Clinical trial NCT03516812
Conditions: Castration-Resistant Prostate Carcinoma Prostate Adenocarcinoma
Sponsor: University of Washington
Start date: 2018-08-29; Completion date: 2024-04-12
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well testosterone (enanthate or cypionate) and olaparib work in treating patients with prostate cancer that has progressed despite hormonal therapy. Hormonal therapy, such as leuprolide, may lessen the amount of male sex hormones made by the body. In patients that have developed progressive cancer in spite of standard hormonal treatment (i.e. castration-resistant prostate cancer), administering testosterone may result in regression of tumors by causing DNA damage in cancer cells that have adapted to low testosterone conditions. Olaparib may stop the growth of tumor cells by blocking some of the enzymes involved in repairing DNA damage. Therefore, giving testosterone and olaparib together may work better in treating castration-resistant prostate cancer by generating DNA damage that the cancer cell is unable to repair.

Detailed description:
PRIMARY OBJECTIVE:

I. Determine the prostate-specific antigen (PSA)50 response rate (i.e., percent of patients with a PSA decline of at least 50% below baseline) following 12-weeks of treatment with bipolar androgen therapy (BAT) plus olaparib in men with asymptomatic metastatic castration-resistant prostate cancer (mCRPC) who have progressed on abiraterone and/or enzalutamide.

SECONDARY OBJECTIVES:

I. Determine the percent of mCRPC patients achieving a radiographic response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria following treatment with BAT plus olaparib.

II. Determine the radiographic progression free survival (PFS) in mCRPC patients treated with BAT plus olaparib using RECIST 1.1 criteria for soft tissue metastases and Prostate Cancer Working Group 3 (PCWG3) criteria for bone metastases.

III. Determine the PSA PFS rate according to PCWG3 criteria in mCRPC patients treated with BAT plus olaparib.

IV. Determine the PFS (i.e. whichever occurs first: clinical, radiographic or PSA progression) in mCRPC patients treated with BAT plus olaparib.

V. Determine the overall survival in mCRPC patients treated with BAT plus olaparib.

VI. Track changes in quality of life (QoL) as determined using the Functional Assessment of Cancer Therapy -Prostate (FACT-P) and International Index of Erectile Function (IIEF) surveys.

VII. Assess the incidence and severity of adverse events according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

EXPLORATORY OBJECTIVES:

I. Evaluate for differences in response and PFS in patients with/without mutations in genes involved in homologous recombination.

II. Determine intratumoral androgen levels using liquid chromatography-mass spectrometry (LC/MS).

III. Assess for evidence of double stranded deoxyribonucleic acid (dsDNA) breaks using gamma-H2AX immunostaining on circulating tumor cells (CTCs) and metastatic tissue.

IV. Assess androgen receptor (AR) and AR splice variant (AR-V) transcript expression levels using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) on CTCs.

V. Assess androgen receptor (AR) and AR splice variant (AR-V) protein expression levels using immunostaining on circulating tumor cells (CTCs) and metastatic tissue.

VI. Sequence tumor DNA (cell-free circulating tumor DNA \[ctDNA\] and/or metastatic tissue).

VII. Conduct transcript profiling studies on CTCs (multiplexed qRT-PCR) and metastatic tissue (ribonucleic acid sequencing \[RNA-seq\]).

OUTLINE:

Patients receive olaparib orally (PO) twice daily (BID) on days 1-28 and testosterone enanthate or cypionate intramuscularly (IM) on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of the study treatment, patients are followed up at 30 days and every 6 months for up to 2 years.

Arms: arm 1: Patients receive olaparib PO BID on days 1-28 and testosterone enanthate or cypionate IM on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Olaparib intervention 3: Quality-of-Life Assessment intervention 4: Survey Administration intervention 5: Testosterone Enanthate intervention 6: Testosterone Cypionate
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Ancillary studies intervention 4: Ancillary studies intervention 5: Given IM intervention 6: Given IM

Protocol documents:
Prot_SAP_000.pdf: 
1(93)
Drug Substance 
Olaparib (AZD2281, KU-
0059436); Testosterone 
Consortium Study 
Number 
9984 
Version Number 
1.6 
Date 
February 24, 2021 
Bipolar Androgen Therapy Plus Olaparib in Patient with Castration-
Resistant Prostate Cancer 
Financial and Medication Support:  AstraZeneca 
Principal Investigator: Michael T. Schweizer, MD 
IRO REC'D MAR 04 2021 
FHCRC IRB Approval  
MAR 25 2021 
Document Released Date
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ............................................................................................................................ 1 
TABLE OF CONTENTS ......................................................................................................... 2 
1. INTRODUCTION ........................................................................................................... 10 
1.1 Disease Background ...................................................................................................... 10 
1.2 Supraphysiologic Testosterone (SPT) in CRPC Background ....................................... 12 
1.2.1 SPT in CRPC Pre-clinical experience ........................................................................ 12 
1.2.2 SPT in CRPC Clinical experience .............................................................................. 14 
1.3 Olaparib Background ..................................................................................................... 16 
1.3.1 Pre-clinical experience ............................................................................................... 17 
1.3.2 Toxicology and safety pharmacology summary ......................................................... 20 
1.3.3 Clinical experience ..................................................................................................... 21 
1.3.3.1 Olaparib in mCRPC ................................................................................................. 21 
1.3.3.2 Emerging Safety Profile .......................................................................................... 24 
1.4 Research hypothesis ...................................................................................................... 29 
1.5 Rationale for conducting this study ............................................................................... 29 
1.6 Benefit/risk and ethical assessment ............................................................................... 30 
2. STUDY OBJECTIVES ................................................................................................... 31 
2.1 Primary objective ........................................................................................................... 31 
2.2 Secondary objectives ..................................................................................................... 31 
2.3 Exploratory objectives ................................................................................................... 31 
3. PATIENT SELECTION CRITERIA .............................................................................. 32 
3.1 Inclusion criteria ............................................................................................................ 32 
3.2 Exclusion criteria ........................................................................................................... 33 
4. STUDY PLAN AND PROCEDURES ............................................................................ 36 
4.1 Overall study design and flow chart .............................................................................. 36 
4.2 Discontinuation of investigational product.................................................................... 39 
4.2.1 Procedures for discontinuation of a subject from investigational product ................. 39 
4.3 Withdrawal from study .................................................................................................. 39 
5. TREATMENT ASSESSMENTS AND EVALUATIONS ............................................. 40 
5.1 Recording of data........................................................................................................... 40 
5.2 Data collection at enrollment and follow-up ................................................................. 40 
5.2.1 Screening (within 30 days of Cycle 1, Day 1) ............................................................ 40 
 
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Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
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5.2.2 Treatment/Intervention Period .................................................................................... 41 
5.2.3 End of study ................................................................................................................ 42 
5.2.4 Follow Up ................................................................................................................... 43 
5.2.5 Long-term Follow Up ................................................................................................. 43 
5.3 Study calendar ............................................................................................................... 44 
6. STUDY ASSESSMENTS ............................................................................................... 46 
6.1 Efficacy .......................................................................................................................... 46 
6.2 Safety ............................................................................................................................. 46 
6.2.1 Definition of adverse events ....................................................................................... 46 
6.2.2 Olaparib adverse events of special interest................................................................. 46 
6.2.3 Assessment of severity ............................................................................................... 46 
6.2.4 Definitions of serious adverse event ........................................................................... 47 
6.2.5 Assessment of relationship ......................................................................................... 48 
6.2.6 Early stopping due to adverse events………………………….……………………45 
6.2.7 Recording of adverse events .......................................................................................... 48 
6.2.7.1 Adverse events after the 30 day follow up period ................................................... 50 
6.2.8 Reporting of serious adverse events ........................................................................... 52 
6.2.9 Laboratory safety assessment ..................................................................................... 53 
6.2.10 Physical examination .................................................................................................. 54 
6.2.11 ECG .......................................................................................................................... 54 
6.2.12 Vital signs ................................................................................................................. 55 
6.2.12.1 Pulse and blood pressure ........................................................................................ 55 
6.2.12.2 Body temperature ................................................................................................... 55 
6.2.13 Bone marrow or blood cytogenetic analysis ............................................................. 55 
6.3 Exploratory biomarkers ................................................................................................. 55 
6.3.1 DNA Damage Repair Gene Status ............................................................................. 55 
6.3.2 Protein expression studies .......................................................................................... 56 
6.3.3 Transcript profiling studies ......................................................................................... 56 
6.3.4 Tissue and Serum Androgen Levels ........................................................................... 56 
6.4 Patient reported outcomes (PRO) .................................................................................. 56 
7. BIOLOGICAL SAMPLING PROCEDURES ................................................................ 57 
7.1 Volume of blood ............................................................................................................ 57 
7.2 Handling, storage and destruction of biological samples .............................................. 57 
8. STUDY CONDUCT........................................................................................................ 58 
8.1 Restrictions during the study ......................................................................................... 58 
8.1.1 Grapefruit juice ........................................................................................................... 58 
8.1.2 Contraception.............................................................................................................. 58 
8.2 Treatments ..................................................................................................................... 58 
8.2.1 Identity of investigational product(s) ......................................................................... 58 
8.2.2 Olaparib doses and treatment regimens ...................................................................... 58 
 
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Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
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8.2.3 Testosterone enanthate ............................................................................................... 59 
8.2.4 Olaparib Labelling ...................................................................................................... 62 
8.2.5 Storage ........................................................................................................................ 62 
8.2.6 Management of toxicity of olaparib ........................................................................... 62 
8.2.7 Management of hematological toxicity ...................................................................... 63 
8.2.7.1 Management of anemia ........................................................................................... 63 
8.2.7.2 Management of neutropenia, leukopenia and thrombocytopenia ............................ 64 
8.2.7.3 Management of prolonged hematological toxicities while on study 
treatment................................................................................................................. 64 
8.2.8 Management of non-hematological toxicity ............................................................... 65 
8.2.8.1 Management of new or worsening pulmonary symptoms ....................................... 65 
8.2.8.2 Management of nausea and vomiting ...................................................................... 65 
8.2.8.3 Interruptions for intercurrent non-toxicity related events ........................................ 66 
8.3 Concomitant and post-study treatment(s) ...................................................................... 66 
8.3.1 Medications that may NOT be administered .............................................................. 69 
8.4 Treatment compliance ................................................................................................... 69 
9. ETHICAL AND REGULATORY REQUIREMENTS .................................................. 69 
9.1 Ethical conduct of the study .......................................................................................... 69 
9.2 Ethics and regulatory review ......................................................................................... 69 
9.3 Informed consent ........................................................................................................... 69 
9.4 Changes to the protocol and informed consent form ..................................................... 70 
10. STUDY MANAGEMENT ............................................................................................ 70 
10.1 Training of study site personnel .................................................................................. 70 
10.2 Monitoring of the study ............................................................................................... 70 
10.2.1 Source data ............................................................................................................... 71 
11. EVALUATION AND CALCULATION OF VARIABLES......................................... 71 
11.1 Calculation or derivation of efficacy variable(s) ......................................................... 71 
11.2 Calculation or derivation of safety variable(s) ............................................................ 74 
11.2.1 Other significant adverse events (OAE) ................................................................... 74 
11.3 Calculation or derivation of patient reported outcome variables ................................ 74 
12. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION.................... 74 
12.1 Description of analysis sets ......................................................................................... 74 
12.2 Methods of statistical analyses .................................................................................... 74 
12.2.1 Safety Analyses ........................................................................................................ 74 
12.2.2 Efficacy Analyses ..................................................................................................... 75 
12.2.3 Exploratory Analyses ............................................................................................... 75 
12.3 Determination of sample size ...................................................................................... 75 
 
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Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
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13. IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR .................................................................................................. 77 
13.1 Overdose ...................................................................................................................... 77 
13.1.1 Paternal exposure ...................................................................................................... 77 
14. LIST OF REFERENCES............................................................................................... 78 
Appendix 1: Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ......................................................................................... 85 
Appendix 2: ECOG Performance Status ............................................................................. 90 
Appendix 3: Highly Effective Methods of Contraception ................................................... 91 
Appendix 4: Quality of Life Surveys: FACT-P and IIEF ................................................... 92 
Appendix 5: DNA Damage Repair Pathway Genes of Interest ........................................... 93 
 
 
 
 
 
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Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
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LIST OF TABLES 
 
Table 1 
Adverse Drug Reactions reported in Clinical Trials………………….….24 
Table 2  
Volume of Blood to Be Drawn From Each Subject……………….…….52 
Table 3 
Management of anemia……………….………………………………...58 
Table 4 
Management of neutropenia, leukopenia and thrombocytopenia………..59 
Table 5 
Dose reductions for olaparib treatment…………………………………..61 
LIST OF FIGURES 
Figure 1 
Clinical states of prostate cancer………………………………………….10 
 
Figure 2  
Timeline of recent Food and Drug Administration (FDA) approval for 
mCRPC drugs…………..………………………………………………....11 
 
Figure 3 
Growth inhibitory effects of supraphysiologic androgens…………..…....13 
 
Figure 4 
Supraphysiologic androgens induce dsDNA breaks in prostate  
cancer cells……..………………………………..……………………….13 
Figure 5.  
PSA responses and Quality of Life changes following BAT…...…...…...15 
Figure 6  
Adverse events observed in trials testing BAT in men with advanced 
prostate cancer……..……………………………..………………………15 
Figure 7 
DDR alterations and percent change in PSA in men receiving BAT…….16 
Figure 8 
Graphical plot of olaparib activity (IC50) across the KU95 cell  
line panel……..……………………………..……………………………18 
Figure 9  
*UDSKLFDOSORWRIRODSDULEVHQVLWLYHFHOOOLQHV,&ȝ0DUUDQJHGE\
known BRCA1/2 mutation status or low expression of HRR genes…….19 
Figure 10  
Results from the Phase II TOPARP Trial……..…………………………22 
Figure 11 
Study schematic……..………..…………………………….……………35 
Figure 12  
Modeled T Kinetics with different T enanthate dosing schedules……….55 
 
 
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Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ADT 
Androgen deprivation therapy 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AR 
Androgen receptor 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BAT 
Bipolar Androgen Therapy 
BD/BID 
Twice daily 
CI 
confidence interval 
CL 
clearance 
Cmax 
peak concentration 
Cmax,ss 
peak concentration at steady state 
Cmin 
trough concentration 
Cmin,ss 
trough concentration at steady state 
CNS 
central nervous system 
CR 
complete response 
CRPC 
Castration-resistant prostate cancer 
CT 
computed tomography 
CTC 
circulating tumor cell 
ctDNA 
cell-free tumor DNA 
DDR 
DNA Damage Repair 
DHEA-S 
Dehydroepiandrosterone sulfate 
DHT 
Dihydrotestosterone 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
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Abbreviation or 
special term 
Explanation 
DSB 
Double strand DNA break 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
disodium edetate dihydrate 
FFPE 
formalin fixed paraffin embedded 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GLP 
Good Laboratory Practice 
HR/HRR 
Homologous recombination/Homologous Recombination Repair 
HRD 
Homologous recombination deficiency 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IF 
Immunofluorescence 
IHC 
immunohistochemistry  
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
LHRH 
luteinizing hormone releasing hormone 
mCRPC 
metastatic castration-resistant prostate cancer 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events  
NHEJ 
Non-homologous end-joining 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PC 
Prostate cancer 
PCWG 
Prostate Cancer Working Group 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
 
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Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
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Abbreviation or 
special term 
Explanation 
PR 
partial response 
PRO 
patient-reported outcome 
QoL 
quality of life 
QTc 
the time between the start of the Q wave and the end of the T wave 
corrected for heart rate 
QTcF 
QT interval on ECG corrected using the Frederica’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SD 
stable disease 
SPT 
Supraphysiologic Testosterone 
SSB 
Single strand DNA break 
SUSAR 
suspected unexpected serious adverse reaction 
T 
Testosterone 
t½ 
half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to peak concentration 
Tmax,ss 
time to peak concentration at steady state 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
USA 
United States of America 
WHO 
World Health Organization 
 
 
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Consortium Study Number  9984 
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1. 
INTRODUCTION 
Shortly after Charles Huggins first reported on the remarkable palliative benefits of androgen 
deprivation therapy (ADT) in men with advanced prostate cancer, case series recounting the 
paradoxical benefits of testosterone (T) supplementation in prostate cancer patients began to 
emerge [1-5]. Recent preclinical studies have shed light on the mechanisms underlying the 
antitumor effects of androgens, and have renewed our interest in exploring high-dose T as a 
therapeutic strategy for men with castration-resistant prostate cancer (CRPC) [6-10]. As such, 
we have recently published the results of a pilot study designed to evaluate the effects of rapid 
cycling between very high and very low serum T levels in men with asymptomatic CRPC, a 
mode of therapy we call bipolar androgen therapy (BAT) [11]. In this study we found that 
~50% of men had PSA declines and radiographic responses (partial or complete responses). 
Because the induction of DNA damage appears to be a key mechanism underlying the clinical 
effects of BAT, we hypothesize that combining BAT with the PARP inhibitor olaparib to 
impair DNA damage repair (DDR) will improve clinical efficacy. 
1.1 
Disease Background 
Prostate cancer is the second most common cause of cancer deaths in men in the US.[12] 
Approximately one in every six American men will be diagnosed with the disease during his 
lifetime. The disease continuum has been modeled as a series of states defined by the presence 
or absence of detectable metastases and whether testosterone levels are in the castrate or non-
castrate range (Figure 1). Each state represents a significant milestone in the illness that forms 
the basis for clinical research and for medical decision making in the context of routine 
clinical practice. The standard treatment for patients with metastatic disease includes surgical 
or medical castration with a luteinizing hormone releasing hormone (LHRH) analog, which is 
continued indefinitely (i.e. androgen deprivation therapy, ADT). The results are predictable, 
with a decline in PSA followed by tumor regression, a period of stability in which the tumor 
does not proliferate and PSA remains stable, followed by rising PSA and regrowth as a 
castration resistant lesion. Prostate cancer progression despite castrate levels of testosterone 
represents a transition to a lethal disease phenotype referred to as castration-resistant prostate 
cancer (CRPC).  
 
Figure 1. Clinical states of prostate cancer. 
 
 
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Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
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Date  February 24, 2021 
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Since 2004 there have been six FDA approved agents for the treatment of metastatic CPRC 
(mCRPC), all on the basis of Phase III data demonstrating a modest survival benefit compared 
to controls (median overall survival advantage approximately 2 to 5 months) (Figure 2).[13-
21]. The first agent, docetaxel, is a semi-synthetic taxane that function by inhibiting 
microtubule activity. Originally it was only indicated for men with mCRPC, but recent data 
has demonstrated that it is highly effective when combined with ADT in the upfront treatment 
of metastatic hormone-sensitive prostate cancer.[18, 21-24] In 2010, the next-generation 
taxane cabazitaxel was also approved for use in patients progressing on docetaxel.[15] 
 
Figure 2: Timeline of recent Food and Drug Administration (FDA) approval for mCRPC drugs. 
Median improvement in overall survival in months (mos) is provided. 
More recently, it has become apparent that the androgen receptor (AR) signaling axis remains 
engaged even in the castration-resistant setting, with AR-regulated genes (e.g. PSA) often 
expressed at high levels[25]. While older literature had described CRPC as a ‘hormone 
refractory’ disease state, the term ‘castration-resistant’ has been adopted largely due to the 
increasing recognition that androgen receptor (AR) signaling still plays a vital role in driving 
prostate cancer growth, and remains a viable target in the CRPC disease space.[26] Indeed, the 
development of newer drugs like abiraterone (an extragonadal inhibitor of androgen 
biosynthesis) and enzalutamide (a pure AR-antagonist) that function to inhibit ligand-AR 
interaction have provided proof of principle that the AR remains an important driver of CRPC 
growth [13, 14, 19, 20]. 
Given their similar mechanisms of action, it is not surprising that evidence of cross-resistance 
between abiraterone and enzalutamide has begun to emerge, with overexpression of AR 
representing the most frequently observed mechanisms of resistance to AR-signaling 
inhibitors [25, 27-35]. Other resistance mechanisms described, include: increased 
extragonadal androgen synthesis; the emergence of constitutively active AR splice variants 
(AR-Vs); AR point mutations; AR-signaling activation via alternative pathways (e.g. 
AKT/mTOR/Pi3K, HER kinases); and activation of other nuclear hormone receptors such as 
the glucocorticoid receptor[25, 36-45]. One or more of these mechanisms may provide a basis 
for why progression on one AR-directed agent may portend a poor response to the other drug 
when used second line.  
 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
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The other two agents approved for mCRPC are sipuleucel-t and radium-223. Sipuleucel-T is 
an ex vivo autologous immunotherapy product and remains the only cancer vaccine shown to 
improve overall survival in Phase III testing [16, 46]. It is designed to produce an immune 
response toward the prostate antigen PAP. Interestingly no difference in disease progression 
was observed between patient receiving sipuleucel-t or placebo in the Phase III study, nor did 
it associate with tumor or PSA responses. Sipuleucel-t is not approved for patients with 
V\PSWRPDWLFGLVHDVHDQGJLYHQWKDWRQO\PHQZLWKDOLIHH[SHFWDQF\PRQWKVZHUHLQFOXGHG
in the pivotal Phase III trial, it is not appropriate for patients with rapidly progressive disease 
or those expected to live <6 months.  Radium-223 is a novel alpha emitting 
radiopharmaceutical that possesses intrinsic bone targeting properties similar to that of other 
alkaline earth elements, such as calcium, and is approved for the treatment of symptomatic, 
bone-metastatic CRPC. Radium-223 is not expected to affect soft tissue metastases, and on 
this basis radium-223 is not indicated for patients with visceral metastases or nodal metastases 
>3 cm[17]. 
As outlined above, the majority of the agents approved for mCRPC are either AR-signaling 
inhibitors (i.e., abiraterone and enzalutamide), only indicated for a narrow subset of patients, 
or have minimal clinical efficacy. Approaches that do not rely on inhibiting the AR-signaling 
axis are sorely needed. Importantly, preclinical studies have demonstrated that high-dose 
testosterone has potent anti-tumor activity in prostate cancer models with high AR levels – 
indicating that treatment with androgen supplementation is likely to be most effective in 
advanced prostate cancer patients who have progressed on drugs that inhibit AR-signaling[6, 
47]. In addition, recent mechanistic studies have indicated that high-dose testosterone may 
exert an antitumor effect by inducing double strand DNA (dsDNA) breaks, providing a 
rationale for combining high-dose testosterone with agents that can impair DNA repair (e.g. 
PARP inhibitors). 
1.2 
Supraphysiologic Testosterone (SPT) in CRPC Background 
1.2.1 
SPT in CRPC Pre-clinical experience 
As prostate cancer cells adapt to low androgen levels, one of the most frequently observed 
events is an adaptive upregulation of the androgen receptor (AR) – likely driving resistance to 
AR-signaling inhibition [25, 35]. We hypothesized that the adaptive autoregulation of AR may 
serve as a therapeutic liability, sensitizing prostate cancer cells to supraphysiologic androgen-
induced cell death. In support of this, we and others have observed that adapted prostate cancer 
cell lines display blunted cell growth when exposed to supraphysiologic androgen levels (Figure 
3) [7, 11, 47-52]. 
 
 
 
 
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Clinical Study Protocol 
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Consortium Study Number  9984 
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Date  February 24, 2021 
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Figure 3: Growth inhibitory effects of supraphysiologic androgens. LNCaP, LAPC-4 and VCaP cells 
were adapted to grow in charcoal-stripped media. After demonstrating castrate-resistant growth, cells 
were exposed to supraphysiologic levels of androgens. A) R1881 dose response. Y-axis is fold change 
in cell number compared to day 0 control after 5 days of exposure. B) Growth of adapted LNCaP cells 
in nude mice treated with a testosterone implant (sq) vs an empty (control) implant (P <0.05 after day 
21). 
Studies exploring the mechanisms behind the paradoxical antitumor effects of SPT have 
demonstrated that in high-AR cell lines, rapidly transitioning from a castrate to high androgen 
environment induces double strand DNA (dsDNA) breaks, an effect likely mediated by 
topoisomerase IIB (TOP2B) [6, 10, 11]. As AR-mediated transcription proceeds, knots and 
tangles in DNA occur. In order to overcome these topologic constraints, TOP2B induces 
transient dsDNA breaks, which are then repaired by the enzyme. Supporting this model is 
preclinical data showing that the TOP2B poison etoposide is able to potentiate dsDNA breaks 
by inhibiting DNA re-ligation (Figure 4) [11]. Furthermore, in vivo experiments demonstrate 
synergy when SPT is combined with DNA damaging doses of radiation [53]. 
 
Figure 4: Supraphysiologic androgens induce dsDNA breaks in prostate cancer cells. Ȗ-H2A.x 
foci in LNCaP cells after exposure to 100 nM DHT or 100 mM etoposide or the combination. 
 
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Consortium Study Number  9984 
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Date  February 24, 2021 
14(93) 
 
1.2.2 
SPT in CRPC Clinical experience 
The aforementioned preclinical work exploring the paradoxical growth inhibitory effects of 
androgens in high AR expressing prostate cancer cell lines renewed our interest in exploring 
high-dose T as a therapeutic strategy for men with mCRPC [6-10]. As such, we developed a 
form of intermittent high-T therapy we termed Bipolar Androgen Therapy (BAT) in which 
serum T levels are rapidly cycled between very high and very low levels in men with 
asymptomatic mCRPC.[11] We hypothesized that BAT would prevent AR levels from 
adapting to either high or low androgen conditions, thereby preventing the emergence of 
resistance to high-dose T. In addition, because studies have shown that the dsDNA breaks and 
apoptosis induced by high-doses of androgens are transient, rapid cycling of T could result in 
repeated rounds of DNA damage, enhancing antitumor effects [53].  
Clinically, BAT has been administered as intramuscular (IM) injections of either testosterone 
enanthate or cypionate (which have identical pharmacokinetics) at a dose of 400 mg every 28 
days. This dose and formulation was selected because it has been shown to drive T levels well 
into the supraphysiologic range (>1500 ng/dL), followed by a rapid decline in T back to the 
near-castrate range at the end of a 28 day cycle [11, 54]. 
In our initial pilot study testing BAT, we treated 16 CRPC patients with BAT combined with 
etoposide for 3 months. Patients whose PSA was falling at the end of this 3 month period were 
allowed to continue on BAT monotherapy until disease progression. In total, 14 patients 
completed the first 3 months of therapy and were response evaluable. Of these 14 men, we 
observed high response rates, with robust PSA responses (Figure 5A) and tumor shrinkage on 
scans in 50% of patients [11]. In a more recent study testing BAT in men with hormone-
sensitive prostate cancer (HSPC) we found that BAT resulted in high-rates of PSA 
suppression and importantly also in improvements in quality of life (Figure 5B)[55]. 
Preliminary results from the RESTORE trial, a Phase II study testing BAT in men progressing 
on enzalutamide (N=30), have also revealed evidence of clinical activity in heavily pre-treated 
mCRPC. In that study 30% of patients had PSA declines IURPEDVHOLQHDQGDPHGLDQ
clinical/radiographic PFS of 8.6 months was observed, which compares favorably to other 
AR-directed therapies given post-enzalutamide [56, 57]. Importantly, BAT was found to be 
well tolerated across the three trials evaluating it in men with advanced prostate cancer 
(Figure 6).  
 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
15(93) 
 
Figure 5. (A) Waterfall Plot Showing Max PSA Change relative to baseline in the pilot BAT study. 
The number at the end of each bar indicates the number of treatment cycles received. Number in 
parentheses indicates percent PSA change in a case where the bar was truncated. (B) Mean change in 
quality of life (QoL) from baseline (based on IIEF survey) in men with hormone sensitive PC receiving 
BAT. Increasing values indicate improved QoL. C1, cycle 1; C2, cycle 2. 
 
 
Figure 6. Adverse events observed in trials testing BAT in men with advanced prostate cancer. 
Note, the BAT Pilot Study tested BAT in combination with etoposide for the first 3 months of 
treatment. One individual developed neutropenic sepsis and subsequently died. This was deemed to be 
a consequence of etoposide and unrelated to BAT. 
 
Compared to our experience with BAT, older studies testing physiologic doses of T in men 
with CRPC have documented modest benefit at best [58, 59]. In these contemporary Phase I 
studies testing physiologic doses of T in men with CPRC, there were no objective 
radiographic responses and PSA declines >50% occurred in only one out of 27 patients [58, 
59]. This is in contrast to our trials testing intermittent doses of SPT (i.e., BAT), where we 
observed high response rates in men with CRPC, with robust PSA responses and tumor 
shrinkage in 50% of patients [11]. 
 
 
 
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Clinical Study Protocol 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
16(93) 
Clinical Evidence for BAT Inducing DNA Damage 
Recently, a case report was published that described an extreme responder to BAT who 
harbored deleterious ATM and BRCA2 mutations. Because this individual’s tumor had an 
intrinsic deficiency in its ability to repair DNA damage, it was hypothesized that dsDNA 
breaks induced by high-dose T were unable to be repaired, and BAT was therefore 
synthetically lethal to tumor cells[60]. As part of ongoing translational work aimed at 
understanding the drivers of response/resistance to BAT, we have performed next-generation 
sequencing on tumor DNA from seven patients receiving BAT on the TRANSFORMER 
clinical trial, which is testing BAT vs. enzalutamide in mCRPC patients who have progressed 
on abiraterone [clinicaltrials.gov: NCT02286921]. Consistent with the findings from the 
aforementioned case report, we have found that the majority of patients exhibiting a PSA 
response have detectable alteration in DNA damage repair pathway genes – further supporting 
the induction of DNA damage as a key mechanism driving clinical responses to BAT (Figure 
7). 
 
Figure 7: Percent change in PSA compared to baseline in men receiving Bipolar Androgen 
Therapy. DDR = DNA damage response; * = truncated at 100% increase in PSA above baseline. 
1.3 
Olaparib Background 
Investigators should be familiar with the current olaparib (AZD2281) Investigator Brochure 
(IB). 
 
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Clinical Study Protocol 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
17(93) 
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 [61-64].  
During the process of cell division, DSBs can be efficiently repaired in normal cells by 
homologous recombination repair (HR).  Tumors with HR deficiencies (HRD), such as 
ovarian cancers in patients with BRCA1/2 mutations, cannot accurately repair the DNA 
damage, which may become lethal to cells as it accumulates [64-66]. In addition, PARP is 
involved in repairing DSB through the alternative non-homologous end-joining (NHEJ) 
pathway, and PARP inhibitors could therefore further impair DSB repair in HR-deficient 
tumors[67-69].  In such tumor types, olaparib may offer a potentially efficacious and less 
toxic cancer treatment compared with currently available chemotherapy regimens.  
BRCA1 and BRCA2 defective tumors are intrinsically sensitive to PARP inhibitors, both in 
tumor models in vivo and in the clinic [70-72]. The mechanism of action for olaparib results 
from the trapping of inactive PARP onto the single-strand breaks preventing their repair [73, 
74].  Persistence of SSBs during DNA replication results in their conversion into the more 
serious DNA DSBs that would normally be repaired by HR repair.  Olaparib has been shown 
to inhibit selected tumor cell lines in vitro and in xenograft and primary explant models as 
well as in genetic BRCA knock-out models, either as a stand-alone treatment or in 
combination with established chemotherapies. In addition, PARP inhibitors have been shown 
across multiple preclinical tumor models to potentiate the antitumor effects of DNA damaging 
cytotoxic agents (e.g. alkylating agents, platinum chemotherapy) as well as radiation [72, 75-
78]. Importantly, many of these studies have shown that the observed anti-tumor effects are 
not restricted to cell lines with loss of HR pathway genes. 
1.3.1 
Pre-clinical experience 
The pre-clinical experience is fully described in the current version of the olaparib 
Investigator’s Brochure (IB).    
A range of tumor cell lines have been investigated using colony formation assays for 
sensitivity to PARP inhibition with olaparib as a single agent. IC50 data were calculated for 
each cell line across KU95, a mixed tumor type panel of 95 cancer cell lines that also 
contained ovarian cancer cell lines (Figure 8). Cell lines representing breast, ovarian, 
colorectal, head and neck, lung and pancreatic tumor types were screened and shown to have 
wide-UDQJLQJFHOOXODUDFWLYLW\IURPWKHORZQ0,&Q0WRLQH[FHVVRIȝ0FHOOOLQHV
ZLWK,&JUHDWHUWKDQȝ0WKHWRSFRQFHQWUDWLRQXVHGZKHUHDQH[DFWIC50 could not be 
GHWHUPLQHGDUHOLVWHGDVȝ0ZLWKD]HUR6GIRUSORWWLQJSXUSRVHV 
 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
18(93) 
Cell lines with known inactivating BRCA1 or BRCA2 mutations, BRCA1 promoter 
methylation or other DNA repair defects e.g., Meiotic Recombination 11 (MRE11; MRE11A), 
were also included. The panel was also profiled for relative protein and messenger ribonucleic 
acid gene expression levels of key DNA damage response (DDR) and HRR associated genes 
such as BRCA1, BRCA2, ATM, ATR, mediator of DNA damage checkpoint protein 1 and 
MRE11A.  
A cell line was classified as HRD when either relative gene or protein expression for 2 or 
more HRR target genes was less the half (50%, 0.5) relative to the mean expression. Cell lines 
with published literature confirming deleterious, homozygous loss-of-function BRCA1 or 
BRCA2 mutations were also classed as HRD [79-82].  
 
Figure 8: Graphical plot of olaparib activity (IC50) across the KU95 cell line panel. 
 
While a broad range, continuum of growth inhibitory (IC50) activity for olaparib was observed 
DFURVVWKHFHOOOLQHSDQHOUDQJLQJIURPȝ0WKURXJKWR!ȝ0DVVRFLDWLRQVZLWK
enhanced olaparib sensitivity (IC50 ȝ0ZHUHREVHUYHGLQFHOOOLQHVZLWKNQRZQBRCA1 or 
BRCA2 mutations or low expression of HRR genes/proteins (Figure 9. These data are 
consistent with the proposed mechanism of action of PARP inhibitors, where deficiencies in 
HR lead to an inability to repair DNA DSBs resulting from PARP inhibitor treatment. While 
there is a clear enrichment for HRD within the most sensitive cell lines (24/30), there are still 
responsive cell lines for which a molecular basis has not yet been ascribed.  
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
19(93) 
 
Figure 9: GraphLFDOSORWRIRODSDULEVHQVLWLYHFHOOOLQHV,&ȝ0DUUDQJHGE\NQRZQ
BRCA1/2 mutation status or low expression of HRR genes.  
Plot of highly olaparib sensitive cell lines (IC50ȝ0FOXVWHUHGE\WKHSUHVHQFHNQRZQGHOHWHULRXV
BRCA1/2 mutations (BRCA mutant), low BRCA1/2 expression (low BRCA expression), low 
expression of 1or more HR genes in the absence of BRCA1/2 mutation/low expression (non-BRCA, 
low HRR expression) or those without any of these defects (unknown defect).  
 
Similarly, in vivo orthotopic BRCA knockout models testing olaparib showed marked anti-
tumor effects. In both a BRCA1-/- orthotopic mouse mammary tumor model and a BRCA2- /- 
orthotopic mouse model, dosing with 50 mg/kg olaparib once daily (od) for 28-days showed 
significant anti-tumor efficacy for single agent olaparib [71, 72].  
 
An analysis of the correlation of olaparib response with several standard-of-care 
chemotherapies in a panel of breast cancer cell lines demonstrated a strong correlation with 
both carboplatin (0.84, p=0.0006) and camptothecin (0.8, p=0.0018). This is consistent with 
what is known about the types of DNA damage they induce (intra-strand and inter-strand 
cross-links for platinum and trapped topoisomerases-DNA adducts for camptothecins, both of 
which result in DNA DSB formation in replicating cells) and the DDR pathways that deal 
with them (primarily HRR in cells undergoing DNA replication). The same does not hold for 
a mechanistically unrelated chemotherapy, such as paclitaxel (-0.11) whose mechanism of 
action is unrelated to the induction of DNA damage.  
An analysis of olaparib and platinum response across several tumor cell lines indications 
where platinum treatment is standard-of-care and included ovarian, non-small cell lung cancer 
(NSCLC) and head and neck squamous cell carcinoma cell lines. Consistent with the breast 
cancer cell line data, the strong correlation between platinum response and olaparib response 
was observed both in vitro (Figure 10) and in vivo.  
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
20(93) 
When olaparib is combined with the mono-methylating agent TMZ, potentiation of its anti-
tumor activity across a number of cancer cell lines is observed. Moreover, other PARP 
inhibitors have also been shown to be effective with a number of non-classical alkylating 
agents including MMS, DTIC and TMZ. However, for the “classic” alkylating agents such as 
cyclophosphamide and N, N’-bis(2-chloroethyl)-N-nitrosourea (BCNU; carmustine) only 
some early literature reports are available on showing potentiation but, to date, no data have 
been generated for olaparib with such agents. Similarly, the effectiveness of olaparib with 
topoisomerase I inhibitors (i.e., camptothecin family) and platinum agents (e.g., cisplatin and 
carboplatin) has been shown in both in vitro and in vivo studies.  
1.3.2 
Toxicology and safety pharmacology summary 
The toxicology and safety pharmacology is fully described in the current version of the 
olaparib Investigator’s Brochure (IB).    
In repeat dose oral toxicity studies of up to 6 months duration in rats and dogs, the principal 
target organ for toxicity was the bone marrow, with associated changes in peripheral 
hematology parameters, which may be related to the primary pharmacology of olaparib. All 
changes showed full or partial recovery following withdrawal of olaparib.  
Olaparib was not mutagenic in an Ames bacterial mutation test, but was clastogenic in a CHO 
chromosome aberration test in vitro. When dosed orally, olaparib also induced micronuclei in 
bone marrow of rats. These findings are consistent with genomic instability resulting from the 
primary pharmacology of olaparib.  
In reproductive toxicology studies in rats, oral dosing of olaparib prior to mating produced no 
adverse effects on male fertility. In female rats, although conception rates were unaffected by 
pre- and peri-conception dosing, embryofetal survival was decreased. Administration of 
olaparib during organogenesis had an adverse effect on embryofetal survival and also 
increased major fetal malformations at dose levels that were not maternally toxic. The effects 
on embryofetal development are considered to be related to the primary pharmacology of 
olaparib.  
Exposures in the repeat dose and reproductive toxicology studies were below those achieved 
at the clinical therapeutic doses of 400 mg bd olaparib (capsule) and 300 mg bd (tablet).  
Combination studies in rats suggest potential for olaparib to exacerbate the effects of TMZ 
and topotecan, although combination of olaparib with these anti-cancer agents did not induce 
any additional target organ toxicities to those seen with single agent administration.  
Monotherapy  
Data from the development program indicate that olaparib is generally well tolerated at 
monotherapy doses up to 400 mg bd (capsule formulation) and 300 mg bd (tablet formulation) 
in patients with solid tumors. Administration of olaparib monotherapy has been associated 
with adverse reactions generally of mild or moderate severity (CTCAE Grade 1 or 2) and 
generally not requiring treatment discontinuation.  
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
21(93) 
Combination studies  
Studies of olaparib in combination with various chemotherapy agents indicate an increase in 
bone marrow toxicity (anemia, neutropenia, thrombocytopenia) greater than expected if the 
agents had been administered alone. The effects are generally transient but treatment delays 
are common and alternative administration schedules/toxicity management processes have 
been evaluated within some of these studies. When this type of toxicity has occurred it has 
been managed by routine clinical practice including dose delays, dose reductions, intermittent 
dosing and/or the use of supportive care measures, including G-CSF.  
1.3.3 
Clinical experience 
Clinical experience with olaparib is fully described in the current version of the olaparib 
Investigator’s Brochure. 
1.3.3.1 
Olaparib in mCRPC 
Failure to accurately repair DNA damage can lead to the accumulation of mutations, and an 
increased cancer risk [83, 84]. Not surprisingly, mutations in DNA repair genes have been 
associated with several cancer predisposition syndromes [85-87]. It has also been shown 
across a variety of malignancies that when DNA damage repair deficiency occurs – often as a 
result of homozygous loss of function mutations in BRCA 1/2, ATM and other genes involved 
in homologous recombination – alternative DNA repair mechanisms are required to prevent 
genomic instability and cell death. Poly (ADP-ribose) polymerase (PARP) has been shown to 
be a key mediator in this respect. As such, strategies to inhibit PARP activity have been 
shown to be effective in a number of cancers with impaired homologous recombination [70, 
88-91]. In addition, more recent data has shown that PARP inhibition may be an effective 
strategy to augment the antitumor effects of other DNA damaging agents (e.g. alkylating and 
platinum chemotherapies) in cancers with intact DDR pathways [91, 92]. 
As part of our participation in the SU2C/AACR/PCF Prostate Cancer Dream Team, we have 
found that ~20% of CRPC patients harbor biallelic loss of a DNA damage repair (DDR) 
pathway gene [35]. In addition, more recent studies from our group have demonstrated that in 
men with metastatic prostate cancer, there is a high incidence (~12%) of deleterious alteration 
in DDR genes [87]. This data provides a strong rationale for a precision oncology approach to 
treating advanced prostate cancer with drugs that impair DDR (e.g. PARP inhibitors). Proof of 
concept for this approach is derived from the TOPARP Trial [88]. This was a Phase II study 
testing olaparib 400 mg by mouth twice daily in men with metastatic CRPC. The primary 
endpoint was response rate, which was defined as either an objective radiographic response 
SHU5(&,67FULWHULDYD36$UHGXFWLRQRIIURPEDVHOLQHLH, PSA50 response) or a 
FRQILUPHGUHGXFWLRQLQFLUFXODWLQJWXPRUFHOOV&7&VIURPFHOOVSHUP/RIEORRGWR
cells per 7.5 mL of blood. Fifty patients were enrolled, and all were post-docetaxel. Forty-nine 
patients received prior abiraterone or enzalutamide. Sixteen patients (33%) met the primary 
endpoint. Responses to olaparib were enriched in the subset of patients with homozygous 
deletions, deleterious mutations, or both in DDR genes (e.g. BRCA1/2, ATM, Fanconi’s 
anemia genes, and CHEK2) (Figure 10). In this cohort, response rate was 88%. The observed 
safety profile of olaparib was consistent with that observed in other solid tumor trials. On the 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
22(93) 
basis of this trial, larger randomized studies have been launched to further evaluate PARP 
inhibitors in men with CRPC. 
 
Figure 10: Results from the Phase II TOPARP Trial [88]. Patients with metastatic, castration-
resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. (A) 
Responses to olaparib were enriched in patients with biallelic loss of DNA repair genes. Radiographic 
PFS (B) and overall survival (C) were significantly longer in patients with biallelic loss of DNA repair 
genes (i.e., biomarker-positive).  
 
In 2020, olaparib was approved as treatment for mCRPC patients who have progressed on 
prior abiraterone or enzalutamide on the basis of the Phase III PROfound study[93]. 
PROfound was a randomized, open-label study evaluating olaparib vs. physician’s choice of 
 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
23(93) 
enzalutamide or abiraterone in men with mCRPC and deleterious germline or somatic 
mutations in HR repair genes. Enrollment was allowed on the basis of a panel of genes 
involved in the HR repair pathway. 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 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 mCRPC patients with somatic or germline 
alterations in ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, 
PALB2, RAD51B, RAD51C, RAD51D and/or RAD54L. 
Of note, PARP inhibitors have also been shown across multiple preclinical tumor models to 
potentiate the antitumor effects of DNA damaging cytotoxic agents (e.g. alkylating agents, 
platinum chemotherapy) as well as radiation [72, 75-78]. Importantly, these effects were not 
restricted to cell lines with biallelic loss of DNA damage pathway genes. Proof of concept for 
combining PARP inhibitors with DNA damaging agents is provided by the I-SPY 2 TRIAL. 
This study was a multi-center, randomized, Phase II “platform” trial testing multiple 
experimental regimens added to a control “backbone” regimen. Patients with high-risk 
primary breast cancer planning to undergo surgery were eligible to receive neoadjuvant 
therapy per protocol [89]. The control arm consisted of 12 weekly cycles of paclitaxel 
followed by 4 cycles, every 2-3 weeks of doxorubicin plus cyclophosphamide. One of the 
experimental arms combined the PARP inhibitor veliparib 50 mg by mouth twice daily and 
carboplatin AUC 6 concurrently with the weekly paclitaxel. The primary endpoint was 
pathologic complete response (pCR) rate as assessed at the time of surgery. In the subset of 
patients with triple negative breast cancer (i.e. HER2 negative, ER/PR negative), the estimated 
rate of pCR was 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-
carboplatin arm compared to 26% (95% PI, 9 to 43%) in the control group. This translated to 
an 88% predicted probability of success in the Phase III setting. Importantly, this study was 
not restricted to patients with loss of DNA repair pathway genes, however, it was noted that 
more patients in the veliparib-carboplatin arm (12/72, 17%) had deleterious mutations in 
BRCA1 or BRCA2 compared to control (2/44, 5%). Several other studies testing olaparib in 
combination with DNA damaging therapies are underway or have recently completed. The 
results of these studies generally support combining PARP inhibitors with DNA damaging 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
24(93) 
therapies. Further details on these trials can be found in the Investigator’s Brochure (Section 
5.2.2: Efficacy: combination studies).  
1.3.3.2 
Emerging Safety Profile 
Olaparib monotherapy has been associated with laboratory findings and/or clinical diagnoses, 
generally of mild or moderate severity (CTCAE Grade 1 or 2) and generally not requiring 
treatment discontinuation. 
The safety profile is based on pooled data from 2901 patients with solid tumors treated with 
olaparib monotherapy in clinical trials at the recommended dose.  
The following adverse reactions have been identified in completed clinical trials with patients 
receiving olaparib monotherapy where patient exposure is known. Adverse Drug Reactions 
are organised by Medical Dictionary for Regulatory Activities (MedDRA) SOC and then by 
MedDRA preferred term in Table 1. Within each SOC, preferred terms are arranged by 
decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of 
adverse reactions aUHGHILQHGDVYHU\FRPPRQFRPPRQWR
XQFRPPRQWRUDUHWRDQGYHU\UDUH
including isolated reports.  
 
 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
25(93) 
Table 1: Adverse Drug Reactions reported in Clinical Trials 
MedDRA SOC 
MedDRA term 
CIOMS 
descriptor/ 
overall frequency 
(All CTCAE 
grades) 
Frequency of CTCAE 
Grade 3 and above 
Neoplasms benign, 
malignant and 
unspecified 
(including 
cysts and polyps) 
Myelodysplastic 
syndrome/acute myeloid 
leukemia 
Uncommon 
Uncommon 
Blood and lymphatic 
system disorders 
Anemiaa 
Very 
common 
Very common 
Neutropeniaa 
Very 
common 
Common 
Leukopeniaa 
Very 
common 
Common 
Thrombocytopeniaa 
Very 
common 
Common 
Lymphopeniaa 
Common 
Uncommon 
Immune system 
disorders 
 
 
 
Hypersensitivitya 
Uncommon 
Rare 
 
 
 
Angioedema b 
Uncommon 
- 
Metabolism and 
nutrition disorders 
Decreased appetite 
Very 
common 
Uncommon 
Nervous system 
disorders 
Dizziness 
Very 
common 
Uncommon 
Headache 
Very 
common 
Uncommon 
Dysgeusia 
Very 
common 
- 
Respiratory, thoracic 
and mediastinal 
disorders 
Cougha 
Very 
common 
Uncommon 
Dyspneaa 
Very 
common 
Common 
Gastrointestinal 
disorders 
Vomiting 
Very 
common 
Common 
Diarrhea 
Very 
common 
Common 
Nausea 
Very 
common 
Common 
Dyspepsia 
Very 
common 
- 
Stomatitisa 
Common 
Uncommon 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
26(93) 
Upper abdominal pain 
Common 
Uncommon 
Skin and subcutaneous 
tissue disorders 
Rasha 
Common 
Rare 
Dermatitis 
Uncommon 
- 
Erythema nodosumb 
Rare 
- 
General disorders 
Fatigue (including 
asthenia) 
Very 
common 
Common 
Investigations 
Blood creatinine 
increased 
Common 
Uncommon 
Mean cell volume 
increased 
Uncommon 
- 
a                   Anaemia includes preferred terms (PTs) of anaemia, anaemia macrocytic, erythropenia, haematocrit 
decreased haemoglobin decreasednormocytic anaemia and red blood cell count decreased; Cough 
includes PTs of cough and productive cough; Dermatitis includes PTs of dermatitis and dermatitis 
allergic; Dyspnoea includes PTs of dyspnoea and dyspnoea exertional; Hypersensitivity includes PTs of 
drug hypersensitivity and hypersensitivity;; Leukopenia includes PTs of leukopenia and white blood cell 
count decreased; Lymphopenia includes PTs of lymphocyte count decreased, and lymphopenia ; 
Neutropenia includes PTs of febrile neutropenia, neutropenia, neutropenic infection, neutropenic sepsis, 
and neutrophil count decreased; Rash includes PTs of exfoliative rash, generalised erythema, rash, rash 
erythematous, rash macular, rash maculo-papular, rash papular and rash pruritic;; Stomatitis includes 
PTs of aphthous ulcer, mouth ulceration and stomatitis.  Thrombocytopenia includes PTs of platelet 
count decreased, and thrombocytopenia. 
b                    Observed in the post-marketing setting. 
 
CIOMS=Council for International Organization of Medical Sciences; CTCAE=Common Terminology 
Criteria for Adverse Events; MedDRA=Medical Dictionary for Regulatory Activities; PT = Preferred 
term; SOC=System organ class. MedDRA version 22.1 
 
 
Description of selected adverse reactions  
Myelodysplastic syndrome/acute myeloid leukaemia 
In clinical studies, across all indications, MDS/AML occurred uncommonly in patients on 
treatment and during the 30-day safety follow up, and <1.5% at any time after starting 
olaparib, including cases actively solicited during the long term follow up for overall survival. 
In patients with BRCAm platinum-sensitive relapsed ovarian cancer who had received at least 
two prior lines of platinum chemotherapy and received study treatment until disease 
SURJUHVVLRQ62/2VWXG\ZLWKRODSDULEWUHDWPHQW\HDUVLQRISDWLHQWVWKH 
incidence of MDS/AML was 8% in patients receiving olaparib and 4% in patients receiving 
placebo at a follow-up of 5 years. In the olaparib arm, 9 out of 16 MDS/AML cases occurred 
after discontinuation of olaparib during the survival follow-up. The incidence of MDS/AML 
was observed in the context of extended overall survival in the olaparib arm and late onset of 
MDS/AML. The risk of MDS/AML remains < 1.5% at 5 year follow up in the first-line 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
27(93) 
setting when olaparib maintenance treatment is given after one line of platinum chemotherapy 
for a duration of 2 years. 
Hematological toxicity  
Anaemia and other haematological toxicities are generally low grade (CTCAE Grade 1 or 2) 
however, there are reports of CTCAE Grade 3 and higher events. Anaemia was the most 
FRPPRQ&7&$(*UDGHDGYHUVHUHDFWLRQUHSRUWHGLQFOLQLFDOVWXGLHVZLWKILUVWRQVHW
generally reported in the first 3 months of treatment. An exposure response relationship 
between olaparib and decreases in haemoglobin has been demonstrated. In clinical studies 
ZLWKRODSDULEPRQRWKHUDS\WKHLQFLGHQFHRI&7&$(*UDGHVKLIWVGHFUHDVHVIURPEDVHOLQH
in haemoglobin was 23%, absolute neutrophils 19%, platelets 6%, lymphocytes 29% and 
leucocytes 20% (all % approximate). 
The incidence of elevations in mean corpuscular volume from low or normal at baseline to 
above the ULN was approximately 55%. Levels appeared to return to normal after treatment 
discontinuation and did not appear to have any clinical consequences. 
Baseline testing, followed by monthly monitoring of complete blood counts is recommended 
for the first 12 months of treatment with olaparib, and periodically after this time to monitor 
for clinically significant changes in any parameter during treatment which may require dose 
interruption or reduction and/or further treatment.  
Other laboratory findings  
,QFOLQLFDOVWXGLHVZLWKRODSDULEWKHLQFLGHQFHRI&7&$(*UDGHVKLIWVHlevations) from 
baseline in blood creatinine was approximately 11%. Data from a double-blind placebo 
controlled study showed median increase up to 23% from baseline remaining consistent over 
time and returning to baseline after treatment discontinuation, with no apparent clinical 
sequelae. The increase in blood creatinine level might be explained by inhibition of renal 
transporters such as OCT2, MATE1 and MATE2K by olaparib, as blood creatinine levels 
were found to return to baseline after treatment discontinuation. 90% of patients had 
creatinine values of CTCAE Grade 0 at baseline and 10% were CTCAE Grade 1 at baseline. 
Nausea and vomiting  
Nausea was generally reported very early, with first onset within the first month of olaparib 
treatment in the majority of patients. Vomiting was reported early, with first onset within the 
first two months of olaparib treatment in the majority of patients. Both nausea and vomiting 
were reported to be intermittent for the majority of patients.  
Combination studies  
Safety data from studies in which olaparib has been administered in combination with other 
agents are discussed in the Investigator’s Brochure. The degree of bone marrow suppression 
observed in some patients in the combination studies has however been greater than would be 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
28(93) 
expected with the chemotherapy agent alone, as per label information. Myelotoxicity has been 
observed in studies evaluating olaparib with the following combination therapies: DTIC; 
carboplatin; paclitaxel; carboplatin + paclitaxel; gemcitabine; topotecan; cisplatin; 
doxorubicin, cisplatin + gemcitabine; or irinotecan.  
The principal hematological toxicities observed have been neutropenia, thrombocytopenia and 
anemia. These findings are consistent with pre-clinical findings [72, 76-78, 94].  
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
29(93) 
Adverse events of special interest  
Myelodysplastic syndrome/acute myeloid leukemia  
The incidence of MDS/AML in patients treated in clinical trials with olaparib monotherapy, 
including long-term survival follow-up, was <1.5% and the majority of events had a fatal 
outcome. All patients had potential contributing factors for the development of MDS/AML, 
having received previous chemotherapy with platinum agents. Many had also received other 
DNA damaging treatments. The majority of reports were in germline BRCA mutation carriers 
and some of the patients had a history of previous cancer or of bone marrow dysplasia. If 
MDS and/or AML are confirmed while on treatment with olaparib, it is recommended that 
olaparib should be discontinued and the patient be treated appropriately.  
New Primary Malignancies other than MDS/AML  
New primary malignancies have been reported in <1% of patients. There were other 
contributing factors/potential alternative explanations for the development of the new primary 
malignancy in all cases, including documented BRCA mutation, treatment with radiotherapy 
and extensive previous chemotherapy including carboplatin, taxanes, anthracyclines and other 
alkylating and DNA damaging agents.  
Pneumonitis  
Pneumonitis has been reported in <1.0% patients treated with olaparib monotherapy in clinical 
studies. Reports of pneumonitis had no consistent clinical pattern and were confounded by a 
number of pre-disposing factors (cancer and/or metastases in lungs, underlying pulmonary 
disease, smoking history, and/or previous chemotherapy and radiotherapy). When olaparib 
was used in clinical studies in combination with other therapies there have been events with a 
fatal outcome. If patients present with new or worsening respiratory symptoms such as 
dyspnea, cough and fever, or abnormal chest radiologic finding is observed, olaparib treatment 
should be interrupted and prompt investigation initiated. If pneumonitis is confirmed, olaparib 
treatment should be discontinued and the patient treated appropriately.  
1.4 
Research hypothesis 
We hypothesize, that co-treatment with BAT and olaparib will result in high response rates, 
and that these responses will be most pronounced in the subset of patient with DNA damage 
repair deficiencies. Because most patients experience improvements in quality of life 
following treatment with high-dose testosterone, we expect combination olaparib plus BAT to 
be safe and well tolerated. In addition, because the DNA damaging effects of BAT are 
restricted to prostate cancer cells with high AR expression, this combination should be 
synthetically lethal to tumor cells and result in minimal toxicity to normal tissues. 
1.5 
Rationale for conducting this study 
There is ample evidence to support testing BAT in combination with olaparib. Preclinical 
models have repeatedly shown that SPT is able to induce DNA damage, an effect that can be 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
30(93) 
augmented through inhibiting the ability of TOP2B to repair dsDNA breaks [6, 10, 11]. The 
antitumor effect of SPT also appears to be enhanced when combined with DNA damaging 
doses of radiation [53]. Further supporting the importance of DNA damage as it relates to the 
clinical effects of SPT, is the observation that mutations in DNA damage repair genes (e.g. 
BRCA 1/2, ATM) may predict for response to BAT. Combining BAT with the PARP inhibitor 
olaparib is expected to result in enhanced clinical activity because PARP inhibitors have (i) 
been shown to impair DNA damage repair, and (ii) to potentiate the effects of other DNA 
damaging therapies (e.g. platinum chemotherapy and radiation) [75, 89]. Olaparib 
monotherapy has also shown preliminary signs of efficacy in heavily pretreated mCRPC 
patients with biallelic loss of DNA damage repair pathway genes [88]. Therefore, testing BAT 
in combination with olaparib is likely to be an effective clinical strategy. 
Both BAT and olaparib have already shown evidence of clinical efficacy in the Phase II 
setting. Therefore the primary objective of this study will to evaluate efficacy. This will be 
determined by assessing PSA response rates after 12-weeks of combination therapy, as 
recommended by the Prostate Cancer Working Group 3 (PCWG3) [95]. Because PARP 
inhibitors have been previously shown to potentiate the effects of other DNA damaging agents 
– independent of DNA damage repair gene mutation status – we expect olaparib will also 
potentiate the clinical effects of BAT, resulting in high response rates compared to historical 
controls. However, since both BAT and olaparib appear most effective in patients with 
biallelic loss of DNA damage repair genes, we anticipate that BAT plus olaparib combination 
therapy will also be most effective in this subset of patients. In order to explore the effects of 
BAT plus olaparib in men with DNA damage repair deficiency, we will require that 50% of 
the study cohort have biallelic loss of DNA damage repair genes previously reported to 
associate with response to olaparib in mCRPC patients [88]. 
1.6 
Benefit/risk and ethical assessment 
As stated above, BAT has been reported to have clinical activity in patients with mCRPC that 
is refractory to second-generation AR-signaling inhibitors (i.e., enzalutamide), and is currently 
being tested in an ongoing randomized Phase II trial in men post-abiraterone 
[clinicaltrials.gov: NCT0228692] [11, 56]. Because BAT likely inhibits tumor growth in high 
AR prostate cancer cells by inducing dsDNA damage, we expect that combining it with 
olaparib to impair DNA damage repair will potentiate the clinical effects of BAT – improving 
response rates compared to BAT monotherapy. If effective, patients enrolled to this study 
would benefit by receiving an effective combination therapy that is otherwise unavailable. 
Only patients with mCRPC post-abiraterone and/or enzalutamide will be enrolled to this 
study. Because standard treatment options in this group only afford a modest survival benefit 
(Figure 2), any potential risks associated with clinical trial participation (as opposed to 
pursuing standard therapy) are justified. 
In contrast to chemotherapy, BAT carries minimal toxicity and is associated with 
improvements in quality (Figure 5B). Furthermore, because BAT-induced DNA damage is 
limited to cells with high AR expression, we anticipate that this combination will induce 
synthetic lethality in prostate cancer cells only – thus resulting in a favorable safety profile. 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
31(93) 
Similarly, olaparib monotherapy has also been shown to be well tolerated in patients with 
advanced solid tumors, including mCRPC patients.  
2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Determine the PSA50 response rate (i.e., percent of patients with a PSA decline of at least 50% 
below baseline) following 12-weeks of treatment with bipolar androgen therapy (BAT) plus 
olaparib in men with asymptomatic metastatic castration-resistant prostate cancer (mCRPC) 
who have progressed on abiraterone and/or enzalutamide. 
2.2 
Secondary objectives 
1. Determine the percent of mCRPC patients achieving a radiographic response per 
RECIST 1.1 criteria following treatment with BAT plus olaparib. 
2. Determine the radiographic progression free survival (PFS) in mCRPC patients treated 
with BAT plus olaparib using RECIST 1.1 criteria for soft tissue metastases and 
Prostate Cancer Working Group 3 (PCWG3) criteria for bone metastases [95, 96]. 
3. Determine the PSA PFS rate according to PCWG3 criteria in mCRPC patients treated 
with BAT plus olaparib [95].  
4. Determine the PFS (i.e. whichever occurs first: clinical, radiographic or PSA 
progression) in mCRPC patients treated with BAT plus olaparib. 
5. Determine the overall survival in mCRPC patients treated with BAT plus olaparib. 
6. Track changes in quality of life (QoL) as determined using the FACT-P and 
International Index of Erectile Function (IIEF) surveys. 
7. Assess the incidence and severity of adverse events according to the National Cancer 
Institute – Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
2.3 
Exploratory objectives 
Correlative work will be conducted in order to better understand the biology underlying 
response and resistance to BAT plus olaparib in men with mCRPC. 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 response and PFS in patients with/without mutations in 
genes involved in homologous recombination. 
2. Determine intratumoral androgen levels using liquid chromatography-mass 
spectrometry (LC/MS) 
3. $VVHVVIRUHYLGHQFHRIGV'1$EUHDNVXVLQJȖ-H2AX immunostaining on circulating 
tumor cells (CTCs) and metastatic tissue 
4. Assess androgen receptor (AR) and AR splice variant (AR-V) transcript expression 
levels using qRT-PCR on CTCs 
5. Assess androgen receptor (AR) and AR splice variant (AR-V) protein expression levels 
using immunostaining on circulating tumor cells (CTCs) and metastatic tissue 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
32(93) 
6. Sequence tumor DNA (cell-free circulating tumor DNA [ctDNA] and/or metastatic 
tissue) 
7. Conduct transcript profiling studies on CTCs (multiplexed qRT-PCR) and metastatic 
tissue (RNA-seq) 
3. 
PATIENT SELECTION CRITERIA 
Number of patients: 30 response evaluable mCRPC patients that have progressed on 
abiraterone and/or enzalutamide will be recruited from the Seattle Cancer Care 
Alliance/University of Washington Medical Center (SCCA/UWMC) genitourinary oncology 
clinic. 
Number of centers: One. 
3.1 
Inclusion criteria 
For inclusion in the study patients should fulfill the following criteria: 
1. Must be willing to provide informed consent prior to any study specific procedures  
2. $JH\HDUV 
3. Documented histologically confirmed adenocarcinoma of the prostate. 
4. Patient 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., PJG/ [95]. 
5. PSA must be at least 1 ng/ml and rising on two successive measurements at least two 
weeks apart. 
6. Patients must have progressed on abiraterone and/or enzalutamide. There must be at least 
a 3-week washout period after stopping the most recent approved therapy for mCRPC 
(i.e., abiraterone, enzalutamide, Ra-223, sipuleucel-t). If applicable, patients should be 
weaned off steroids at least 1 week prior to starting treatment. 
7. No prior chemotherapy for the treatment of mCRPC. Patients may have received docetaxel 
for the treatment of hormone-sensitive prostate cancer. 
8. Prior treatment with non-chemotherapy investigational agents is permitted. There must be 
at least a 3-week washout period after stopping any investigational cancer agent. 
9. Patients must have normal organ and bone marrow function measured within 28 days prior 
to administration of study treatment as defined below: 
 
+HPRJORELQJG/ZLWKQREORRGWUDQVIXVLRQLQWKHSDVWGD\V 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
33(93) 
 
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 
7RWDOELOLUXELQ[LQVWLWXWLRQDOXSSHUOLPLWRIQRUPDO8/1 
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Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase 
(SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate 
7UDQVDPLQDVH6*37[LQVWLWXWLRQDOXSSHUOLPLWRIQRUPDOXQOHVVOLYHU
PHWDVWDVHVDUHSUHVHQWLQZKLFKFDVHWKH\PXVWEH[8/1 
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Patients must have creatinine clearance estimated using the Cockcroft-Gault 
equation  or based on 24 hour urine test RIP/PLQ 
Estimated creatinine clearance = 
(140-age [years]) x weight (kg)     
  
 
 
 
 
 
serum creatinine (mg/dL) x 72 
10. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (see Appendix 2).  
11. 3DWLHQWVPXVWKDYHDOLIHH[SHFWDQF\ZHHNV 
12. Male patients and their partners, who are sexually active and of childbearing potential, 
must agree to the use of two highly effective forms of contraception in combination [see 
Appendix 3 for acceptable methods], throughout the period of taking study treatment and 
for 3 months after last dose of study drug(s) to prevent pregnancy in a partner.  
13. Patient is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations. 
14. At least one lesion (measurable and/or non-measurable) that can be accurately assessed at 
baseline by CT, PET, MRI and/or bone scan and is suitable for repeated assessment. 
15. Must have archival tissue available, be willing to undergo metastatic biopsy or have a 
sufficient plasma ctDNA concentration in order to perform next-generation DNA 
sequencing.  
16. The study will require that 50% of enrolled subjects have homozygous deletions, 
deleterious mutations, or both in one or more of the DDR genes listed in Appendix 5. The 
other 50% of patients must have an intact DDR pathway (i.e., no mutations/deletions in 
genes listed in Appendix 5)[88]. 
3.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site) 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
34(93) 
2. Previous enrollment in this study 
3. Participation in another clinical study with an investigational product during the last 3 
weeks 
4. Any previous treatment with PARP inhibitor, including olaparib. 
5. Other malignancy XQOHVVFXUDWLYHO\WUHDWHGZLWKQRHYLGHQFHRIGLVHDVHIRU\HDUV
except: adequately treated non-melanoma skin cancer. 
6. 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 
7. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative 
reasons) within 3 weeks prior to study treatment  
8. 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. 
9. 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 3 weeks for enzalutamide, 5 weeks for phenobarbital and 3 weeks 
for other agents. 
10. Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 
2) caused by previous cancer therapy, excluding alopecia. 
11. Patients with myelodysplastic syndrome/acute myeloid leukemia or with features 
suggestive of MDS/AML. 
12. 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. 
13. Major surgery within 2 weeks of starting study treatment and patients must have recovered 
from any effects of any major surgery. 
14. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, 
non-malignant systemic disease or active, uncontrolled infection.  Examples include, but 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
35(93) 
are not limited to, uncontrolled ventricular arrhythmia, history of prior myocardial 
infarction, uncontrolled major seizure disorder, XQFRQWUROOHGK\SHUWHQVLRQ%3
history of prior stroke, uncontrolled diabetes (hgb A1C >7), 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. 
15. Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication.  
16. Immunocompromised patients, e.g., patients who are known to be serologically positive 
for human immunodeficiency virus (HIV). 
17. Patients with a known hypersensitivity to olaparib or any of the excipients of the product. 
18. Patients with a known hypersensitivity to the testosterone cypionate or any of the 
excipients of the product 
19. Patients with known active hepatitis (i.e., Hepatitis B or C) due to risk of transmitting the 
infection through blood or other body fluids 
20. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation 
(dUCBT) 
21. Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood 
cells and platelet transfusions are acceptable, for timing refer to inclusion criteria no. 10) 
22. Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition 
(including laboratory abnormalities) that could interfere with patient safety or provision of 
informed consent to participate in this study. 
23. Any psychological, familial, sociological, or geographical condition that could potentially 
interfere with compliance with the study protocol and follow-up schedule. 
24. Evidence of disease that, in the opinion of the investigator, would put the patient at risk 
from testosterone therapy (e.g. femoral metastases with concern over fracture risk, spinal 
metastases with concern over spinal cord compression, lymph node disease with concern 
for ureteral obstruction).  
25. Patients with pain attributable to their prostate cancer 
26. Tumor causing urinary outlet obstruction that requires catheterization for voiding. Patients 
that require catheterization to void secondary to benign strictures or other non-cancer 
causes will be permitted to enroll.  
27. Prior history of deep venous thrombosis or pulmonary embolism within 5 years prior to 
enrollment in the study and not currently on systemic anticoagulation. 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
36(93) 
28. Patients with NYHA (New York Heart Association) class III or IV heart failure or history 
of a prior myocardial infarction (MI) prior to enrollment in the study. 
4. 
STUDY PLAN AND PROCEDURES 
4.1 
Overall study design and flow chart 
This will be a single arm, Phase II study designed to evaluate the clinical activity of bipolar 
androgen therapy (BAT) plus olaparib in patients with asymptomatic metastatic castration-
resistant prostate cancer (mCRPC) (i.e. progressive prostate cancer in spite of serum 
testosterone <50 ng/dL) that has already progressed on abiraterone and/or enzalutamide 
(Figure 11). While DNA damage repair (DDR) deficiency is not required to be eligible for the 
study, all patients must have next-generation sequencing performed at baseline to assess DDR 
status. The study will require that 50% of enrolled subjects have homozygous deletions, 
deleterious mutations, or both in one or more of the DDR genes listed in Appendix 5. The 
other 50% of patients must have an intact DDR pathway (i.e. no mutations/deletions in genes 
listed in Appendix 5). 
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 enrollment. Eligible patients will initiate T enanthate or T 
cypionate 400 mg intramuscular every 28 days, which has been shown to result in rapid 
fluctuations between supraphysiologic and near castrate serum T levels in men maintained on 
ADT [11]. Patients will also receive olaparib 300 mg by mouth twice daily. One treatment 
cycle will be defined as 28-days, and consist of 1 dose of T enanthate or T cypionate on Day 1 
combined with continuous daily dosing of olaparib (Days 1-28).  
PSA will be measured on Day 1 of each treatment cycle prior to receiving T enanthate or T 
cypionate. Radiographic assessment with bone and CT scans will occur every 12-weeks. The 
primary endpoint will be PSA after 3-cycles of BAT plus olaparib (i.e. 12-weeks). Patients 
will be permitted to continue until disease progression by radiographic (per RECIST 1.1 or 
PCWG3) or clinical criteria (e.g. increasing pain), whichever comes first [95, 96]. Prior to 
completing 3-cycles of treatment, patients should not discontinue treatment for PSA 
progression alone; however, if after 3-cycles the PSA has not decreased 50% from baseline 
(i.e. PSA50 response) that patient may withdraw from the study if their treating physician feels 
it is in their best interest. It is also essential that PSA be measured before injection of 
Testosterone given that some patients may experience a transient increase in PSA immediately 
following T dosing. PSA values obtained at timepoints other than those required per protocol 
will be ignored and not used for the purpose of determining disease progression. 
Blood and tumor tissue for secondary analyses and correlative studies will be collected. 
Metastatic biopsies will be obtained at baseline, on Day 8 of Cycle 1 and again upon 
progression when possible. This tissue will be used for molecular studies and to measure 
intratumoral androgen levels. Blood for molecular studies will be collected serially at 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
37(93) 
baseline, Day 8 of Cycle 1, Day 1 of Cycle 4 and at the time of progression (PSA, 
radiographic, or clinical).  
The primary objective of this study is to determine the PSA50 response rate following 12-
weeks of treatment with BAT plus olaparib, which will be defined as the proportion of men 
with a PSA at least 50% below baseline at this timepoint. Secondary objectives will be to 
determine the radiographic response rate (per RECIST 1.1), radiographic PFS (per RECIST 
1.1), PSA PFS (per PCWG3), PFS (i.e. whichever occurs first: clinical, radiographic or PSA 
progression), overall survival, QoL changes, and to assess safety (per CTCAE v4.0) [95, 96].  
Correlative work will be conducted in order to better understand the biology underlying 
response and resistance to BAT plus olaparib in men with mCRPC. Serial blood samples will 
be obtained from all patients, and metastatic tissue will be obtained at baseline and again at 
progression when possible. Examples of studies to be conducted may include, but are not 
limited to: evaluating for differences in response and disease progression in patients 
with/without mutations in genes involved in homologous recombination, studies to determine 
intratumoral androgen levels using LC/MS, assessing for evidence of dsDNA breaks, 
evaluating AR and AR-V expression at the protein and transcript levels, sequencing tumor 
DNA, and tumor transcript profiling studies.
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
38(93) 
 
 
Figure 11. Study schematic. PSA5 36$GHFOLQH50% from baseline. 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
39(93) 
 
4.2 
Discontinuation of investigational product 
Patients may be discontinued from investigational product (IP) in the following situations: 
x 
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment 
x 
Adverse event that, in the opinion of the Principal Investigator contraindicates 
further dosing 
x 
Severe non-compliance with the study protocol that, in the opinion of the Principal 
Investigator or Sponsor, warrants withdrawal (e.g., refusal to adhere to scheduled 
visits) 
x Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute myeloid 
leukemia (AML) 
x 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 
x Initiation of alternative anticancer therapy including another investigational agent 
x Study drug held for >4 weeks due to an AE 
Withdrawal of consent 
If consent is withdrawn, the subject will not receive any further investigational product or 
further study observation. Biospecimens obtained as part of trial participation will be retained, 
however. 
4.2.1 
Procedures for discontinuation of a subject from investigational product  
Subjects who are permanently discontinued from further receipt of investigational product, 
regardless of the reason (withdrawal of consent, due to an AE, other), will be identified as 
having permanently discontinued treatment.  
 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 5.2.4, including the collection of any protocol-specified blood 
specimens, unless consent is withdrawn or the subject is lost to follow-up or enrolled in 
another clinical study.  All subjects will be followed for survival.  Subjects who decline to 
return to the site for evaluations will be offered follow-up by phone as an alternative. 
4.3 
Withdrawal from study 
Subjects that withdraw prior to the 12-week timepoint will be replaced. Any subject needing 
to be replaced will be counted as a non-responder.  
 
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Clinical Study Protocol 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
40(93) 
5. 
TREATMENT ASSESSMENTS AND EVALUATIONS 
5.1 
Recording of data 
All data will be recorded in the electronic case report forms (eCRFs), which will be 
maintained on secure servers at the SCCA and/or UWMC. Patient data will be de-identified, 
and access to the de-identification key will only be available to the Principal Investigator and 
his designees as necessary. 
5.2 
Data collection at enrollment and follow-up 
During the Treatment/Intervention Period study procedures and assessments must be done 
within 7 days (+/-) of the specified study visit date unless otherwise noted. Screening 
procedures and assessments must be done within 30 days prior to enrollment unless 
otherwise noted. End of Study procedures and assessments must be within 30 days of 
stopping study drug(s).  
Note: If a subject withdraws from the study prior to the 12-week timepoint, the “End of 
Study” procedures will be completed at the time of withdrawal.  
5.2.1 
Screening (within 30 days of Cycle 1, Day 1) 
1. Informed consent 
2. Comprehensive medical history and physical exam, including height and weight, 
medication reconciliation, blood pressure, heart rate and ECOG performance status 
assessment 
3. CBC (Complete blood count) with differential and platelet count 
4. CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, BUN, 
Serum Creatinine, Calcium, Total Protein, Albumin, Total Bilirubin, AST, ALT, 
Alkaline Phosphatase, CO2) 
5. PSA 
6. Testosterone 
7. Estradiol 
8. aPTT (activated partial thromboplastin time), PT/INR (prothrombin 
time/international normalized ratio) 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
41(93) 
9. Radiologic tests (i.e., CT chest/abdomen/pelvis and bone scan) 
10. ECG 
11. Metastatic biopsy  
Note: If a biopsy cannot be safely performed, archival tissue obtained within the last 
year may be used as long as patient had castration-resistant prostate cancer, as 
determined by the treating physician, at that time. 
5.2.2 
Treatment/Intervention Period 
1. Comprehensive medical history and physical exam, including weight, medication 
reconciliation, blood pressure, heart rate and ECOG performance status assessment 
[Day 1 of every cycle] 
2. Olaparib dispensation [Day 1 of every cycle] 
3. Unused olaparib collection [Day 1 of every cycle beginning Cycle 2] 
4. Treatment with testosterone enanthate or testosterone cypionate [Day 1 of every 
cycle] 
5. CBC (Complete blood count) with differential and platelet count [Day 1 of every 
cycle] 
6. CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, BUN, 
Serum Creatinine, Calcium, Total Protein, Albumin, Total Bilirubin, AST, ALT, 
Alkaline Phosphatase, CO2) [Day 1 of every cycle] 
7. PSA [Day 1 of every cycle] 
8. Testosterone [Cycle 1, Day 8 (+/- 7 days) and Cycle 2, Day 1] 
9. Estradiol [Cycle 1, Day 8 (+/- 7 days) and Cycle 2, Day 1] 
10. Radiologic tests (i.e. CT chest/abdomen/pelvis and bone scan) [Every 3 cycles 
beginning Cycle 4, Day 1] 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
42(93) 
11. ECG [within 7 days prior to starting study treatment and as clinically indicated] 
12. Blood for exploratory biomarkers [Cycle 1, Day 1 and Cycle 1, Day 8 (+/- 7 days; 
optional)] 
13. Optional metastatic biopsy [Cycle 1, Day 8 (+/- 7 days)] 
14. Quality of life questionnaires (FACT-P and IIEF) [Every 3 cycles] 
15. Brief pain inventory [Every cycle] 
5.2.3 
End of study 
End of Study is defined as the last visit where the decision is made to discontinue treatment. 
All required procedures must be completed within 30 days of receiving the last dose of study 
drug(s). Treatment/Intervention Period assessments may used for the End of Study timepoint 
if within the 30 day timeframe. 
1. Comprehensive medical history and physical exam, including weight, medication 
reconciliation, blood pressure, heart rate and ECOG performance status assessment  
2. Unused olaparib collection 
3. CBC (Complete blood count) with differential and platelet count  
4. CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, BUN, 
Serum Creatinine, Calcium, Total Protein, Albumin, Total Bilirubin, AST, ALT, 
Alkaline Phosphatase, CO2) 
5. PSA  
6. Radiologic tests (i.e., CT chest/abdomen/pelvis and bone scan)  
7. Blood for exploratory biomarkers  
8. Optional metastatic biopsy  
9. Quality of life questionnaires (FACT-P and IIEF) 
10. Brief pain inventory 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
43(93) 
5.2.4 
Follow Up 
A 30-day safety follow-up will be required (+/-7 days). End of Study assessments may be 
used for the follow-up timepoint if these have occurred +/-7 days of the follow-up visit. 
1. Comprehensive medical history and physical exam, including weight, medication 
reconciliation, blood pressure, heart rate and ECOG performance status assessment  
2. CBC (Complete blood count) with differential and platelet count  
3. CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, BUN, 
Serum Creatinine, Calcium, Total Protein, Albumin, Total Bilirubin, AST, ALT, 
Alkaline Phosphatase, CO2) 
5.2.5 
Long-term Follow Up 
The Long-term Follow Up assessment is to confirm if patient is still alive, and to document 
the date of death if deceased. This may be conducted in person or remotely (i.e., via phone, 
email or postal). Long-term Follow Up will occur every 6 months (+/- 30 days) up to 2 years 
following last dose of study drug(s) or sooner if the study is terminated.
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
44(93) 
Study calendar 
  
Screening 
Treatment/Intervention Period 
End of Study 
Follow Upb 
Long-term 
Follow upc 
Cycle 1a 
Cycle 2 
Cycle 3 
Cycle 4 
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X 
 
X 
X 
 
 
 
 
 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
45(93) 
ƐƚƌĂĚŝŽů 
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ũ͘ŝŽƉƐǇĂŶĚĞǆƉůŽƌĂƚŽƌǇďůŽŽĚĚƌĂǁĂƚƚŚŝƐƚŝŵĞƉŽŝŶƚǁŝůůďĞŽƉƚŝŽŶĂů͘ 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
46(93) 
6. 
STUDY ASSESSMENTS 
6.1 
Efficacy 
Efficacy will be determined by assessing PSA and radiographic changes (e.g. bone scan, CT 
scan) while on study. Ideally, these assessments will be performed at SCCA/UWMC, 
however, if necessary due to extenuating circumstances (e.g. insurance coverage issues) these 
may be performed at an outside lab/imaging center. 
6.2 
Safety 
The Principal Investigator (Michael Schweizer, MD) is responsible for ensuring that all staff 
involved in the study are familiar with the content of this section. 
6.2.1 
Definition of adverse events 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
6.2.2 
Olaparib adverse events of special interest 
Adverse events of special interest [AESI] are events of scientific and medical interest specific 
to the further understanding of olaparib’s safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca. An AESI may be serious or non-serious. 
Adverse Events of Special Interest for olaparib are the Important Potential Risks of 
MDS/AML, new primary malignancy (other than MDS/AML) and pneumonitis.   
ANY event of MDS/AML, new primary malignancy, or pneumonitis should be reported to 
AstraZeneca Patient Safety whether it is considered a non-serious AE [eg non-melanoma skin 
cancer] or SAE, and regardless of investigator’s assessment of causality or knowledge of the 
treatment arm.    
A questionnaire will be sent to any investigator reporting an AESI, as an aid to provide further 
detailed information on the event.  During the study there may be other events identified as 
AESIs that require the use of a questionnaire to help characterise the event and gain a better 
understanding regarding the relationship between the event and study treatment. 
6.2.3 
Assessment of severity 
Assessment of severity is one of the responsibilities of the sub-investigators and Principal 
Investigator in the evaluation of AEs and SAEs. Severity will be graded according to the NCI 
 
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CTCAE v4.03. The determination of severity for all other events not listed in the CTCAE 
should be made by the treating physician (i.e. Sub-Investigator, Principal Investigator) based 
upon medical judgment and the severity categories of Grade 1 to 5 as defined below. 
 
Grade 1 (mild) 
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not 
generally interfere with usual activities of daily living. 
 
Grade 2 (moderate) 
An event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual 
activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
 
Grade 3 (severe) 
An event that requires intensive therapeutic intervention. The 
event interrupts usual activities of daily living, or significantly 
affects the clinical status of the subject. 
 
Grade 4 (life threatening) An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death or with physical or mental disabilities 
that affect or limit the ability of the subject to perform activities 
of daily living (i.e., eating, ambulation, toileting, etc). 
 
Grade 5 (fatal) 
Death (loss of life) as a result of an event. 
 
6.2.4 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, 
treatment, wash-out, follow-up), at any dose of the study drugs that fulfills one or more of the 
following criteria: 
x Results in death 
x Is immediately life-threatening 
x Requires in-patient hospitalization or prolongation of existing hospitalization  
x Results in persistent or significant disability or incapacity  
x Is a congenital abnormality or birth defect 
x Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed 
by the investigator(s) in consultation with the Principal Investigator and communicated to 
AstraZeneca. 
 
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Adverse Events (AEs) for malignant tumors reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumor event should be assessed and 
reported as a Non-Serious AE. For example, if the tumor is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumor, the AE may not fulfill the attributes for being assessed as 
Serious, although reporting of the progression of the malignant tumor as an AE is valid and 
should occur. Also, some types of malignant tumors, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as Non-Serious; 
examples include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via 
cone biopsy.  
The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (i.e., it is not the tumor for which entry into the study is a criterion and that is 
being treated by the IP under study and is not the development of new or progression of 
existing metastasis to the tumor under study). Malignant tumors that – as part of normal, if 
rare, progression – undergo transformation (e.g., Richter's transformation of B cell chronic 
lymphocytic leukemia into diffuse large B cell lymphoma) should not be considered a new 
malignant tumor. 
6.2.5 
Assessment of relationship 
All AEs will be evaluated for relationship to the medical treatment or procedure. The treating 
physician (i.e., Sub-Investigator, Principal Investigator) should document his/her opinion of 
the relationship of the event to study medication as follows: 
x Unrelated- The adverse event is clearly not related to the investigational agent(s). 
x Unlikely- The adverse event is doubtfully related to the investigational agent(s). 
x Possible-The adverse event may be related to the investigational agent(s). 
x Probable-The adverse event is most likely related to the investigational agent(s). 
x Definite- The adverse event is clearly related to the investigational agent(s). 
6.2.6 
Early stopping due to adverse events 
This study will stop early if >3 subjects experience a SAE determined to be at least possibly 
related to the study drugs, with the following exceptions: 
x +RVSLWDOL]DWLRQODVWLQJKRXUV 
x Non-life threatening hematologic toxicities (e.g. febrile neutropenia without 
evidence of septic shock, anemia) 
 
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Consortium Study Number  9984 
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6.2.7 
Recording of adverse events 
Adverse events will be recorded on electronic case report forms (eCRFs) using a recognized 
medical term or diagnosis that accurately reflects the event. Adverse events will be assessed 
by the treating physician (i.e., Sub-Investigator, Principal Investigator) for severity, 
relationship to the investigational product, and possible etiologies. Adverse event assessments 
will then be verified by the Principal Investigator who will also determine whether the event 
meets criteria of an SAE and therefore requires immediate notification to AstraZeneca.  
The following variables will be collected for each AE: 
 
x AE (verbatim) 
x The date when the AE started and stopped 
x Changes in NCI CTCAE grade and the maximum CTCAE grade 
attained 
x Whether the AE is serious or not 
x Causality rating against olaparib (yes or no) 
x Action taken with regard to olaparib  
x Causality rating against testosterone (yes or no) 
x Action taken with regard to testosterone  
x Outcome 
 
In addition, the following variables will be collected for SAEs as applicable: 
 
x Date AE met criteria for serious AE 
x Date treating physician (i.e. Sub-Investigator, Principal Investigator) 
became aware of serious AE 
x Reason AE is considered serious  
x Date of hospitalization 
x Date of discharge 
x Probable cause of death 
x Date of death 
x Autopsy performed 
x Description of AE 
x Causality assessment in relation to Study procedure(s) 
 
Events, which are unequivocally due to disease progression, should not be reported as an AE 
during the study. 
Time period for collection of adverse events 
Adverse events and serious adverse events will be recorded from time of first dose of study 
drug(s), throughout the treatment period and including the follow-up period (30 days after the 
last dose of olaparib or testosterone, whichever occurred most recently). 
 
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During the course of the study all AEs and SAEs should be proactively followed up for each 
subject. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
If a subject discontinues from treatment for reasons other than disease progression, and 
therefore continues to have tumor assessments, drug or procedure-related SAEs must be 
captured until the patient is considered to have confirmed PD and will have no further tumor 
assessments. 
The treating physician (i.e. Sub-Investigator, Principal Investigator) is responsible for 
following all SAEs until resolution, until the subject returns to baseline status, or until the 
condition has stabilized with the expectation that it will remain chronic, even if this extends 
beyond study participation. 
6.2.7.1 
Adverse events after the 30 day follow up period 
For Pharmacovigilance purposes and characterization, any case of MDS/AML or new primary 
malignancy occurring after the 30 day follow up period should be reported to AstraZeneca 
Patient Safety whether it is considered a non-serious AE [e.g., non-melanoma skin cancer] or 
SAE, and regardless of investigator’s assessment of causality or knowledge of the treatment 
arm.  Investigators will be asked during the regular follow up for overall survival if the patient 
has developed MDS/AML or a new primary malignancy and prompted to report any such 
cases.   
At any time after a patient has completed the study, if an Investigator learns of any SAE 
including sudden death of unknown cause, and he/she considers there is a reasonable 
possibility that the event is causally related to the investigational product, the investigator 
should notify AstraZeneca, Patient Safety. 
If patients who are gaining clinical benefit are allowed to continue study treatment post data 
cut off and/or post study completion then all SAEs must continue to be collected and reported 
to Patient Safety within the usual timeframe. 
Otherwise, after study treatment completion (i.e., after any scheduled post treatment follow-up 
period has ended) there is no obligation to actively report information on new AEs or SAEs 
occurring in former study patients. This includes new AEs/SAEs in patients still being 
followed up for survival but who have completed the post treatment follow up period (30 
days). 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
treating physician (i.e. Sub-Investigator, Principal Investigator) for as long as medically 
indicated, but without further recording in the eCRF.  After 90 days, only subjects with 
ongoing investigational product-related SAEs will continue to be followed for safety. 
 
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It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.4.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE. 
Adverse Events based on signs and symptoms 
When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms.  However, if a diagnosis is known and 
there are other signs or symptoms that are not generally part of the diagnosis, the 
diagnosis and each sign or symptom will be recorded separately. 
Adverse Events based on examinations and tests 
Deterioration as compared to baseline in protocol-mandated laboratory values, 
vital signs should only be reported as AEs if they fulfill any of the SAE criteria or 
are the reason for discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated 
laboratory result/vital sign will be considered as additional information.  
Wherever possible the reporting investigator uses the clinical, rather than the 
laboratory term (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. 
Note: Cases where a subject shows an AST or $/7[8/1or WRWDOELOLUXELQ[8/1PD\
need to be reported as SAEs, please refer to Appendix 1 ‘Actions required in cases of 
combined increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for further 
instructions. 
Disease progression 
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  The 
development of new metastasis or progression of existing metastasis should be considered as 
disease progression and not an AE.  Events, which are unequivocally due to disease 
progression, should not be reported as an AE during the study. 
 
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Consortium Study Number  9984 
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New cancers 
The development of a new primary cancer (including skin cancer) should be regarded as an 
AE (see Section 6.2.2).  New primary malignancies are those that are not the primary reason 
for the administration of the study treatment and have developed after the inclusion of the 
patient into the study.  They do not include metastases of the original cancer.  Symptoms of 
metastasis or the metastasis itself should not be reported as an AE/SAE, as they are considered 
to be disease progression. 
Lack of efficacy 
When there is deterioration in the patient’s clinical condition, there may be uncertainty as to 
whether this is lack of efficacy or an AE.  In such cases, unless the Sponsor or the reporting 
physician considers that the study treatment contributed to the deterioration of the condition, 
or local regulations state to the contrary, the deterioration should be considered to be a lack of 
efficacy and not an AE. 
Deaths 
All deaths that occur during the study, or within the protocol-defined 30-day post-study 
follow-up period after the administration of the last dose of study treatment, must be reported 
as follows: 
x Death clearly the result of disease progression should be reported to the study monitor at 
the next monitoring visit and should be documented in the eCRF but should not be 
reported as an SAE. 
x Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to the study monitor as a SAE within 24 hours (see 
Section 6.2.7 for further details).  The report should contain a comment regarding the 
co-involvement of progression of disease, if appropriate, and should assign main and 
contributory causes of death.  This information can be captured in the ‘death eCRF’. 
x Deaths with an unknown cause should always be reported as a SAE.  A post mortem 
maybe helpful in the assessment of the cause of death, and if performed a copy of the post-
mortem results should be forwarded to AstraZeneca within the usual timeframes. 
6.2.8 
Reporting of serious adverse events 
Investigators and other site personnel must report to AstraZeneca, any serious or unexpected 
adverse events that occur.  A copy of the report for any serious or unexpected adverse events 
must be faxed to AstraZeneca.  It is the responsibility of the investigator to compile all 
necessary information and ensure that these reports are submitted to AstraZeneca. 
* A cover page should accompany the report indicating the following: 
x External Scientific Research (ESR) 
 
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x D-Code Assigned by AstraZeneca 
x The investigator’s name and address 
x The Protocol Title and AstraZeneca ESR reference number 
x Causality of event(s) 
* Investigative site must also indicate, either in the SAE report or the cover page, the causality 
of events in relation to all study medications and if the SAE is related to disease progression, 
as determined by the Principal Investigator. 
* Send SAE re ort and accom an in  cover a e b  wa  o  Email to 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must also 
be provided to AstraZeneca. 
Serious adverse events that do not require expedited reporting, still need to be reported to 
AstraZeneca preferably using the MedDRA coding language for serious adverse events.  This 
information should be reported on a monthly basis and under no circumstance less frequently 
than quarterly. 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to 
the investigational product.  All SAEs will be documented.  The investigator is responsible for 
informing the IRB and/or the Regulatory Authority of the SAE as per local requirements. 
Non-serious adverse events and SAEs will be collected from the time consent is given, 
throughout the treatment period and up to and including the 30 day follow-up period.  After 
withdrawal from treatment, subjects must be followed-up for all existing and new AEs for 30 
calendar days after the last dose of trial drug and/or until event resolution.  All new AEs 
occurring during that period must be recorded (if SAEs, then they must be reported to 
AstraZeneca).  All study-related toxicities/ SAEs must be followed until resolution, unless in 
the Investigator’s opinion, the condition is unlikely to resolve due to the patient’s underlying 
disease. 
6.2.9 
Laboratory safety assessment 
Full hematology assessments for safety (hemoglobin, red blood cells [RBC], platelets, mean 
cell volume [MCV], mean cell hemoglobin concentration [MCHC], mean cell hemoglobin 
[MCH], white blood cells [WBC], absolute differential white cell count (neutrophils, 
lymphocytes, monocytes, eosinophils and basophils) and absolute neutrophil count or 
segmented neutrophil count and Band forms should be performed at each visit and when 
clinically indicated.  If absolute differentials not available please provide % differentials. 
Coagulation [activated partial thromboblastin time (APTT) and international normalized ratio 
 
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[17]] will be performed at baseline and if clinically indicated unless the patient is receiving 
warfarin.  
Biochemistry assessments for safety (sodium, potassium, calcium, magnesium, fasting 
glucose, creatinine, total bilirubin, gamma glutamyltransferase [GGT], alkaline phosphatase 
[ALP], aspartate transaminase [AST], alanine transaminase [ALT], urea or blood urea 
nitrogen [BUN], total protein, albumin and lactic dehydrogenase [LDH]). 
Urinalysis by dipstick should be performed at baseline and then only if clinically indicated. 
Microscopic analysis should be performed by the hospital’s local laboratory if required. 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
hematological toxicities as defined in Section 8.2.7. 
These tests will be performed by the hospital’s local laboratory.  Additional analyses may be 
performed if clinically indicated. 
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF. 
In case a subject shows an AST or $/7[8/1or WRWDOELOLUXELQ2xULN please refer to 
Appendix 1 ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions 
For blood volume see Section 7.1. 
6.2.10 
Physical examination 
Physical examinations will occur as outline in Sections 5.2 and 5.3. Organ systems to be 
assessed will be based on the treating clinician’s medical judgment. 
6.2.11 
ECG 
ECGs are required within 7 days prior to starting study treatment and when clinically 
indicated. 
Twelve-lead ECGs will be obtained after the patient has been rested in a supine position for at 
least 5 minutes in each case.  The Investigator or designated physician will review the paper 
copies of each of the timed 12-lead ECGs on each of the study days when they are collected. 
ECGs will be recorded at 25 mm/sec.  All ECGs should be assessed by the investigator as to 
whether they are clinically significantly abnormal / not clinically significantly abnormal.  If 
there is a clinically significant abnormal finding, the Investigator will record it as an AE on 
the eCRF.  The original ECG traces must be stored in the patient medical record as source 
data. 
 
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6.2.12 
Vital signs 
6.2.12.1 Pulse and blood pressure 
Blood pressure and pulse rate will be measured using an automated blood pressure cuff/heart 
monitor.  For timings of assessments refer to Sections 5.2 and 5.3. 
6.2.12.2 Body temperature 
Body temperature will be measured in degrees Celsius using an automated thermometer. For 
timings of assessments refer to Sections 5.2 and 5.3. 
6.2.13 
Bone marrow or blood cytogenetic analysis 
Bone marrow or blood cytogenetic analysis may be performed according to standard 
hematological practice for patients with prolonged hematological toxicities as defined in 
Section 8.2.7. Bone marrow analysis should include an aspirate for cellular morphology, 
cytogenetic analysis and flow cytometry, and a core biopsy for bone marrow cellularity.  If it 
is not possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, 
then attempts should be made to carry out the tests on a blood sample.  If findings are 
consistent with MDS/AML, study drug should be discontinued and a full description of 
findings should be submitted with an SAE report by the investigator to AstraZeneca Patient 
Safety for documentation on the Patient Safety database.    Presence or absence of blood 
cytogenetic abnormalities and flow cytometry will be documented on the clinical database.      
6.3 
Exploratory biomarkers 
This study will incorporate a number of exploratory biomarkers. Given our rapidly evolving 
understanding of prostate cancer pathobiology and genetics, it is impossible to prospectively 
define all the relevant biomarkers for the patient population enrolled on this study. All samples 
will be collected at the timepoints indicated in Sections 5.2 and 5.3 of the protocol. Details 
regarding the collection, processing, shipping and storage of samples for exploratory research 
will be described in the Laboratory Manual. Examples of the studies to be conducted may 
include, but will not be limited to those described below. Additional studies aimed at 
understanding response and resistance to the study drugs may be added as new information 
becomes available. 
6.3.1 
DNA Damage Repair Gene Status 
All patients will undergo targeted next-generation sequencing in order to evaluate for the 
presence of a DDR gene alteration at baseline. This will be accomplished using the UW-
OncoPlex platform, which has been validated for use with tumor tissue derived DNA and cell-
free tumor DNA (ctDNA)[97]. The preferred sample for sequencing is one taken following 
the completion of the most recent prior line of therapy.  Samples taken at this time reflect the 
current DDR status of the tumor and are considered clinically most relevant. A fresh 
metastatic biopsy is therefore preferred for UW-OncoPlex testing. If patient refuses metastatic 
biopsy or it is felt that this cannot be conducted safely, the most recent tissue sample may be 
used, RULIDSDWLHQWKDVD36$QJP/, a plasma sample may be used for ctDNA 
 
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sequencing. Optional biopsies will be requested at timepoints indicated in Sections 5.2 and 
5.3. 
Note: If prior to enrolling, a patient has already had their tumor sequenced using a clinical 
grade next-generation sequencing assays (e.g. FoundationOne, Caris, etc), these results may 
be used for determining baseline DDR gene mutational status. Tumor tissue should still be 
obtained as outlined above to confirm DDR status using UW-OncoPlex, however.  
6.3.2 
Protein expression studies 
Protein expression studies will be conducted on circulating tumor cells (CTCs) and/or tumor 
tissue using immunofluorescence (IF) and immunohistochemistry (IHC), respectively. 
Expression of full-length AR (AR-FL), AR splice variants (AR-Vs), Ȗ-H2AX as well as 
potentially other proteins will be assessed. IHC will be will be performed using commercially 
available antibodies and standard lab techniques. CTCs for protein studies will be isolated 
using the RareCyte platform, which involves density-based enrichment followed IF staining 
and digital microscopy[98].  
6.3.3 
Transcript profiling studies 
Transcript profiling studies will be conducted on circulating tumor cells (CTCs) and/or tumor 
tissue. Transcript profiling on tumor tissue will be performed using RNA-seq, qRT-PCR or 
other gene expression profiling methods as appropriate (e.g. NanoString), and will follow 
standard lab techniques. AdnaTest will be used to isolate CTCs for transcript expression 
studies[45]. AdnaTest isolates CTCs using antibody coated magnetic beads, which are 
designed to select populations of prostate cancer cells, and is suitable for transcript profiling 
studies. Blood samples will be processed using AdnaTest and used for multiplexed qRT-PCR 
studies. 
6.3.4 
Tissue and Serum Androgen Levels 
Tissue and serum androgens (e.g. T and DHT) and hormonal substrates (e.g. DHEA-S) will be 
determined in serum and metastatic biopsy specimens using liquid chromatography-mass 
spectrometry (LC/MS) according to previously described methods[99-102]. 
6.4 
Patient reported outcomes (PRO) 
The FACT-P and IIEF quality of life questionnaires will be administered periodically 
throughout the duration of the study (Appendix 4). Patients will be provided with blank 
questionnaires and encouraged to complete these at home prior to scheduled clinic visits as 
outlined in Sections 5.2 and 5.3. These may also be completed in the clinic if preferred by the 
patient. If completed at home, questionnaires must be completed within the time windows 
indicated in Sections 5.2 and 5.3. Scoring of these surveys will be performed as previously 
described [103, 104]. 
 
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7. 
BIOLOGICAL SAMPLING PROCEDURES 
7.1 
Volume of blood 
Table 2 provides an approximation of the amount of blood that will be drawn for the safety 
and biomarker assessments outlined in Sections 5.2 and 5.3. In general, these labs will not all 
be drawn at the same visit, and this table provides an estimate for the upper limit of blood 
volume required from a patient at any given visit. The number of samples taken, as well as the 
volume required for each analysis, may be changed during the study as new data on the study 
treatment becomes available.  
The total volume of blood that will be drawn from each subject in this study is as follows: 
Table 2. Volume of Blood to Be Drawn From Each Subject  
Assessment 
Sample 
volume 
(mL) 
No. of 
samples 
Total 
volume 
(mL) 
Safety1 
Clinical chemistry 
5 
1 
5 
 
Hematology 
3 
1 
3 
 
Coagulation 
3 
1 
3 
 
Hepatitis panel 
5 
1 
5 
 
 
Exploratory biomarker 
research 
CTC studies 
10 
2 
20 
 
ctDNA studies 
10 
1 
10 
 
Serum hormone 
levels 
10 
1 
10 
Total 
46 
8 
56 
1.  
The sample volumes for safety assessments are approximate volumes that are subject to change. 
Additional blood samples may be needed depending on the results of these studies and if patients 
require follow up testing or undergo additional procedures (e.g. fresh metastatic biopsy). 
7.2 
Handling, storage and destruction of biological samples 
Biospecimen samples will be stored for up to five years following the completion of this 
study. Samples will be stored at University of Washington and/or Fred Hutchinson Cancer 
Research Center (UW/FHCRC). These samples may also be sent to our research partners 
participating in this study, including AstraZeneca. Specimens will not be used for reasons 
unrelated to this research study. All specimens will be kept in locked research laboratories at 
UW/FHCRC. The use of these specimens will be supervised by the Principal Investigator 
(Michael Schweizer, MD) and his designees. 
 
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8. 
STUDY CONDUCT 
8.1 
Restrictions during the study 
 
8.1.1 
Grapefruit juice 
It is prohibited to consume grapefruit juice while on olaparib therapy. 
 
8.1.2 
Contraception 
Patients with partners of child bearing potential, who are sexually active, must agree to the use 
of two highly effective forms of contraception. This should be started from the signing of the 
informed consent and continue throughout period of taking study medication and for 3 months 
after last dose of study drug. Male patients should not donate sperm throughout the period of 
taking olaparib and for 3 months following the last dose of olaparib. 
For details refer to Appendix 3 Acceptable Birth Control Methods. 
8.2 
Treatments 
8.2.1 
Identity of investigational product(s) 
The AstraZeneca Pharmaceutical Development R&D Supply Chain will supply olaparib to the 
investigator as round or oval green film coated tablets 
Investigational product 
Dosage form and strength 
Olaparib 
100 mg tablet 
Olaparib 
150 mg tablet 
 
 
a 
Descriptive information for olaparib can be found in the Investigator’s Brochure 
8.2.2 
Olaparib doses and treatment regimens 
Olaparib will be packed in high-density polyethylene (HDPE) bottles with child-resistant 
closures.  Each dosing container will contain sufficient medication for at least 28 days plus 
overage.  Olaparib will be dispensed to patients on Day 1 and every 28 days thereafter until 
the patient completes the study, withdraws from the study or closure of the study.   
Study treatment is available as tablets containing 50mg of olaparib. 
Patients will be administered olaparib twice daily at 300 mgs bid continually. 300 mg olaparib 
should be taken at the same time each day, approximately 12 hours apart with one glass of 
water.  The olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or 
divided. Olaparib tablets can be taken with or without food. 
 
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Clinical Study Protocol 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
59(93) 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted.  Should any patient enrolled on the 
study miss a scheduled dose for whatever reason (e.g., as a result of forgetting to take the 
tablets or vomiting), the patient will be allowed to take the scheduled dose up to a maximum 
of 2 hours after that scheduled dose time.  If greater than 2 hours after the scheduled dose 
time, the missed dose is not to be taken and the patient should take their allotted dose at the 
next scheduled time. 
Dose Reductions  
For guidance on dose reductions for management of AEs refer to Section 8.2.6. 
For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors 
cannot be avoided see Section 8.3. 
Renal Impairment    
If subsequent to study entry and while still on study therapy, a patient’s estimated CrCl 
IDOOVEHORZWKHWKUHVKROGIRUVWXG\LQFOXVLRQPOPLQUHWHVWLQJVKRXOGEHSHUIRUPHG
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 200mg BD. 
 
Because the CrCl determination is only an estimate of renal function, in instances where the 
CrCl falls to between 31 and 50 mL/min, the investigator should use his or her discretion in 
determining whether a dose change or discontinuation of therapy is warranted. 
 
Olaparib has not been studied in patients with severe renal impairment (creatinine clearance 
 30 ml/min) or end-stage renal disease; if patients develop severe impairment or end stage 
disease it is recommended that olaparib be discontinued. 
 
8.2.3 
Testosterone   
Testosterone esters are less polar than free testosterone. Testosterone esters in oil injected 
intramuscularly are absorbed slowly from the lipid phase; thus, testosterone enanthate or 
testosterone cypionate can be given at intervals of two to four weeks. These two forms of 
testosterone exhibit identical pharmacokinetic properties and may be used interchangeably in 
this study based on availability at the pharmacy [54]. These agents are administered as 
intramuscular injections given deep in the gluteal muscle. They should not be given 
intravenously. Testosterone cypionate is in cottonseed oil with benzyl alcohol as a 
preservative. Testosterone enanthate is in sesame oil with chlorobutanol as a preservative.  
 
 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
60(93) 
Testosterone in plasma is 98 percent bound to a specific testosterone-estradiol binding 
globulin, and about 2 percent is free. Generally, the amount of this sex-hormone binding 
globulin in the plasma will determine the distribution of testosterone between free and bound 
forms, and the free testosterone concentration will determine its half-life.  
 
About 90 percent of a dose of testosterone is excreted in the urine as glucuronic and sulfuric 
acid conjugates of testosterone and its metabolites; about 6 percent of a dose is excreted in the 
feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the 
liver. Testosterone is metabolized to various 17-keto steroids through two different pathways. 
The half-life of testosterone enanthate is approximately 4.5 to 8 days, and has been shown to 
consistently result in supraphysiologic serum T levels following an intramuscular dose of 
PJ (Figure 12) [54]. 
 
 
Figure 12: Modeled T Kinetics with different T enanthate dosing schedules (250 mg IM). Dashed line 
indicates physiologic T range (adapted from Nieschlag, et al[54]).  
 
Testosterone Precautions 
 
1. Patients with benign prostatic hypertrophy may develop acute urethral obstruction. 
Priapism or excessive sexual stimulation may develop.  
2. Oligospermia may occur after prolonged administration or excessive dosage. 
3. Testosterone Cypionate and Testosterone Enanthate should not be used 
interchangeably with testosterone propionate because of differences in duration of 
action. 
4. Testosterone Cypionate and Testosterone Enanthate are not for intravenous use. 
 
Drug interactions 
 
 
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Clinical Study Protocol 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
61(93) 
1. Androgens may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant 
may require reduction in order to maintain satisfactory therapeutic 
hypoprothrombinemia. 
2. Concurrent administration of oxyphenbutazone and androgens may result in elevated 
serum levels of oxyphenbutazone.  
3. In diabetic patients, the metabolic effects of androgens may decrease blood glucose 
and, therefore, insulin requirements. 
 
Drug/Laboratory test interferences 
Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 
serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain 
unchanged, however, and there is no clinical evidence of thyroid dysfunction. 
 
Adverse Reactions 
The following adverse reactions in the male have occurred with some androgens: 
 
1. Endocrine and urogenital: Gynecomastia and excessive frequency and duration of 
penile erections. Oligospermia may occur at high dosages. 
2. Skin and appendages: Hirsutism, male pattern of baldness, seborrhea, and acne. 
3. Fluid and electrolyte disturbances: Retention of sodium, chloride, water, potassium, 
calcium, and inorganic phosphates. 
4. Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function tests, rarely 
hepatocellular neoplasms and peliosis hepatis. 
5. Hematologic: Suppression of clotting factors II, V, VII, and X, bleeding in patients on 
concomitant anticoagulant therapy, and polycythemia. 
6. Nervous system: Increased or decreased libido, headache, anxiety, depression, and 
generalized paresthesia. 
7. Allergic: Hypersensitivity, including skin manifestations and anaphylactoid reactions. 
8. Miscellaneous: Inflammation and pain at the site of intramuscular injection. 
 
Drug Abuse and Dependence 
Controlled Substance Class: 
Testosterone is a controlled substance under the Anabolic Steroids Control Act, and 
testosterone have been assigned to Schedule III. 
 
Overdosage 
There have been no reports of acute overdosage with the androgens. 
 
Administration 
 
 
Testosterone injections are for intramuscular use only. It should not be given intravenously. 
Intramuscular injections should be given deep in the gluteal muscle. 
 
Supply 
 
 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
62(93) 
Testosterone is commercially available. It will be purchased for the study through the 
SCCA/UWMC pharmacy and billed to the trial. 
 
Testosterone Enanthate Injection, USP, 200 mg/mL is available as: 
5 mL Multiple Dose vial, Cartons of 1 vial      NDC 0143-9750-01 
 
Testosterone Cypionate Injection, USP, 200 mg/mL is available as: 
10 mL Multiple Dose vial, Cartons of 1 vial     NDC 0574-0820-10 
 
8.2.4 
Olaparib Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfill GMP Annex 13 requirements for labelling.  
Label text will be translated into local language.  
Each bottle of olaparib will have an investigational product label permanently affixed to the 
outside stating that the material is for clinical trial/investigational use only and should be kept 
out of reach of children. The label will include the dosing instructions and a space for the 
enrollment code (E-code) to be completed at the time of dispensing. 
The label will include the following information: 
x blank lines for quantity of tablets to be taken 
x enrollment code (E-code) 
x date of dispensing 
x Instructions stating that the olaparib tablets should be taken at approximately the same 
time each morning and evening 
8.2.5 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  For 
olaparib, the investigational product label on the bottle and the Investigator Brochure specifies 
the appropriate storage. Testosterone vials should be stored at controlled room temperature 
20°C to 25°C (68°F to 77°F) [see USP]. Protect from light. Use carton to protect contents 
from light until used. 
8.2.6 
Management of toxicity of olaparib  
Any toxicity observed during the course of the study could be managed by interruption of the 
dose of study treatment or dose reductions. Repeat dose interruptions are allowed as required, 
for a maximum of 4 weeks on each occasion. If the interruption is any longer, the study team 
must be informed. Study treatment can be dose reduced to 250 mg twice daily as a first step 
and to 200 mg twice daily as a second step. If the reduced dose of 200 mg twice daily is not 
tolerable, no further dose reduction is allowed and study treatment should be discontinued.  
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
63(93) 
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. 
Once dose is reduced, escalation is not permitted (except following concomitant treatment 
with CYP3A4 inhibitors). 
8.2.7 
Management of hematological toxicity 
8.2.7.1 
Management of anemia 
Table 3 
Management of anemia 
Hemoglobin 
Action to be taken 
Hb < 10 but JGO
(CTCAE Grade 2) 
Give appropriate supportive treatment and investigate causality.  
Investigator judgement to continue olaparib with supportive treatment  (eg 
transfusion) or interrupt dose for a maximum of 4 weeks. Study treatment 
can be restarted if Hb has recovered to > 9g/dl.  
Subsequent occurrences: 
If  Hb< 10 but JGO 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 JGOGRVHLQWHUUXSWIRUPD[RIZHHNVXQWLO+E
g/dl and upon recovery dose reduction may be considered (to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second step). 
Hb < 8 g/dl 
(CTCAE Grade 3) 
Give appropriate supportive treatment (e.g. transfusion) and investigate 
causality.  
,QWHUUXSWRODSDULEIRUDPD[LPXPRIZHHNVXQWLOLPSURYHGWR+E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 
SURORQJHGKHPDWRORJLFDOWR[LFLW\ZHHNLQWHUUXSWLRQGHOD\LQVWXG\WUHDWPHQWGXHWR&7&
grade 3 or worse anemia and/or development of blood transfusion dependence), refer to 
Section 8.2.7.3 for the management of this.  
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
64(93) 
 
8.2.7.2 
Management of neutropenia, leukopenia and thrombocytopenia 
Table 4 
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. 
)RUFDVHVZKHUHSDWLHQWVGHYHORSSURORQJHGKHPDWRORJLFDOWR[LFLW\ZHHN
interruption/delay in study treatment due to CTC grade 3 or worse), refer to Section 8.2.7.3.  
8.2.7.3 
Management of prolonged hematological toxicities while on study treatment 
If a patient develops prolonged hematological toxicity such as: 
x 
ZHHNLQWHUUXSWLRQGHOD\LQVWXG\WUHDWPHQWGXHWR&7& grade 3 or worse anemia 
and/or development of blood transfusion dependence 
x 
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neutropenia (ANC < 1 x 109/L) 
x 
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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 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
65(93) 
hematological practice. Study treatment should be discontinued if blood counts do not recover 
to CTC grade 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. 
8.2.8 
Management of non-hematological toxicity 
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each 
occasion. If the interruption is any longer than this the study monitor must be informed.  
Where toxicity reoccurs following re-challenge with study treatment, and where further dose 
interruptions are considered inadequate for management of toxicity, then the patient should be 
considered for dose reduction or must permanently discontinue study treatment. 
Study treatment can be dose reduced to 250 mg bid as a first step and to 200 mg bid as a 
second step. Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 adverse event 
occurs which the investigator considers to be related to administration of study treatment. 
8.2.8.1 
Management of new or worsening pulmonary symptoms  
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities occur 
in the absence of a clear diagnosis, an interruption in study treatment dosing is recommended 
and further diagnostic workup (including a high resolution CT scan) should be performed to 
exclude pneumonitis. 
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then study treatment can be restarted, if deemed appropriate by the 
investigator. If significant pulmonary abnormalities are identified, these need to be discussed 
with the Study Physician. 
8.2.8.2 
Management of nausea and vomiting 
Events of nausea and vomiting are known to be associated with olaparib treatment. In study 
D0810C00019 nausea was reported in 71% of the olaparib treated patients and 36% in the 
placebo treated patients and vomiting was reported in 34% of the olaparib treated patients and 
14% in the placebo treated patients. These events are generally mild to moderate (CTCAE 
grade 1 or 2) severity, intermittent and manageable on continued treatment. The first onset 
generally occurs in the first month of treatment for nausea and within the first 6 months of 
treatment for vomiting. For nausea, the incidence generally plateaus at around 9 months, and 
for vomiting at around 6 to 7 months. 
No routine prophylactic anti-emetic treatment is required at the start of study treatment, 
however, patients should receive appropriate anti-emetic treatment at the first onset of nausea 
or vomiting and as required thereafter, in accordance with local treatment practice guidelines.  
Alternatively, olaparib tablets can be taken with a light meal/snack (eg, 2 pieces of toast or a 
couple of biscuits). 
 
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Clinical Study Protocol 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
66(93) 
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). 
8.2.8.3 
Interruptions for intercurrent non-toxicity related events 
Study treatment dose interruption for conditions other than toxicity resolution should be kept 
as short as possible. If a patient cannot restart study treatment within 4 weeks for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with the primary investigator (Dr. Michael Schweizer). 
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 5 
Dose reductions for olaparib treatment.  
NOTE: Dose of testosterone will remained fixed throughout the study. Dose 
reductions in testosterone could result in physiologic serum T levels, which in 
contrast to supraphysiologic levels, may promote tumor growth. 
Initial Dose 
Following re-challenge post 
interruption: Dose reduction 1 
Dose reduction 2 
300mg twice daily 
250mg twice daily 
200mg twice daily 
8.3 
Concomitant and post-study treatment(s) 
The use of any natural/herbal products or other traditional remedies should be discouraged, 
but use of these products, as well as any medication or vaccine including over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements that the patient is receiving at the 
time of enrolment or receives during the study must be recorded along with: 
x Reason for use 
x Dates of administration including start and end dates 
x Dosage information including dose and frequency 
 
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Clinical Study Protocol 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
67(93) 
Medications that may NOT be administered 
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (Hormone 
replacement therapy (HRT) is acceptable), radiotherapy, biological therapy or other novel 
agent) is to be permitted while the patient is receiving study medication. 
Live virus and live bacterial vaccines should not be administered whilst the patient is 
receiving study medication and during the 30 day follow up period. An increased risk of 
infection by the administration of live virus and bacterial vaccines has been observed with 
conventional chemotherapy drugs and the effects with olaparib are unknown. 
Restricted concomitant medications 
Strong or Moderate CYP3A inhibitors  
Known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, boosted 
protease inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate 
CYP3A inhibitors (ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) should not 
be taken with olaparib. 
If there is no suitable alternative concomitant medication then the dose of olaparib should be 
reduced for the period of concomitant administration. The dose reduction of olaparib should 
be recorded in the eCRF with the reason documented as concomitant CYP3A inhibitor use.  
• 
Strong CYP3A inhibitors – reduce the dose of olaparib to 100mg bd for the duration of 
concomitant therapy with the strong inhibitor and for 5 half lives afterwards. 
• 
Moderate CYP3A inhibitors - reduce the dose of olaparib to 150mg bd 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 or Moderate CYP3A inducers 
Strong (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide and St John’s Wort) and moderate CYP3A inducers (eg. bosentan, 
efavirenz, modafinil) of CYP3A should not be taken with olaparib. 
If the use of any strong or moderate CYP3A inducers are considered necessary for the 
patient’s safety and welfare this could diminish the clinical efficacy of olaparib. 
If a patient requires use of a strong or moderate CYP3A inducer or inhibitor then they must be 
monitored carefully for any change in efficacy of olaparib. 
P-gp inhibitors 
It is possible that co-administration of P-gp inhibitors (eg amiodarone, azithromycin) may 
increase exposure to olaparib. Caution should therefore be observed. 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
68(93) 
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.  
The efficacy of hormonal contraceptives may be reduced if co administered with olaparib.  
Caution should therefore be observed if substrates of these isoenzymes or transporter proteins 
are co-administered. 
Examples of substrates include: 
x CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine 
x CYP1A2 – duloxetine, melatonin 
x CYP2B6 – bupropion, efavirenz 
x OATP1B1 - bosentan, glibenclamide, repaglinide, statins and valsartan 
x OCT1, MATE1, MATE2K – metformin 
x OCT2  - serum creatinine 
x OAT3  -furosemide, methotrexate 
Anticoagulant Therapy 
Patients who are taking warfarin are not permitted to enroll in the study. Subcutaneous heparin 
and low molecular weight heparin are permitted. Patients that can be safely transitioned to 
heparin will be permitted to enroll. 
Anti-emetics/Anti-diarrheals 
If a patient develops nausea, vomiting and / or diarrhea, then these symptoms should be 
reported as AEs (see section 6.2) and appropriate treatment of the event given. 
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 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
69(93) 
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.  
Subsequent therapies for cancer  
Details of first and subsequent therapies for cancer and/or details of surgery for the treatment 
of the cancer, after discontinuation of treatment, will be collected.  Reasons for starting 
subsequent anti-cancer therapies including access to other PARP inhibitors or investigational 
drugs will be collected and included in the exploratory assessments of OS. 
8.3.1 
Medications that may NOT be administered 
No other chemotherapy, immunotherapy, hormonal therapy or other novel agent is to be 
permitted while the patient is receiving study medication. 
8.4 
Treatment compliance 
Patients will utilize a Pill Diary throughout the duration of the study to ensure compliance 
with treatment.  
9. 
ETHICAL AND REGULATORY REQUIREMENTS 
9.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements Subject data protection. 
9.2 
Ethics and regulatory review 
The local IRB must review and approval the protocol and informed consent prior to study 
activation. The IRB must comply with applicable local and national laws and regulations, 
including protections against conflicts of interest. Prior to site activation, the following 
regulatory items must be completed: 
x Protocol is signed and understood by Principal Investigator 
x Investigator’s Brochure or product labeling, if applicable, is reviewed and 
understood by Principal Investigator and maintained in a file 
x Protocol, protocol amendments, and informed consent forms are approved by IRB 
and documentation of IRB name and address and approval are maintained on file 
with the Principal Investigator 
9.3 
Informed consent 
Written informed consent will be obtained by the study Investigator or a study sub-
Investigator  working on this study. An explanation of the nature of study, its purpose, 
procedures involved, expected duration, potential risks and benefits will be provided to each 
participant by the treating physician (i.e., Sub-Investigator, Principal Investigator) or the 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
70(93) 
research nurse. Each participant will be informed that participation in the study is voluntary 
and that he may withdraw from the study at any time, and that withdrawal of consent will not 
affect his subsequent medical treatment. Participants will be allowed time needed to make an 
informed decision. Participants will be encouraged to ask questions about the study and the 
consent before signing the consent form. Original signed consent forms will be filed in each 
patient’s research chart, while each patient will receive a copy of the consent document. No 
patient will enter the study before his informed consent has been obtained. 
The Research Coordinator and Principal Investigator (Michael Schweizer, MD) will be 
responsible for reviewing the consent forms and verifying eligibility. Once it has been 
confirmed that a new candidate has provided consent and is eligible to participate in the study, 
the patient will be registered and assigned a unique study identification number. 
9.4 
Changes to the protocol and informed consent form 
Any changes to the protocol or consent will be made in the form of an amendment and must 
be approved by the IRB before implementation. These changes may only be made by the 
Principal Investigator (i.e., Michael Schweizer, MD). 
10. 
STUDY MANAGEMENT 
10.1 
Training of study site personnel 
Prior to opening this study for accrual, each participating site will be required to have a Site 
Initiation Visit (SIV). The SIV will involve a presentation by the Principal Investigator to 
review the protocol in detail. The SIV should be attended (in person or virtually) by the 
Principal Investigator, study coordinator, investigational drug services representative and any 
other sub-investigators. If any of the aforementioned personnel are unable to attend the SIV, 
the participating site will be responsible for distributing the protocol and SIV presentation for 
review. Training should be documented on delegation logs at each participating site. 
 
10.2 
Monitoring of the study 
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 
 
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Consortium Study Number  9984 
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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 Principal 
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/ Principal 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 objectives. 
10.2.1 
Source data 
Source data will be maintained in study binders or electronically in secure servers as 
appropriate. Servers will be maintained at SCCA/UWMC and any hard copies of source data 
will be kept in a locked office or locked filling cabinets. 
11. 
EVALUATION AND CALCULATION OF VARIABLES 
Prostate cancer has a tendency to metastasize to bone and lymph nodes and is often associated 
with non-measurable metastatic disease per RECIST 1.1 criteria, even in its later stages [96, 
105]. To maximize patient eligibility, those with non-measurable disease at baseline (per 
RECIST 1.1) will be permitted to enroll. Because evaluating for objective radiographic 
response will not be possible in all patients enrolled, we will determine the effects of 
treatment on PSA. The primary objective of this study will therefore be to determine the 
SURSRUWLRQRISDWLHQWVZLWK50% decline in PSA from baseline following initiation of 
treatment (i.e. PSA50 response rate). As recommended by the PCWG3, this will be assessed 
following 12-weeks of BAT plus olaparib therapy [95].  
11.1 
Calculation or derivation of efficacy variable(s) 
PSA Response: The percent decline in PSA compared to baseline (i.e. most recent PSA value 
prior to first dose of study drugs) will be calculated for each patient for every on-study PSA 
value obtained. PSA50 UHVSRQVHZLOOEHGHILQHGDVDGHFOLQHLQ36$50% compared to 
baseline. The primary objective is to determine the PSA50 response rate (i.e. proportion of 
patients achieving a PSA50 response) 12-weeks after initiating therapy. 
PSA Progression: PSA progression will be defined as follows: 
 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
72(93) 
x For subjects showing an initial decline in PSA from baseline, PSA progression will be 
GHILQHGDVDQLQFUHDVHLQ36$WKDWLVDQGQJP/DERYHWKHnadir, and which is 
confirmed by a second value 3 or more weeks later (i.e., a confirmed rising trend). 
x For those subjects with no decline in PSA from baseline, PSA progression will be 
GHILQHGDVDQLQFUHDVHLQ36$WKDWLVDQGQJP/DIWHUZHHNV 
Radiographic Response: RECIST 1.1 guidelines will be used to define measurable, non-
measurable, target lesions (TLs) and non-target lesions (NTLs) [96]. Measurable vs. non-
measurable lesions will be defined as follows: 
x Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest diameter t20 mm using conventional techniques or t10 mm 
with spiral CT scan. 
x Non-measurable lesions - all other lesions, including small lesions (longest diameter 
<20 mm with conventional techniques or <10 mm with spiral CT scan) and those that 
can truly not be measured (i.e., bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, lymphangitis cutis/pulmonis, cystic lesions, and also 
abdominal masses that are not confirmed and followed by imaging techniques). 
All measurements should be taken and recorded in metric notation, using a ruler or calipers.  All 
baseline evaluations should within the 28-day screening period.  
CT chest/abdomen/pelvis should be used to characterize each identified and reported lesion at 
baseline and during follow-up. Ideally iodinated contrast should be used, but if this is not 
possible (e.g. contrast allergy, renal insufficiency), then all subsequent scans should also forgo 
the use of contrast. 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes). For the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is required.  
Baseline Documentation of “Target” and “Non-Target” Lesions 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and their suitability for accurate repeated measurements (either by imaging techniques or 
clinically).  
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD.  The baseline sum LD will be used as reference by which to characterize the 
objective tumor. 
 
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Consortium Study Number  9984 
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All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline.  Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up.  
 
Radiographic response will be defined as a complete response (CR) or partial response (PR). 
The following response criteria, modified from RECSIT 1.1, will be used: 
Complete Response (CR): 
Disappearance of all target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD 
Progressive Disease (PD): 
At least a 20% increase in the sum LD of target lesions 
(including new measurable lesions), compared to the nadir sum 
LD 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the nadir sum LD 
since the treatment started 
 
Survival Endpoints: 
x Progression free survival (PFS) will be defined as the time from the start of treatment 
until disease progression (per modified RECIST criteria or PCWG3 criteria for bone 
lesions), clinical progression (as determined by the treating physician), or death, 
whichever occurs first. 
x PSA PFS will be defined as the time from the start of treatment until PSA progression 
(as defined by PCWG3 criteria) [95]. 
x Overall survival (OS) will be defined as the time from the start of treatment until death 
from any cause. 
It is important to note that bone metastases are considered non-measurable lesions. 
Determining progression in bone metastases will therefore be defined according to PCWG3 
criteria as follows: 
x Appearance of at least two new lesions on bone scan, with at least two additional 
lesions on confirmatory bone scan. Confirmatory bone scan should ideally occur at 
the next planned scan according to the Schedule of Study Assessments, but no earlier 
than 4 weeks.  
x If at least two additional new lesions are seen on the confirmatory scan, the date of 
progression is the date of the bone scan when the first two new lesions were 
documented  
 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
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x Changes in intensity of uptake alone do not constitute either progression or 
regression 
 
11.2 
Calculation or derivation of safety variable(s) 
11.2.1 
Other significant adverse events (OAE) 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and DAEs.  Based on the expert’s judgment, 
significant adverse events of particular clinical importance may, after consultation with the 
Global Patient Safety Physician, be considered OAEs and reported as such.  A similar review 
of laboratory, vital signs, ECG and other clinical data will be performed for identification of 
OAEs. 
Examples of these are marked hematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment. 
There are currently no identified OAEs for olaparib 
11.3 
Calculation or derivation of patient reported outcome variables 
Quality of life (QOL) will be recorded through the FACT-P and the International Index of 
Erectile Function (IIEF) surveys. These instruments has been previously validated and are 
used extensively in clinical trials to assess the effects of treatment intervention on quality of 
life. Details regarding these surveys can be found in Appendix 4. 
12. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
12.1 
Description of analysis sets 
The safety and efficacy analysis sets will include all subjects that received at least one dose of 
the study drug. Subjects that drop out, for any reason, prior to 12-weeks (i.e. primary endpoint 
assessment timepoint) will be replaced. 
12.2 
Methods of statistical analyses 
12.2.1 
Safety Analyses 
We will characterize AEs by type and grade as outlined in Section 6.2. Safety will be 
summarized as the severity and frequency of a given AE. 
 
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Consortium Study Number  9984 
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12.2.2 
Efficacy Analyses 
Primary Objective 
The primary objective will be to determine the PSA50 response rate (i.e. proportion of patients 
ZLWKDGHFOLQHLQ36$50% from baseline) to BAT plus olaparib in mCRPC patients 
following 12-weeks of therapy. This will be calculated as the percentage with 95% confidence 
interval (CI) of the total number of subjects that achieved a PSA50 response. Subjects who 
drop out of the study prior to 12-weeks will be counted as treatment failures (i.e. non-
responders), however, these patients will be replaced.  
 
Secondary Objectives 
Secondary objectives will include determining: overall survival, radiographic PFS, PSA PFS, 
PSA50 response UDWHLHGHFOLQHLQ36$IURPEDVHOLQH, and radiographic response rate. 
Definition for progression and response endpoints are provided in Section 11.1.  Survival 
endpoints will be presented with Kaplan-Meier curves, and the median survival with 95% CI 
will be calculated. Rates will be reported as percentages with 95% CI. Best on study PSA and 
radiographic response for each patient will be presented in a waterfall plot. Average change in 
QOL scores (total and for each domain) for each survey will be calculated at each timepoint. 
A paired t-test will used to assess for statistically significant changes in QOL from baseline to 
the 12-week timepoint, and linear mixed effects models will be used to evaluate trends over 
all timepoints. 
 
12.2.3 
Exploratory Analyses 
Exploratory correlative work will be conducted with the goal to understand the mechanism 
mediating response and resistance to BAT plus olaparib, and to determine if there are 
biomarkers that are predictive of response to combination therapy. Examples of studies to be 
conducted may include, but are not limited to: evaluating for differences in response and 
disease progression in patients with/without mutations in genes involved in homologous 
recombination, studies to determine intratumoral androgen levels using LC/MS, assessing for 
evidence of dsDNA breaks, evaluating AR and AR-V expression at the protein and transcript 
levels, sequencing tumor DNA, and tumor transcript profiling studies. Baseline exploratory 
biomarker levels/values, as well as changes in these levels/values pre-/post-treatment will be 
correlated with the primary endpoint and secondary endpoints using chi-square tests and 
logistic regression, or (for PFS and OS) using proportional hazards models, Kaplan-Meier 
methods and log-rank tests. 
12.3 
Determination of sample size 
The primary objective will be to determine the PSA50 response rate for combination BAT and 
olaparib 12-weeks after starting therapy. PSA50 response rate will be defined as the proportion 
RISDWLHQWVDFKLHYLQJD50% decline in PSA from baseline. Across two prior studies testing 
BAT in men with CRPC, we observed a PSA50 response rate of ~30% [11, 56]. In a prior 
study testing olaparib in men with CRPC, approximately 75% of patients with evidence of 
 
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Consortium Study Number  9984 
Edition Number 1.6 
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DNA damage repair deficiency (DDR) had a PSA50 response to olaparib monotherapy[88]. 
Therefore, given that we will require 1/2 of the study cohort to have evidence of DDR 
deficiency and the other half to have intact DDR genes, we estimate that the null rate (H0) for 
combination therapy will be approximately 50%. Combination therapy will be deemed worthy 
of further study if we detect a PSA50 UHVSRQVHUDWHRI75% (H1) for the entire study cohort, 
which would compare favorably to a null (H0) PSA50 response rate of 50%. Based on these 
assumptions, a sample size of 30 patients will provide 82% power to detect a difference 
between the null (H0) and alternative (H1) hypotheses at a two-sided type I error ĮRI 
A key secondary objective of this study is to evaluate candidate biomarkers for their ability to 
discriminate between responders and non-responders to BAT plus olaparib. Because DNA 
damage repair (DDR) deficiency appears to predict for responses to olaparib and may predict 
for response to BAT, we will ensure that half of the patients enrolled (N=15) will have DDR 
deficiency. DDR deficiency will be defined by the presence of homozygous deletions, 
deleterious mutations, or both in DNA-repair genes (e.g. BRCA 1/2, ATM) previously shown 
to associate with response to olaparib [88]. Assuming a two-VLGHGW\SH,HUURUĮRI10% and 
a PSA50 response rate of 13/15 for patients with DDR deficiency (based on prior experience), 
we will have 65% power to detect a difference in PSA50 response versus 8/15 patients without 
DDR deficiency [88]. Similarly, we will have 98% power to detect a difference versus 4/15 
patients without DDR deficiency.  
 
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Consortium Study Number  9984 
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13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
13.1 
Overdose  
There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established.  
Olaparib must only be used in accordance with the dosing recommendations in this protocol. 
Any dose or frequency of dosing that exceeds the dosing regimen specified in this protocol 
should be reported as an overdose. The Maximum Tolerated Dose is 300 mg bid (tablet). 
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately. 
x An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose CRF module. 
x An overdose without associated symptoms is only reported on the Overdose CRF module. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
investigators or other site personnel inform appropriate AstraZeneca representatives within 
one day, i.e., immediately but no later than the end of the next business day of when he or 
she becomes aware of it.  
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.  
For overdoses associated with SAE, standard reporting timelines apply, see Section 6.2.7.  For 
other overdoses, reporting should be done within 30 days.  
13.1.1 
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
3 months following the last dose. 
Pregnancy of the patient’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should if possible be followed up and documented.  
The outcome of any conception occurring from the date of the first dose until 3 months after 
the last dose should be followed up and documented. 
 
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Consortium Study Number  9984 
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78(93) 
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Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
79(93) 
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Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
80(93) 
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Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
81(93) 
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Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
82(93) 
70. 
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treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays 
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Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: 
clearing up the misunderstandings. Mol Oncol 2011; 5: 387-393. 
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tumor cell growth by AZD2281 and cisplatin. Clin Cancer Res 2008; 14: 3916-3925. 
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cancer cell lines reveals three new deleterious mutants. Cancer Res 2006; 66: 41-45. 
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Beyond PARP Inhibitors. Cancer Discov 2017; 7: 20-37. 
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Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 
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Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 
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and breast cancer. Ann Oncol 2010; 21 Suppl 7: vii334-338. 
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Pritchard CC, Mateo J, Walsh MF et al. Inherited DNA-Repair Gene Mutations in 
Men with Metastatic Prostate Cancer. N Engl J Med 2016; 375: 443-453. 
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Mateo J, Carreira S, Sandhu S et al. DNA-Repair Defects and Olaparib in Metastatic 
Prostate Cancer. N Engl J Med 2015; 373: 1697-1708. 
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Rugo HS, Olopade OI, DeMichele A et al. Adaptive Randomization of Veliparib-
Carboplatin Treatment in Breast Cancer. N Engl J Med 2016; 375: 23-34. 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
83(93) 
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Mirza MR, Monk BJ, Herrstedt J et al. Niraparib Maintenance Therapy in Platinum-
Sensitive, Recurrent Ovarian Cancer. N Engl J Med 2016; 375: 2154-2164. 
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recent advances and future development. J Clin Oncol 2015; 33: 1397-1406. 
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Gojo I, Beumer JH, Pratz KW et al. A Phase 1 Study of the PARP Inhibitor Veliparib 
in Combination with Temozolomide in Acute Myeloid Leukemia. Clin Cancer Res 2016. 
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de Bono J, Mateo J, Fizazi K et al. Olaparib for Metastatic Castration-Resistant 
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Scher HI, Morris MJ, Stadler WM et al. Trial Design and Objectives for Castration-
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Kalhorn TF, Page ST, Howald WN et al. Analysis of testosterone and 
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Taplin ME, Montgomery B, Logothetis CJ et al. Intense androgen-deprivation therapy 
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Cancer 2005; 5: 21-28. 
 
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Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
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Date  February 24, 2021 
84(93) 
  
 
 
 
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Consortium Study Number  9984 
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Date  February 24, 2021 
85(93) 
Appendix 1: 
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.  
During the course of the study the treating physician (i.e. Sub-Investigator, lead/ Principal 
Investigator) will remain vigilant for increases in liver biochemistry.  The Principal 
Investigator is responsible for determining whether a patient meets potential Hy’s Law (PHL) 
criteria at any point during the study. 
The Principal 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 (IMP).  
The Principal Investigator is responsible for recording data pertaining to PHL/HL cases and 
for reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the 
outcome of the review and assessment in line with standard safety reporting processes. 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine $PLQRWUDQVIHUDVH$/7[8SSHU/LPLWRI
Normal (ULN) together with 7RWDO%LOLUXELQ7%/[8/1DWDQ\SRLQWGXULQJWKHVWXG\
following the start of study medication irrespective of an increase in Alkaline 
Phosphatase (ALP).  
Hy’s Law (HL) 
AST or ALT [8/1WRJHWKHU with 7%/[8/1ZKHUHQRRWKHUUHDVRQRWKHUWKDQWKH
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.   
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination: 
 
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Consortium Study Number  9984 
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86(93) 
x $/7[8/1 
x $67[8/1 
The Principal Investigator will without delay review each new laboratory report, and if the 
identification criteria are met will: 
x Determine whether the patient meets PHL criteria (see above) by reviewing 
laboratory reports from all previous visits 
x Promptly enter the laboratory data into the laboratory eCRF 
Follow-up 
 
Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Principal Investigator will: 
x Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
 
Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the treating physician (i.e. Sub-Investigator, Principal 
Investigator) will: 
x Notify the Principal Investigator who will notify AstraZeneca representative. 
x The treating physician (i.e. sub-investigator, Principal Investigator) contacts the 
Principal Investigator, to provide guidance, discuss, and agree on an approach for 
the study patient’s follow-up and the continuous review of data. Subsequent to this 
contact the treating physician (i.e. sub-investigator, Principal Investigator) will: 
o 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. 
o Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. 
o Complete the 3 Liver eCRF Modules as information becomes available. 
x If at any time (in consultation with the treating phsyician) the PHL case meets 
serious criteria, report it as an SAE using standard reporting procedures 
 
Review and Assessment of Potential Hy’s Law Cases 
The instructions in this Section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the treating 
physician contacts the Principal Investigator in order to review available data and agree on 
whether there is an alternative explanation for meeting PHL criteria other than DILI caused by 
the IMP.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate.   
According to the outcome of the review and assessment, the Principal Investigator will follow 
the instructions below. 
 
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Consortium Study Number  9984 
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Date  February 24, 2021 
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If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
x If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
x If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
x Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  
 
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 
 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
x Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above 
x Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met.  Update the SAE report according to the 
outcome of the review 
Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting 
Study Treatment  
This section is applicable to patients 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 Principal Investigator 
will: 
x 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 
 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
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 
If there is a significant change notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Potential Hy’s Law Criteria met of this Appendix 
# 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 Principal Investigator, this may be in 
consultation with the treating physician if there is any uncertainty. 
 
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 Principal Investigator should determine the cause for the previous occurrence of PHL 
criteria being met and answer the following question: 
x Was the alternative cause for the previous occurrence of PHL criteria being met 
found to be the disease under study e.g. chronic or progressing malignant disease, 
severe infection or liver disease, or did the patient meet PHL criteria prior to 
starting study treatment and at their first on study treatment visit as described in 
Actions Required When Potential Hy’s Law Criteria are Met Before and After 
Starting Study Treatment? 
If No: follow the process described in Potential Hy’s Law Criteria met of this Appendix 
If Yes: 
x 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 
x If there is a significant change follow the process described in this Appendix 
# 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 Principal Investigator; this may be in 
consultation with the treating physician if there is any uncertainty. 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
89(93) 
Reference 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf 
 
 
 
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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
90(93) 
 
Appendix 2: 
ECOG Performance Status 
 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, 
office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% 
of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to 
bed or chair 
5 
Dead 
 
Reference 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group.Am J Clin Oncol. 1982;5:649-655. 
 
 
 
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Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
91(93) 
Appendix 3: 
Highly Effective Methods of Contraception 
 
Olaparib is regarded as a compound with medium/high foetal 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: 
x 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]  
x Vasectomised sexual partner PLUS male condom.  With participant assurance that partner 
received post-vasectomy confirmation of azoospermia. 
x Tubal occlusion PLUS male condom  
x IUD PLUS male condom.  Provided coils are copper-banded 
 
Acceptable hormonal methods: 
x Normal and low dose combined oral pills PLUS male condom  
x Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the only highly 
efficacious progesterone based pill. 
x Hormonal shot or injection (eg., Depo-Provera) PLUS male condom 
x Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom  
x Norelgestromin / EE transdermal system PLUS male condom  
x 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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Clinical Study Protocol 
Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
92(93) 
Appendix 4: 
Quality of Life Surveys: FACT-P and IIEF 
 
References 
Esper P, Mo F, Chodak G et al. Measuring quality of life in men with prostate cancer using 
the functional assessment of cancer therapy-prostate instrument. Urology 1997; 50: 920-928. 
 
Rosen RC, Riley A, Wagner G et al. The international index of erectile function (IIEF): a 
multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: 822-830. 
 
 
 
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Drug Substance Olaparib (AZD2281, KU-0059436); Testosterone 
Consortium Study Number  9984 
Edition Number 1.6 
Date  February 24, 2021 
93(93) 
 
Appendix 5: 
DNA Damage Repair Pathway Genes of Interest 
 
This study will require that 50% of enrolled subjects have homozygous deletions, deleterious 
mutations, or both in one or more of the DNA damage repair (DDR) genes (i.e. DDR 
deficiency). A list of genes previously shown to associate with response to olaparib is below. 
Given that our understanding of genomic factors that may predict response to olaparib is 
evolving, additional alterations in genes associated directly or indirectly in homologous 
recombination repair response or PARP inhibitor sensitivity may be used at the PI’s 
discretion. The other 50% of patients must have an intact DDR pathway (i.e. no 
mutations/deletions in these genes).  
DDR genes of interest: 
x BRCA2 
x ATM 
x FANCA 
x CHEK2 
x BRCA1 
x PALB2 
x HDAC2 
x RAD51 
x MLH3 
x ERCC3 
x MRE11 
x NBN 
x CDK12 
 
Reference 
Mateo J, Carreira S, Sandhu S et al. DNA-Repair Defects and Olaparib in Metastatic Prostate 
Cancer. N Engl J Med 2015; 373: 1697-1708. 
 
 
9984
IRB Approved 
Document Release Date: 03/25/2021
Printed on 3/25/202