Testosterone and Olaparib in Treating Participants With Castration-Resistant Prostate Cancer

PRIMARY OBJECTIVES:

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) (i.e., intermittent high dose testosterone) 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.

OUTLINE:

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

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

Inclusion Criteria:

- Must be willing to provide informed consent prior to any study specific procedures

- Documented histologically confirmed adenocarcinoma of the prostate

- 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., ≤ 50 mg/dL)

- PSA must be at least 1 ng/ml and rising on two successive measurements at least two
weeks apart

- 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

- No prior chemotherapy for the treatment of mCRPC; patients may have received docetaxel
for the treatment of hormone-sensitive prostate cancer

- 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

- Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days (within 28 days
prior to administration of study treatment)

- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (within 28 days prior to administration
of study treatment)

- Platelet count ≥ 100 x 10^9/L (within 28 days prior to administration of study
treatment)

- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (within 28 days
prior to administration of study treatment)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) ≤
2.5 x institutional upper limit of normal unless liver metastases are present in which
case they must be ≤ 5 x ULN (within 28 days prior to administration of study
treatment)

- Patients must have creatinine clearance estimated using the Cockcroft-Gault equation
of ≥ 51 mL/min (within 28 days prior to administration of study treatment)

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Patients must have a life expectancy ≥ 16 weeks

- Male patients and their partners, who are sexually active and of childbearing
potential, must agree to the use of two highly effective forms of contraception in
combination throughout the period of taking study treatment and for 3 months after
last dose of study drug(s) to prevent pregnancy in a partner

- Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations

- At least one lesion (measurable and/or non-measurable) that can be accurately assessed
at baseline by computed tomography (CT), positron-emission tomography (PET), magnetic
resonance imaging (MRI) and/or bone scan and is suitable for repeated assessment

- Must have archival tissue available, be willing to undergo metastatic biopsy or have a
sufficient plasma circulating tumor DNA (ctDNA) concentration in order to perform
next-generation DNA sequencing

- The study will require that 50% of enrolled subjects have homozygous deletions,
deleterious mutations, or both in one or more of the DNA damage response (DDR) genes;
the other 50% of patients must have an intact DDR pathway

Exclusion Criteria:

- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site)

- Previous enrollment in this study

- Participation in another clinical study with an investigational product during the
last 3 weeks

- Any previous treatment with poly-adenosine diphosphate ribose polymerase (PARP)
inhibitor, including olaparib

- Other malignancy within the last 5 years except: adequately treated non-melanoma skin
cancer or other solid tumors including lymphomas (without bone marrow involvement)
curatively treated with no evidence of disease for ≥ 5 years

- Resting electrocardiogram (ECG) with corrected QT interval (QTc) > 470 msec on 2 or
more time points within a 24 hour period or family history of long QT syndrome

- Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
reasons) within 3 weeks prior to study treatment

- Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.,
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil); the required washout
period prior to starting olaparib is 2 weeks

- Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's wort) or
moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil); the required washout
period prior to starting olaparib is 3 weeks for enzalutamide, 5 weeks for
phenobarbital and 3 weeks for other agents

- Persistent toxicities (> Common Terminology Criteria for Adverse Event [CTCAE] grade
2) caused by previous cancer therapy, excluding alopecia

- Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)

- 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

- Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of any major surgery

- Patients considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection; examples
include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 5
years) myocardial infarction, uncontrolled major seizure disorder, uncontrolled
hypertension (blood pressure [BP] ≥ 160/100), stroke within the past 5 years,
uncontrolled diabetes (hemoglobin [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

- Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study medication

- Immunocompromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV)

- Patients with a known hypersensitivity to olaparib or any of the excipients of the
product

- Patients with a known hypersensitivity to the testosterone cypionate or any of the
excipients of the product

- Patients with known active hepatitis (i.e., hepatitis B or C) due to risk of
transmitting the infection through blood or other body fluids

- Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT)

- Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable)

- 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

- Any psychological, familial, sociological, or geographical condition that could
potentially interfere with compliance with the study protocol and follow-up schedule

- 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)

- Patients with pain attributable to their prostate cancer

- 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

- Prior history of deep venous thrombosis or pulmonary embolism within 5 years prior to
enrollment in the study and not currently on systemic anticoagulation

- Patients with NYHA (New York Heart Association) class III or IV heart failure or
history of a prior myocardial infarction (MI) within the last five years prior to
enrollment in the study