle will be defined as 28-days, and consist of continuous daily 
dosing of olaparib. All patients will then undergo germline and somatic whole exome sequencing 
(WES) to assess iHRD status. Only those found to be iHRD+ will be used for the purpose of 
assessing the primary endpoint (i.e. best PSA response). Those patients that are LOH score-
positive/iHRD-negative will be allowed to continue on treatment, however, and will be used in 
assessment of exploratory objectives. All patients will continue on androgen deprivation therapy 
(ADT) (i.e. surgical or medical castration) and should have a two-week washout from their most 
recent mCRPC therapy and weaned from steroids prior to enrolment. 


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PSA will be measured on day 1 of each treatment cycle. Radiographic assessment with bone and 
CT scans will occur every 12 weeks. The primary endpoint will be lowest on-treatment PSA and 
primary objective is to determine the PSA50 rate. Patients will be permitted to continue until 
disease progression by radiographic (per RECIST 1.1), PSA (per PWCG3 criteria) or clinical 
criteria (e.g. increasing pain), whichever comes first. Prior to completing 3 cycles of treatment, 
patients should not discontinue treatment for PSA progression alone. Patients will come off study 
at time of clinical, radiographic, or PSA progression. Secondary objectives will include 
assessment of radiographic PFS, PSA PFS, overall survival, and adverse events.  
For an overview of the study design see Figure 1, Section 1.3. For details on treatments given 
during the study, see Section 5.5 Treatments Administered.   
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives and 
Endpoints.   
4.2 
Scientific rationale for study design 
Overall rationale and study population: 
The purpose of this study is to explore the efficacy of using a functional method of calling HRR 
deficiency (HRD) to predict response to olaparib. Men with mCRPC will be eligible if they have 
a positive LOH score on metastatic tissue and/or cell-free circulating tumor DNA (ctDNA), 
which has been associated with response to PARP inhbition10. They are eligible for inclusion 
into the study if they have progressed on abiraterone or enzalutamide, which is in concordance 
with the current population for which olaparib is indicated. 
Study design: 
This is a single arm, Phase II study designed to provide an initial estimate of clinical activity of 
olaparib in mCRPC patients that have iHRD+ tumors. Because there is no control group this 
study will not be blinded.  
Primary and secondary outcome measures: 
Lowest on-treatment PSA was chosen as a primary endpoint, as decline in PSA is generally 
associated with tumor control and can be assessed as early as 12 weeks. Radiographic response 
rate was not chosen as many prostate cancer patients have primarily osseous metastases and are 
not evaluable per RECIST criteria. This study follows the PCWG3 criteria for assessing PSA and 
defining PSA progression1.  Secondary outcomes included are also reflective of PCWG3 
guidelines.  
4.3 
Justification for dose 
The dose of olaparib used in this study is 300 mg twice daily, which is the currently FDA 
approved dose. 


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4.4 
End of study definition 
The end of study is defined as the last expected visit/contact of the last patient undergoing the 
study. Follow up will continue for up to one year after the last patient discontinues treatment.  
5. 
STUDY POPULATION 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned to a study intervention.  Under no circumstances can there be 
exceptions to this rule. Patients who do not meet the entry requirements are screen failures, refer 
to section 5.4. 
5.1 
Inclusion criteria 
Patients are eligible to be included in the study only if all of the following inclusion criteria and 
none of the exclusion criteria apply: 
1. 
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. 
2. 
Subject must be > 18 years of age at the time of signing the informed consent form. 
3. 
Individuals who have documented histologically confirmed adenocarcinoma of the 
prostate. 
4. 
Subject must have evidence of castration resistant prostate cancer as evidenced by 
PSA progression (per Prostate Cancer Working Group 3 [PCWG3] criteria) and a 
castrate serum testosterone level (i.e. < 50 mg/dL)1. 
5. 
PSA must be at least 2 ng/mL and rising on two successive measurements at least two 
weeks apart.  
6. 
At least one lesion (measurable and/or non-measurable) that can be accurately 
assessed at baseline by CT scan, MRI, or PET and is suitable for repeated assessment.  
7. 
Must have progressed on abiraterone and/or a second-generation AR antagonist (i.e. 
enzalutamide, apalutamide, or darolutamide). If these were given in the hormone 
sensitive setting, patients must also have progressed on at least one prior approved 
therapy for CRPC. 
8. 
Must have archival tissue available or be willing to undergo metastatic biopsy in order 
to perform next-generation DNA sequencing and undergo whole exome sequencing.  
9. 
Patient must have a positive LOH score on prior UW OncoPlex testing 


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10. 
Patients must have normal organ and bone marrow function measured within 28 days 
prior to administration of study treatment as defined below: 
− 
Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days   
− 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
− 
Platelet count ≥ 100 x 109/L 
− 
Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) 
− 
Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase 
(SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate 
Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver 
metastases are present in which case they must be ≤ 5x ULN 
− 
Patients must have creatinine clearance estimated of ≥51 mL/min using the 
Cockcroft-Gault equation or based on a 24 hour urine test: 
Estimated creatinine clearance = 
(140-age [years]) x weight (kg)    
 
 
 
 
 
serum creatinine (mg/dL) x 72 
11. 
Eastern Cooperative Oncology Group (ECOG) performance status ≤2  
12. 
Patients must have an estimated life expectancy ≥ 16 weeks. 
13. 
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 ([see appendix C for acceptable methods]) if they are 
of childbearing potential 
5.2 
Exclusion criteria  
1. 
As judged by the investigator, any evidence of serious and/or unstable pre-existing 
medical or psychiatric condition which in the investigator’s opinion makes it 
undesirable for the patient to participate in the trial. 
2. 
Other malignancy unless curatively treated with no evidence of disease for ≥5 years 
except: adequately treated non-melanoma skin cancer and non-muscle invasive 
bladder cancer. 
3. 
Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as 
judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic 
arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte 
disturbances, etc.), or patients with congenital long QT syndrome. 


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4. 
Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) 
grade 2) caused by previous cancer therapy, excluding alopecia. 
5. 
Patients with myelodysplastic syndrome/acute myeloid leukemia or with features 
suggestive of MDS/AML. 
6. 
Patients with symptomatic uncontrolled brain metastases.  A scan to confirm the 
absence of brain metastases is not required. The patient can receive a stable dose of 
corticosteroids before and during the study as long as these were started at least 4 
weeks prior to treatment.  Patients with spinal cord compression unless considered to 
have received definitive treatment for this and evidence of clinically stable disease for 
28 days. 
7. 
Patients considered a poor medical risk due to a serious, uncontrolled medical 
disorder, non-malignant systemic disease or active, uncontrolled infection.  Examples 
include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 
months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal 
cord compression, superior vena cava syndrome, extensive interstitial bilateral lung 
disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric 
disorder that prohibits obtaining informed consent. 
8. 
Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication.  
9. 
Immunocompromised patients, e.g., patients who are known to be serologically 
positive for human immunodeficiency virus (HIV) and are not receiving active 
treatment or have a detectable viral load. 
10. 
Patients with known active hepatitis (i.e. Hepatitis B or C).  
− 
Active hepatitis B virus (HBV) is defined by a known positive HBV surface 
antigen (HBsAg) result.  Patients with a past or resolved HBV infection 
(defined as the presence of hepatitis B core antibody and absence of 
HBsAg) are eligible. 
− 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. 
11. 
Any previous treatment with PARP inhibitor, including Olaparib. 
12. 
Any previous treatment with platinum chemotherapy in the metastatic castration-
resistant setting. 
13. 
Patients receiving any systemic chemotherapy or radiotherapy (except for palliative 
reasons) within 3 weeks prior to study treatment.  


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14. 
Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. 
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout 
period prior to starting olaparib is 2 weeks. 
15. 
Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort ) or 
moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout 
period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 
weeks for other agents. 
16. 
Major surgery within 2 weeks of starting study treatment and patients must have 
recovered from any effects of any major surgery. 
17. 
Previous allogenic bone marrow transplant or double umbilical cord blood 
transplantation (dUCBT). 
18. 
Patients with a known hypersensitivity to olaparib or any of the excipients of the 
product. 
19. 
Involvement in the planning and/or conduct of the study. 
20. 
Judgment by the investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements. 
5.3 
Lifestyle restrictions 
No restrictions are required.  
5.3.1 
Meals and dietary restrictions 
It is prohibited to consume grapefruit juice while on olaparib therapy. 
5.3.2 
Activity 
Contraception 
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 (as described in Appendix C) if they are of childbearing potential.  Male 
patients should not donate sperm throughout the period of taking olaparib and for 3 months 
following the last dose of olaparib. 
For details of acceptable methods of contraception refer to Appendix C Acceptable Birth Control 
Methods. 


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5.4 
Screen failures 
Screen failures are defined as patients who signed the informed consent form to participate in the 
clinical study but are not subsequently entered in the study. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.   
These patients should have the reason for study withdrawal recorded in the CRF.  
5.5 
Study Treatments 
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study participant 
according to the study protocol. Study treatment in this study refers to the drug olaparib.  
Treatments administered 
5.5.1 
Investigational products 
 
Table 2 
Study Treatments 
 
 
Treatment 1 
 
 
Study treatment name: 
 
Olaparib 
 
Dosage formulation: 
Tablets 
 
 
 
 
 
 
Route of administration  
Oral 
 
 
Dosing instructions: 
 
Olaparib tablets should be taken at the same time 
each day, approximately 12 hours apart with one 
glass of water.  The tablets should be swallowed 
whole and not chewed, crushed, dissolved or 
divided. Olaparib tablets can be taken with or 
without food. 
 
 
Packaging and labelling 
 
Study treatment will be provided in high-density 
polyethylene (HDPE) bottles with child-resistant 
closures. Each container will be labeled in 
accordance with Good Manufacturing Practice 
(GMP) Annex 13 and per country regulatory 
requirement. 
 
 


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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. 
5.6 
Preparation/handling/storage/accountability 
 The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only patients enrolled in the study may receive study treatment and only authorized site staff 
may dispense study treatment. Lynparza will be supplied from commercial stock, as bulk 
supplies to a single site only. The Sponsor will be responsible for labelling and onward 
distribution to sub-sites if applicable.  At site, all study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the investigator and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
5.7 
Treatment compliance  
Patients should be given clear instructions on how and when to take their study treatment.  
Patients will self-administer olaparib. They will receive a pill diary as shown in Appendix D.   
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 until reconciliation is completed by the study monitor.  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. 
5.8 
Concomitant therapy 
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 


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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 
 
Anti-emetics/Anti-diarrheals 
From screening part 2 onwards, should a patient develop nausea, vomiting and/or diarrhea, then 
these symptoms should be reported as AEs (see section 8.3) and appropriate treatment of the 
event given. 
Medications that may NOT be administered 
Table 4 
Prohibited medications 
Prohibited medication/class of drug: 
 
Anticancer therapy: 
Chemotherapy 
Immunotherapy 
Radiotherapy (except palliative) 
Biological therapy 
Other novel agents 
Not permitted while the patient is receiving study 
medication 
Live virus vaccines 
Live bacterial vaccines 
Not permitted while the patient is receiving study 
medication and during the 30 day follow up period.  
An increased risk of infection by the administration 
of live virus and bacterial vaccines has been observed 
with conventional chemotherapy drugs and the effects 
with olaparib are unknown. 
 
 
 
 
 


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Table 5 
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 5 
Restricted concomitant medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed ): 
• CYP3A4 substrates with narrow 
therapeutic margin: cisapride, 
cyclosporine, ergot alkaloids, 
fentanyl, pimozide, sirolimus, and 
tacrolimus 
• 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 
• BCRP substrates: methotrexate, 
rosuvastatin 
• P-gp substrates: simvastatin, 
pravastatin, dabigatran, digoxin and 
colchicine 
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 statins or sensitive 
CYP3A4 substrates are co-administered. 
Appropriate clinical monitoring is recommended 
for patients receiving P-gp substrates or CYP3A 
substrates with a narrow therapeutic margin 
concomitantly with olaparib. 
 
Anticoagulant therapy 
Patients who are taking warfarin may participate 
in this trial; however, it is recommended that 
international normalised ratio (INR) be 
monitored carefully at least once per week for 
the first month, then monthly if the INR is stable. 
Non-vitamin K antagonist oral anticoagulants 
(NOACs), subcutaneous heparin and low 
molecular weight heparin may be given 
concomitantly with olaparib and INR monitoring 
is not required. If NOACs are used, it is 
preferable to avoid CYP3A substrates (e.g 
apixaban and rivaroxaban) if possible. 


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Table 5 
Restricted concomitant medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed ): 
Palliative radiotherapy 
Palliative radiotherapy may be used for the 
treatment of pain at the site of bony metastases 
that were present at baseline, provided the 
investigator does not feel that these are indicative 
of clinical disease progression during the study 
period.  Study treatment should be discontinued 
for a minimum of 3 days before a patient 
undergoes therapeutic palliative radiation 
treatment.  Study treatment should be restarted 
within 4 weeks as long as any bone marrow 
toxicity has recovered.   
Administration of other anti-cancer agents 
 
Patients must not receive any other concurrent 
anti-cancer therapy, including investigational 
agents, while on study treatment. Patients may 
continue the use of bisphosphonates or 
denosumab for bone disease and corticosteroids 
for the symptomatic control of brain metastases 
provided the dose is stable before and during the 
study and they were started at least 4 weeks prior 
to beginning study treatment.  
 
 
 
5.8.1 
Background medication 
All patients will be maintained on androgen deprivation therapy (ADT) if they have not had a 
prior orchiectomy for the duration of the study. Patients may also be receiving osteoclast 
inhibitors for prevention of skeletal related events and these will be permitted to continue. 
5.8.2 
Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the patient’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the Case Report Form. 
In addition, any unplanned diagnostic, therapeutic or surgical procedure performed during the 
study period must be recorded in the CRF. 
5.9 
Dose modification 
Dose Reductions  


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In case a dose reduction is necessary, the Study treatment will be administered as follows:  
Table 6 
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 
250 mg twice daily 
200 mg twice daily 
 
 
Table 7 
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 8 
Dose reductions for olaparib 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 
 
For guidance on dose reductions for management of AEs (including renal impairment) refer to 
section 6.5.  
For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors cannot 
be avoided see section 6.5. 
When dose reduction is necessary patients will take one 150 mg tablet and one 100 mg tablet 
twice daily or two x 100 mg tablet twice daily (see Section 8.4.6), or one 150 mg tablet twice 
daily or one 100 mg tablet twice daily (see Section 6.5). 
5.10 
Treatment after the end of the study 
Not applicable - please see Section 4.1 for details of treatment after the study database has been 
closed. discontinuation of treatment and patient withdrawal 


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5.11 
Discontinuation of study treatment  
Patients may be discontinued from investigational product (IP) in the following situations. Note 
that discontinuation from study treatment is NOT the same thing as a complete withdrawal from 
the study 
• 
Patient decision. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment 
• 
Adverse Event 
• 
Severe non-compliance with the Clinical Study Protocol  
• 
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 
• 
Study drug held for >4 weeks due to an AE 
5.11.1 
Procedures for discontinuation of study treatment 
The investigator should instruct the patient to contact the site before or at the time if Study 
treatment is stopped.  A patient that decides to discontinue Study treatment will always be asked 
about the reason(s) and the presence of any AEs.  The date of last intake of Study treatment 
should be documented in the CRF (electronic or paper).  All Study treatment should be returned 
by the patient at their next on-site study visit or unscheduled visit.  Patients permanently 
discontinuing Study treatment should be given locally available standard of care therapy, at the 
discretion of the Investigator. 
Any patient discontinuing investigational product should be seen post discontinuation for the 
evaluations and sample collections outlined in the study schedule.  
After discontinuation of the study medication at any point in the study, all ongoing AEs or SAEs 
must be followed until resolution unless, in the Investigator’s opinion the condition is unlikely to 
resolve due to the patients underlying disease, or the patient is lost to follow up (see Section 
5.12) All new AEs and SAEs occurring during the 30 calendar days after the last dose of study 
medication must be reported (if SAEs, they must be reported within 24 hours as described in 
Section 6.4.2) and followed to resolution as above. Patients should be seen within 30 days after 
discontinuing study medication to collect and / or complete AE information. For guidance on 
reporting adverse events after the 30 day follow up period see Section 6.4.2.1. 
Discontinuation of Study treatment, for any reason, does not impact on the patient´s participation 
in the study.  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 


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and safety information.  This 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. 
5.12 
Lost to follow-up 
Patients will be considered lost to follow-up only if no contact has been established by the time 
that 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 Sponsor 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 protocol. 
In order to support key endpoints 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 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 where it is possible to do so under applicable local laws 
to obtain current survival status. (The applicable CRF modules will be updated).  
5.13 
Withdrawal from the study 
Patients are free to withdraw from the study at any time without prejudice to further treatment. 
Patients who withdraw consent for further participation in the study will not receive any further 
olaparib 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 Sponsor Investigator will follow up AEs outside of the clinical 
study.  
Biospecimens obtained, as part of trial participation will be retained.  
6. 
STUDY ASSESSMENTS AND PROCEDURES 
Assessments will be performed according to the Schedule of Activities (SoA).  


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6.1 
Assessment of HRD 
6.1.1 
LOH Score 
During pre-screening patients will be assessed for loss of heterozygosity (LOH) by the 
application of an LOH score that has been optimized for use on UW OncoPlex, a clinical grade 
sequencing assay. LOH events are detected using the R package Sequenza18, which uses data 
from tumor-normal sample pairs to probabilistically estimate tumor cellularity, ploidy, and 
allele-specific copy number abnormalities.  Whole genome duplication or loss events, which 
arise from non-HRD associated mechanisms, are disqualified19. Using custom scripts, the LOH 
score is defined as the ratio of the genome affected by loss of heterozygosity events relative to 
the total number of sequenced nucleotides for which the tumor copy number state can be 
successfully inferred19. 
6.1.2 
iHRD Status 
All patients will have iHRD status assessed during the screening phase by undergoing paired 
germline and somatic whole exome sequencing. iHRD is a genomic classification framework 
that incorporates LOH score, COSMIC Signature 3, COSMIC Signature 8, tumor ploidy, tumor 
purity and mutation burden to determine the classification status. The classification outcome is 
read as binary 1 and 0, equated to iHRD+ and iHRD- respectively. 
6.2 
Efficacy assessments  
6.2.1 
Primary Objective 
The primary objective is to determine the percentage of men achieving at least a 50% decline in 
PSA (PSA50 response) after twelve weeks of treatment with Olaparib 300mg by mouth twice 
daily. PSA will be collected from peripheral blood every cycle during the treatment phase. The 
lowest on treatment PSA will be defined as the lowest value following at least 12 weeks of 
treatment (i.e. the beginning of Cycle 4).  
6.2.2 
Secondary and Exploratory Objectives 
ORR and Radiographic Progression Free Survival 
Radiographic assessments which include computed tomography scan of the chest, abdomen, and 
pelvis as well as a nuclear medicine bone scan will be conducted every 12 weeks (every 3 
cycles) after screening. Radiographic response and progression will be defined per RECIST 1.1 
criteria. RECIST 1.1 is an accepted methodology by regulatory authorities and will be used to 
assess tumor response in patients with soft tissue disease. For patients with bony disease, 
progression will be defined per PCWG3 criteria1.  
Exploratory Objectives 
Correlative blood work and tissue analysis will be performed per the planned time points in the 
SoA. Full details of collection, processing, shipping, and storage of samples will be included in 
the Lab Manual.  


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6.3 
Safety assessments  
Planned time points for all safety assessments are provided in the SoA. 
6.3.1 
Clinical safety laboratory assessments 
Blood samples for determination of clinical chemistry and hematology will be taken at the times 
indicated in the assessment schedules as clinically indicated (see the SoA). Clinical laboratory 
safety 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 sponsor 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 this section in Table 9.  
Table 9 
Laboratory safety variables 
Hematology/Hemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-Hemoglobin (Hb) 
S/P-Creatinine 
B-Leukocyte count 
S/P-Bilirubin, total 
B-Absolute neutrophil count 
S/P-Alkaline phosphatase (ALP) 
B-Absolute lymphocyte count 
S/P-Aspartate transaminase (AST) 
B-Platelet count 
S/P-Alanine transaminase (ALT) 
B-Mean cell volume (MCV) 
S/P-Albumin 
 
S/P-Potassium 
S/P-Calcium, total 
Urinalysis (dipstick) 
 
U-Hb/Erythrocytes/Blood 
U-Protein/Albumin 
U-Glucose 
S/P-Sodium 
S/P- Urea or Blood Urea Nitrogen (BUN) 
S/p- Total Protein 
 
 
NB. In case a patient shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN 
please refer to Appendix A ‘Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law’, for further instructions. 


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Coagulation 
· 
activated partial thromboplastin time (APTT) will be performed at screening and if 
clinically indicated   
· 
international normalized ratio 20 will be performed at screening and if 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. 
 
Bone marrow or blood cytogenetic samples 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
hematological toxicities as defined in Section 6.5.5.1 
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. Full reports must be provided by the 
investigator for documentation on the Patient Safety database. These data are not required to be 
entered into CRF. 
6.3.2 
Physical examinations 
Physical examinations will be performed according to the assessment schedules (see the SoA). 
Full physical examinations will include assessments of the head, eyes, ears, nose, and throat, and 
the respiratory, cardiovascular, GI, musculoskeletal, neurological, and dermatological 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 6.4.7.  
6.3.3 
Vital signs 
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the SoA. Body weight is also recorded at each visit along with vital signs.  
6.3.4 
Electrocardiograms 
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, 2 additional 12-lead ECGs should be 
obtained over a brief period (e.g., 30 minutes) to confirm the finding 
6.4 
Data Monitoring and Collection of Adverse Events 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 


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Trial monitoring will be in accordance with the Fred Hutchinson Cancer Research Center 
(FHCRC)/University of Washington Cancer Consortium Institutional Data and Safety 
Monitoring Plan. Under the provisions of this plan, FHCRC Clinical Research Support 
coordinates data and compliance monitoring conducted by consultants, contract research 
organizations, or FHCRC employees unaffiliated with the conduct of the study. Independent 
monitoring visits occur at specified intervals determined by the assessed risk level of the study 
and the findings of previous visits per the institutional DSMP. 
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and 
Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) and the 
FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB). The 
review committees evaluate accrual, adverse events, stopping rules, and adherence to the 
applicable data and safety monitoring plan for studies actively enrolling or treating patients. The 
IRB reviews the study progress and safety information to assess continued acceptability of the 
risk-benefit ratio for human subjects. Approval of committees as applicable is necessary to 
continue the study. 
The trial will comply with the standard guidelines set forth by these regulatory committees and 
other institutional, state and federal guidelines. 
Additionally, scheduled meetings will take place weekly and will include the Sponsor 
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/ Sponsor 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. 
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative).   
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs see 
section 8.3.3.   
6.4.1 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.   
6.4.2 
Time period and frequency for collecting AE and SAE information  
Adverse Events will be collected from time of enrolment throughout the treatment period and 
including the follow-up period until last contact. 
SAEs will be recorded from the time of signing of informed consent form. 


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All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix B.  The investigator will submit any updated SAE data to the sponsor within 24 
hours of it being available. 
Investigators are not obligated to actively seek AE or SAE in former study patients. However, if 
the investigator learns of any SAE, including a death, at any time after a patient’s last visit and 
he/she considers the event to be reasonably related to the Study treatment or study participation, 
the investigator may notify the sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix B. 
 
Adverse events after the end of treatment visit 
For Pharmacovigilance purposes and characterization, any SAE of MDS/AML or new primary 
malignancy occurring after end of treatment 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 study patients. This includes new AEs/SAEs in patients still being followed 
up for survival but who have completed their end of treatment visit. 
6.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient at 
subsequent visits/contacts.  All AEs/non-serious AEs/AEs of special interest (as defined in 
Section 6.4.13, will be followed until resolution, stabilization, the event is otherwise explained, 
or the patient is lost to follow-up  
Any AEs that are unresolved at the patient’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the Investigator for as long as medically indicated, 
but without further recording in the CRF.  AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary. 


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Any SAE or non-serious adverse event that is ongoing at the time of the end of treatment visit, 
must be followed up to resolution unless the event is considered by the investigator to be 
unlikely to resolve, or the patient is lost to follow up. 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 
6.4.4 
Adverse event data collection 
'The following variables will be collect for each AE; 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
CTCAE grade and changes in CTCAE grade 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the Investigational Product(s) (yes or no) 
• 
Action taken with regard to Investigational Product(s) 
• 
AE caused subject’s withdrawal from study (yes or no) 
• 
Outcome. 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for serious AE 
• 
Date Investigator became aware of serious AE 
• 
AE is serious due to 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to Study procedure(s) 
• 
Causality assessment to other medication' 


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• 
Description of AE 
6.4.5 
Causality collection 
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, 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 Appendix B to the Clinical 
Study Protocol. 
6.4.6 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient  or care provider or reported in response to the 
open question from the study site staff: “Have you had any health problems since the previous 
visit/you were last asked?”, or revealed by observation will be collected and recorded in the 
CRF.  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. 
6.4.7 
Adverse events based on examinations and tests 
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarized in the CSR.  Deterioration as compared to baseline in protocol-mandated laboratory 
values and vital signs should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign will 
be considered as additional information.  Wherever possible the reporting Investigator uses the 
clinical, rather than the laboratory term (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 AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE unless unequivocally related to 
the disease under study. 


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6.4.8 
Hy’s law 
Cases where a patient shows elevations in liver biochemistry require further evaluation and 
occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to be 
reported as SAEs.  Please refer to Appendix A for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law 
6.4.9 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  The 
development of new, or progression of existing metastasis to the primary cancer under study 
should be considered as disease progression and not an AE.  Events, which are unequivocally 
due to disease progression, should not be reported as an AE during the study. 
6.4.10 
New Cancers 
The development of a new primary cancer should be reported as an AE (see Section 6.4.13 
Olaparib Adverse Events of Special Interest) and would in most cases meet seriousness criteria 
(with the exception of some non-melanoma skin cancers). New primary malignancies are those 
that are not the primary reason for the administration of the study treatment and have developed 
after the inclusion of the patient into the study.  They do not include metastases of the original 
cancer.  Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as 
they are considered to be disease progression. 
Adverse Events (AEs) for malignant tumours 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 tumour event should be assessed and 
reported as a Non-Serious AE. For example, if the tumour is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, 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 tumours, 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 tumour event in question is a new 
malignant tumour (i.e., it is not the tumour 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 tumour under study). Malignant tumours 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 tumour. 


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6.4.11 
Lack of efficacy 
When there is deterioration in the cancer, for which the study treatment(s) is being used, there 
may be uncertainty as to whether this is lack of efficacy or an AE.  In such cases, unless the 
Sponsor or the reporting physician considers that the study treatment contributed to the 
deterioration of the condition, or local regulations state to the contrary, the deterioration should 
be considered to be a lack of efficacy and not an AE. 
6.4.12 
Deaths 
All deaths that occur during the study, or within the protocol-defined 30-day post-study 
follow-up period after the administration of the last dose of study treatment, must be reported as 
follows: 
• 
Death clearly the result of disease progression should be reported to the study monitor 
at the next monitoring visit and should be documented in the CRF but should not be 
reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the disease under study, 
the AE causing the death must be reported to the study monitor as a SAE within 
24 hours (see Section 8.4.1 for further details).  The report should contain a comment 
regarding the co-involvement of progression of disease, if appropriate, and should 
assign main and contributory causes of death.  This information can be captured in 
theCRF. 
Deaths with an unknown cause should always be reported as a SAE.  A postmortem maybe 
helpful in the assessment of the cause of death, and if performed a copy of the post-mortem 
results should be forwarded to AstraZeneca within the usual timeframes. 
6.4.13 
Olaparib adverse events of special interest 
Adverse events of special interest [AESI] are events of scientific and medical interest specific to 
the further understanding of olaparib’s safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca. Adverse Events of Special Interest for 
olaparib are the Important Identified Risks of MDS/AML, and the Important Potential Risks of 
new primary malignancy (other than MDS/AML) and pneumonitis.   
A questionnaire will be sent to any investigator reporting an AESI, as an aid to provide further 
detailed information on the event.  During the study there may be other events identified as 
AESIs that require the use of a questionnaire to help characterise the event and gain a better 
understanding regarding the relationship between the event and study treatment. 
6.5 
Safety reporting and medical management 
6.5.1 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the CRF. 


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If any SAE occurs in the course of the study, then Investigators or other site personnel inform the 
appropriate AstraZeneca representatives within one day i.e., immediately but no later than 24 
hours  of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1 
calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days 
of initial receipt for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE within 
one calendar day i.e., immediately but no later than 24 hours of when he or she becomes aware 
of it. 
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study Protocol. 
6.5.2 
Pregnancy/Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 3 
months following the last dose. 
Pregnancy of the patient’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) occurring from the date of the first dose until 3 months 
after the last dose should, if possible, be followed up and documented. 
6.5.3 
Overdose 
There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established.  
Olaparib must only be used in accordance with the dosing recommendations in this protocol. 
Any dose or frequency of dosing that exceeds the dosing regimen specified in this protocol 
should be reported as an overdose. The Maximum Tolerated Dose is 300 mg twice daily (tablet). 
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately. 
• 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF. 
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.2.  
For other overdoses, reporting must occur within 30 days. 


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6.5.4 
Medication error 
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately but 
no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up Fatal/Life-
Threatening)or 5 (other serious initial and follow up) calendar days if there is an SAE associated 
with the medication error (see Section 6.4.2) and within 30 days for all other medication errors. 
The definition of a Medication Error can be found in Appendix B. 
6.5.5 
Management of adverse events  
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. 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. If the reduced dose of 200 mg 
twice daily is not tolerable, no further dose reduction is allowed, and study treatment should be 
discontinued.  
Once dose is reduced, escalation is not permitted (except following concomitant treatment with 
CYP3A4 inhibitors – see Section 6.5 
 
Management of hematological toxicity 
Management of anemia 
Table 10 
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.  
Investigator 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 investigator judgement to continue olaparib with 
supportive treatment (eg. 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).  


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Hemoglobin 
Action to be taken 
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.  
 
Management of neutropenia, leukopenia and thrombocytopenia 
Table 11 
Management of neutropenia, leukopenia and thrombocytopenia 
Toxicity 
Study treatment dose adjustment 
CTCAE Grade 1-2 
Investigator judgement to continue treatment or if dose interruption, this 
should be for a maximum of 4 weeks; appropriate supportive treatment and 
causality investigation 
CTCAE Grade 3-4 
Dose interruption until recovered to CTCAE gr 1 or better for a maximum 
of 4 weeks. If repeat CTCAE grade 3-4 occurrence, dose reduce olaparib to 
250 mg twice daily as a first step and 200 mg twice daily as a second step 
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by the 
investigator with close follow up and interruption of study drug if CTC grade 3 or worse 
neutropenia occurs. 
Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not recommended, 
however, if a patient develops febrile neutropenia, study treatment should be 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 haematological 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.  
 


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Management of prolonged hematological toxicities while on study treatment 
If a patient develops prolonged hematological toxicity such as: 
• 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse anaemia 
and/or development of blood transfusion dependence 
• 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse neutropenia 
(ANC < 1 x 109/L) 
• 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (Platelets < 
50 x 109/L) 
Check weekly differential blood counts including reticulocytes and peripheral blood smear. If any 
blood parameters remain clinically abnormal after 4 weeks of dose interruption, the patient should 
be referred to hematologist for further investigations. Bone marrow analysis and/or blood 
cytogenetic analysis should be considered at this stage according to standard hematological 
practice. Study treatment should be discontinued if blood counts do not recover to CTC gr 1 or 
better within 4 weeks of dose interruption. 
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should be 
reported as an SAE and full reports must be provided by the investigator to AstraZeneca Patient 
Safety. Olaparib treatment should be discontinued if patient’s diagnosis of MDS and/or AML is 
confirmed. 
 
 
Management of non-hematological toxicity 
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion. If 
the interruption is any longer than this the study monitor must be informed.  Where toxicity 
reoccurs following re-challenge with study treatment, and where further dose interruptions are 
considered inadequate for management of toxicity, then the patient should be considered for dose 
reduction or must permanently discontinue study treatment. 
Study treatment can be dose reduced to 250 mg 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. 
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 study treatment dosing is recommended and 
further diagnostic workup (including a high resolution CT scan) should be performed to exclude 
pneumonitis. 
Following investigation, if no evidence of abnormality is observed on CT imaging and symptoms 
resolve, then study treatment can be restarted, if deemed appropriate by the investigator. If 


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significant pulmonary abnormalities are identified, these need to be discussed with the Study 
Physician. 
Management of nausea and vomiting 
Events of nausea and vomiting are known to be associated with olaparib treatment. These events 
are generally mild to moderate (CTCAE grade 1 or 2) severity, intermittent and manageable on 
continued treatment. The first onset generally occurs in the first month of treatment for nausea and 
within the first 6 months of treatment for vomiting. For nausea, the incidence generally plateaus 
at around 9 months, and for vomiting at around 6 to 7 months. 
No routine prophylactic anti-emetic treatment is required at the start of study treatment, however, 
patients should receive appropriate anti-emetic treatment at the first onset of nausea or vomiting 
and as required thereafter, in accordance with local treatment practice guidelines.  Alternatively, 
olaparib tablets can be taken with a light meal/snack (ie 2 pieces of toast or a couple of biscuits). 
As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), generally a 
single agent antiemetic should be considered eg. dopamine receptor antagonist, antihistamines or 
dexamethasone. 
Interruptions for intercurrent non-toxicity related events 
Study treatment dose interruption for conditions other than toxicity resolution should be kept as 
short as possible. If a patient cannot restart study treatment within 4 weeks for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be discussed 
with the Primary Investigator. 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF.  
Study treatment should be stopped 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. 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
radiation treatment. Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered. 
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 12 
Dose reductions for study 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 
 


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Renal impairment 
If subsequent to study entry and while still on study therapy, a patient’s estimated CrCl falls 
below the threshold for study inclusion (≥51 ml/min), retesting should be performed promptly.  
A dose reduction is recommended for patients who develop moderate renal impairment 
(calculated creatinine clearance by Cockcroft-Gault equation 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 investigator should use his or her discretion in 
determining whether a dose change or discontinuation of therapy is warranted. 
Olaparib has not been studied in patients with severe renal impairment (creatinine clearance 
≤ 30 ml/min) or end-stage renal disease; if patients develop severe impairment or end stage 
disease is it recommended that <<select olaparib or study treatment>> be discontinued. 
6.6 
Genetics 
6.6.1 
Collection of mandatory genetic samples 
The patient’s consent to participate in the genetic research components of the study is 
mandatory.  
The tissue sample for genetic research will be obtained from the patients from archival tissue or 
from metastatic biopsy during pre-screening period and post-treatment.  
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
Genetic signatures indicating homologous recombination deficiency will be analyzed.  This 
analysis is required to include the patient in the study.   
6.7 
Biomarkers 
Optional samples for biomarker research that should be collected from patients in the study 
where possible are the following: 
• 
Tumor biopsies will be taken at baseline and at progression for investigation of genetic 
signatures and transcriptome analysis to evaluate their association with the observed 
clinical responses to olaparib. 
• 
Please refer to the Laboratory Manual for further details regarding blood sample 
collection, shipping and storage. 
 
In addition, blood will be collected, and analysis may be performed on exploratory biomarkers 
thought to play a role in homologous recombination deficiency including, but not limited to, 


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genome-wide analysis for RNA, serum analytes, or tissue biomarkers to evaluate their 
association with observed clinical responses to olaparib. 
Other samples may be used for research to develop methods and further refine assays for 
predicting response to olaparib and clarifying mechanisms of resistance. All samples will be 
collected at the timepoints indicated in the SoA. Details regarding the collection, processing, 
shipping, and storage of samples for exploratory research will be defined in the Laboratory 
Manual.  
6.7.1 
Storage, re-use and destruction of biomarker samples 
Samples will be stored for a maximum of 5 years from the date of the Last Patient’s Last Visit, 
after which they will be destroyed.  Samples will be stored at the University of Washington 
and/or Fred Hutchinson Cancer Research Center (UW/FHCRC). These samples may also be sent 
to our research partners participating in this study, including Astra Zeneca. Specimens will not 
be used for reasons unrelated to this research study. All specimens will be kept in locked 
research laboratories at UW/FHCRC. The Sponsor Investigator will supervise the use of these 
specimens. The results of this biomarker research will be reported either in the CSR itself or as 
an addendum, or separately in a scientific report or publication. Statistical Considerations  
6.8 
Sample size determination  
Based on the PROFOUND study, we estimate a response rate of 20% (H0) in patients with any 
HR mutations (e.g. BRCA2, ATM, CDK12, CHEK2, etc).2 We will require a 50% (H1) response 
rate in iHRD positive patients to justify further development of this approach for selecting 
patients for olaparib treatment. Therefore, assuming we enroll 20 iHRD positive patients, this 
study would provide 87% power at a one-sided alpha of 0.03 to detect a 50% response rate 
compared to the null rate of 20%. Given that prior experience has shown that ~75% of patients 
with a positive LOH score will also have evidence of iHRD positivity, we will enroll a total of 
30 patients to identify at least 22 iHRD positive subjects. This should allow for a drop out rate of 
10% to ensure that at least 20 iHRD positive subjects are able to reach 12 weeks of treatment for 
the primary endpoint analysis. 
6.9 
Statistical analyses 
6.9.1 
Efficacy analyses 
Primary Objective 
The primary objective is to determine the percentage of patients who are iHRD+ that achieve a 
PSA50 response (i.e. ≥50% decline in PSA from baseline). The lowest on treatment PSA will be 
defined as the lowest value following at least 12 weeks of treatment (i.e. the beginning of Cycle 
4). The PSA50 response rate will be calculated along with 90% confidence intervals (CI) using 
Wilson’s method. PSA changes will be presented as waterfall plots per PCWG3 
recommendations. If a patient drops out of the study prior to assessing best PSA response he will 
be considered as not having had a PSA50 response. 
ORR Response 


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For patients with measurable disease, ORR will be defined as a 30% decrease from baseline per 
RECIST 1.1 criteria at any time point. The percent of patients with ORR and 90% CI, calculated 
using Wilson’s method, will be provided. Radiographic responses will be presented as waterfall 
plots. 
rPFS, PSA PFS, OS 
These endpoints are defined in section 3.5. The distributions of each endpoint will be estimated 
using the Kaplan-Meier method. Median times to event will be reported with 90% CIs using 
linear interpolation between steps of the survival curve.   
Exploratory Objectives 
Response rates and time to event endpoints as described above will be compared between 
patients who are iHRD+ and iHRD-. PSA and radiographic response rates including percentage 
and 90% CIs, calculated using Wilson’s method, will be reported. Differences in response rates 
will be quantified using logistic regression with no additional adjustment. Time to event 
endpoints will be compared with log-rank tests. 
If dropout is greater than anticipated, primary and secondary endpoint analyses will still be based 
on patients with 12 weeks of follow-up. However, the exploratory analysis will examine extreme 
scenarios in which endpoints for dropouts are imputed to minimize differences between iHRD+ 
and iHRD- patients. 
We will additionally be looking at association between response rate and different predictors of 
homologous recombination deficiency including large scale state-transition (LST) score, 
COSMIC signature 3/8, and presence of underlying HR mutation. We will report the presence of 
underlying HR mutations in both the iHRD(+) and iHRD(-) groups. Depending on the final 
makeup of the study population, we will report PSA and radiographic response rates among 
various subsets which may include iHRD(+) and BRCA mutant iHRD(-) patients. We will also 
use the results of this trial to optimize iHRD classification framework and develop a clinical 
pipeline for calling iHRD from targeted exome panels.  We will also describe the results of 
transcript profiling studies from tumor biopsies and compare pre and post treatment profiles.  
6.9.2 
Safety analyses 
All patients who initiate study treatment will be evaluated for safety, combined across both 
cohorts. Adverse events will be summarized as number (%) of patients by system organ class, 
CTCA term and grade, where grade is the maximum across a patient’s treatment period.  


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7. 
REFERENCES 
 
1. 
Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-
Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical 
Trials Working Group 3. J Clin Oncol. 2016;34(12):1402-1418. 
2. 
Hussain M. Profound: Phase 3 Study of Olaparib Versus Enzalutamide or Abiraterone 
For Metastatic Castration-Resistant Prostate Cancer (mCRPC) With Homologous 
Recombination Repair (HRR) Gene Alterations. Paper presented at: ESMO Congress 
20192019. 
3. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-
30. 
4. 
Sartor O, de Bono JS. Metastatic Prostate Cancer. N Engl J Med. 2018;378(7):645-657. 
5. 
Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic 
Prostate Cancer. The New England journal of medicine. 2015;373(18):1697-1708. 
6. 
Abida W, Campbell D, Patnaik A, et al. Non-BRCA DNA Damage Repair Gene 
Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-
Resistant Prostate Cancer: analysis from the phase 2 TRITON2 study. Clin Cancer Res. 
2020. 
7. 
Mateo J, Porta N, Bianchini D, et al. Olaparib in patients with metastatic castration-
resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, 
open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21(1):162-174. 
8. 
Ceccaldi R, Rondinelli B, D'Andrea AD. Repair Pathway Choices and Consequences at 
the Double-Strand Break. Trends Cell Biol. 2016;26(1):52-64. 
9. 
Lord CJ, Ashworth A. BRCAness revisited. Nature reviews Cancer. 2016;16(2):110-120. 
10. 
Abkevich V, Timms KM, Hennessy BT, et al. Patterns of genomic loss of heterozygosity 
predict homologous recombination repair defects in epithelial ovarian cancer. British 
journal of cancer. 2012;107(10):1776-1782. 
11. 
Birkbak NJ, Wang ZC, Kim JY, et al. Telomeric allelic imbalance indicates defective 
DNA repair and sensitivity to DNA-damaging agents. Cancer discovery. 2012;2(4):366-
375. 
12. 
Popova T, Manie E, Rieunier G, et al. Ploidy and large-scale genomic instability 
consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer 
Res. 2012;72(21):5454-5462. 
13. 
Polak P, Kim J, Braunstein LZ, et al. A mutational signature reveals alterations 
underlying deficient homologous recombination repair in breast cancer. Nature genetics. 
2017;49(10):1476-1486. 
14. 
Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in 
human cancer. Nature. 2013;500(7463):415-421. 
15. 
Nik-Zainal S, Davies H, Staaf J, et al. Landscape of somatic mutations in 560 breast 
cancer whole-genome sequences. Nature. 2016;534(7605):47-54. 
16. 
de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate 
Cancer. N Engl J Med. 2020. 
17. 
de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate 
Cancer. N Engl J Med. 2020;382(22):2091-2102. 


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18. 
Favero F, Joshi T, Marquard AM, et al. Sequenza: allele-specific copy number and 
mutation profiles from tumor sequencing data. Annals of oncology : official journal of the 
European Society for Medical Oncology / ESMO. 2015;26(1):64-70. 
19. 
Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-
grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, 
phase 2 trial. Lancet Oncol. 2017;18(1):75-87. 
20. 
Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in 
metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223. 
 


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Appendix A Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law 
A 1 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management of 
elevated liver biochemistries.   
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a patient meets potential 
Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the investigational medicinal 
product (IP).   
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes. 
A 2 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× upper limit of normal 
(ULN) together with total bilirubin (TBL) ≥ 2×ULN at any point during the study following the 
start of study medication irrespective of an increase in alkaline phosphatase (ALP).   
Hy’s Law (HL) 
AST or ALT ≥ 3 × ULN  together with TBL ≥ 2 ×ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.   
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame within which the elevations 
in transaminases and TBL must occur. 
A 3 
Identification of potential Hy’s Law cases 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any patient who meets any of the following identification criteria in isolation or in 
combination: 
• 
ALT ≥ 3 × ULN 


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• 
AST ≥ 3 × ULN 
• 
TBL ≥ 2 × ULN 
When the identification criteria are met the Investigator will without delay: 
• 
Determine whether the patient meets PHL criteria (see Appendix A 2 for definition) by 
reviewing laboratory reports from all previous visits  
• 
The Investigator will without delay review each new laboratory report and if the 
identification criteria are met will: 
• 
Determine whether the patient meets PHL criteria (see Appendix A 2 for definition) by 
reviewing laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory CRF 
A 4 
Follow-up 
A 4.1 
Potential Hy’s Law criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
A 4.2 
Potential Hy’s Law criteria met 
If the patient does meet PHL criteria the Investigator will: 
• 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated  
• 
Investigate the etiology of the event and perform diagnostic investigations as 
medically indicated.   
• 
If at any time the PHL case meets serious criteria, report it as an SAE using standard 
reporting procedures. 
A 5 
Review and assessment of potential Hy’s Law cases 
The instructions in this section should be followed for all cases where PHL criteria are met. 
If there is an alternative explanation for the ALT or AST and TBL elevations, a determination of 
whether the alternative explanation is an AE will be made and subsequently whether the AE 
meets the criteria for a SAE: 


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• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
• 
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly  
If there is no explanation that would explain the ALT or AST and TBL elevations other than the 
IMP: 
• 
Report an SAE (report term ‘Hy’s Law’) 
− 
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made: 
• 
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above 
• 
Continue follow-up and review.  Once the necessary supplementary information is 
obtained, repeat the review and assessment to determine whether HL criteria are met.  
Update the SAE report according to the outcome of the review amending the reported 
term if an alternative explanation for the liver biochemistry elevations is determined. 
A 6 
Actions required when potential Hy’s Law criteria are met before and 
after starting study treatment 
This section is applicable to patients with liver metastases who meet PHL criteria on Study 
treatment having previously met PHL criteria at a study visit prior to starting Study treatment. 
At the first on-study treatment occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change in the patients’ condition# compared with the last 
visit where PHL criteria were met.#  
• 
If there is no significant change, no action is required 
• 
If there is a significant change, then follow the subsequent process described in 
Appendix B 5. 
• 
A ‘significant’ change in the patient’s condition refers to a clinically relevant change 
in any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms.  


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The determination of whether there has been a significant change will be at the 
discretion of the Investigator. 
A 7 
Actions required for repeat episodes of potential Hy’s Law 
This section is applicable when a patient meets PHL criteria on study treatment, and has already 
met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence.   
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
Was the alternative cause for the previous occurrence of PHL criteria being met found to be the 
disease under study (eg, chronic or progressing malignant disease, severe infection or liver 
disease), or did the subject meet PHL criteria prior to starting study treatment and at first on-
study treatment visit, as described in Appendix  A 6? 
If No: Follow the process described in Appendix A 4.1. 
If Yes: Determine if there has been a significant# change in the patient’s condition compared 
with when PHL criteria were previously met. 
If there is no significant change, no action is required. 
If there is a significant change, follow the process described in Appendix A 4. 
A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator. 
 
 


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Appendix B Adverse event definitions and additional safety information 
B 1 
Definition of adverse events 
An adverse event is the development of any untoward medical occurrence in a patient or clinical 
study patient administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.   An AE can therefore be any unfavourable and unintended sign 
(e.g.  an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product.   
The term AE is used to include both serious and non-serious AEs and can include a deterioration 
of a pre-existing medical occurrence.  An AE may occur at any time, including run-in or washout 
periods, even if no Study treatment has been administered. 
B 2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity.   
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardize the patient or may require medical 
treatment to prevent one of the outcomes listed above. 
B 3 
Life threatening 
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might 
have caused death (e.g., hepatitis that resolved without hepatic failure). 
B 4 
Hospitalization 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons for 
it may be (e.g., bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 


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B 5 
Important medical event or medical treatment 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
• 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (e.g., neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse 
B 6 
Intensity rating scale: 
The grading scales found in the revised National Cancer Institute CTCAE latest 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 can be 
downloaded from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The 
applicable version of CTCAE should be described clearly. 
For each episode of an adverse event, all changes to the CTCAE grade attained as well as the 
highest attained CTC grade should be reported. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe intensity need 
not necessarily be considered serious.  For example, nausea that persists for several hours may be 
considered severe nausea, but not a SAE unless it meets the criteria shown in Appendix B 2. On 
the other hand, a stroke that results in only a limited degree of disability may be considered a 
mild stroke but would be a SAE when it satisfies the criteria shown in Appendix B 2. 
B 7 
A Guide to Interpreting the Causality Question 
When making an assessment of causality consider the following factors when deciding if there is 
a ‘reasonable possibility’ that an AE may have been caused by the drug. 


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• 
Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug? 
• 
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
• 
No alternative cause.  The AE cannot be reasonably explained by another etiology 
such as the underlying disease, other drugs, other host or environmental factors. 
• 
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge. 
• 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship. 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognized feature of overdose of the drug? 
• 
Is there a known mechanism? 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are facts 
(evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough information 
to make an informed judgment.  With limited or insufficient information in the case, it is likely 
that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of effect 
should be classified as no reasonable possibility. 
B 8 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant or 
has the potential to cause harm to the participant.   
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 


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Medication error includes situations where an error.   
• 
occurred 
• 
was identified and intercepted before the participant received the drug 
• 
did not occur, but circumstances were recognize 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 participant 
• 
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 participant received the medication (excluding IVRS/IWRS errors) 
• 
Wrong drug administered to participant (excluding IVRS/IWRS errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting from IVRS/IWRS - including those which lead to one of 
the above listed events that would otherwise have been a medication error  
• 
Participant accidentally missed drug dose(s) e.g.  forgot to take medication 
• 
Accidental overdose (will be captured as an overdose) 
• 
Participant failed to return unused medication or empty packaging 
• 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product  
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 


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Appendix C Acceptable Birth Control Methods 
Olaparib is regarded as a compound with medium/high fetal risk. 
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 if they are of childbearing potential (as listed below).  Male patients should not 
donate sperm throughout the period of taking olaparib and for 3 months following the last dose 
of olaparib. 
 
Acceptable Non-hormonal birth control methods include: 
• 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 1 month after the last dose of study drug <<for 3 
months after last dose for male patients>>. [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]  
• Vasectomized sexual partner PLUS male condom.  With participant assurance that 
partner received post-vasectomy confirmation of azoospermia. 
• Tubal occlusion PLUS male condom  
• IUD PLUS male condom.  Provided coils are copper-banded 
 
Acceptable hormonal methods: 
• Normal and low dose combined oral pills PLUS male condom  
• Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the only highly 
efficacious progesterone based pill. 
• Hormonal shot or injection (eg., 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 (eg., levonorgestrel releasing IUS -Mirena®) PLUS 
male condom  
• Intravaginal device (e.g., EE and etonogestrel) PLUS male condom  
 
 


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Appendix D  Pill Diary Template 
Participant ID: 
Cycle Number:  
Day 
Date 
Number of 
Olaparib 
Capsules 
Time of 
Dose 
Number of 
Olaparib 
Capsules 
Time of 
Dose 
Notes 
1 
 
 
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2 
 
 
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3 
 
 
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16 
 
 
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17 
 
 
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18 
 
 
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19 
 
 
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25 
 
 
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26 
 
 
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27 
 
 
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28 
 
 
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Appendix E Recommendations from Prostate Cancer Clinical Trials 
Working Group 3 (PCWG3)1 
Suggested outcome measures for clinical trials in metastatic prostate cancer as excerpted from 
PCWG3 recommendations.1 
E 1 
PSA Progression 
PSA progression is defined as the time from start of therapy to first PSA increase that is > 25% 
and > 2 ng/mL above the nadir, which is confirmed by a second values > 3 weeks later (i.e., a 
confirmed rising trend).  
 
E 2 
Bone Progression 
Progression in the bone is defined as at least two new lesions on first post-treatment scan, with at 
least two additional lesions on the next scan (2+2 rule). If at least two additional new lesions are 
seen on the next (confirmatory) scan, the date of progression is the date of the first post-
treatment scan, when the first two new lesions were documented. For all scans after the first 
post-treatment scan, at least two new lesions relative to the first post-treatment scan confirmed 
on a subsequent scan. Date of progression is the date of the scan that first documents the second 
lesion. Changes in intensity of uptake alone do not constitute either progression or regression.