Olaparib and Radium Ra 223 Dichloride in Treating Men With Metastatic Castration-Resistant Prostate Cancer That Has Spread to the Bone

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) of olaparib in combination with radium Ra 223
dichloride (radium-223). (Phase 1) II. Evaluate the radiographic progression-free survival
(rPFS). (Phase 2)

SECONDARY OBJECTIVES:

I. Evaluate safety and tolerability as assessed by Common Terminology Criteria for Adverse
Events (CTCAE) version 5.0.

II. To evaluate rPFS as stratified by disease extent (=< 20 or > 20 bone lesions) and prior
docetaxel use (yes or no).

III. Evaluate rPFS in patients harboring or lacking evidence of homologous recombination
deficiency (HRD) IV. Evaluate rPFS in patients based on prior abiraterone and/or enzalutamide
use (yes versus no).

V. Evaluate prostate specific antigen (PSA) response rate as defined by >= 50% decline in PSA
from baseline.

VI. Evaluate total alkaline phosphatase response defined as a reduction of >= 30% from the
baseline value, confirmed >= 4 weeks later.

VII. Evaluate time to PSA progression as defined by Prostate Cancer Clinical Trials Working
Group (PCTWG) 3 criteria.

VIII. Evaluate radiographic objective response rate as defined by Response Evaluation
Criteria in Solid Tumor (RECIST) version 1.1.

IX. Evaluate time to increase in the total alkaline phosphatase (ALP) level defined as an
increase of >= 25% from baseline at >= 12 weeks, in patients with no decrease from baseline,
or as an increase of >= 25% above the nadir, confirmed >= 3 weeks later, in patients with an
initial decrease from baseline.

X. Evaluate time to initiation of next active anti-cancer therapy (including androgen
receptor[AR] signaling agents, cytotoxic chemotherapy, immunotherapy, or investigational
agents).

XI. Evaluate time to first symptomatic skeletal event (SSE). XII. Evaluate overall survival
(OS).

EXPLORATORY OBJECTIVES:

I. Evaluate impact on quality of life (QOL) as determined by Functional Assessment of Cancer
Therapy-Prostate (FACT-P) questionnaire and Brief Pain Inventory (BPI).

II. Estimate the frequency of mutations in the deoxyribonucleic acid (DNA) repair pathway in
patients with metastatic castration-resistant prostate cancer (CRPC) as determine by
Oncopanel testing and by whole exome sequencing (WES).

III. Characterize changes in ribonucleic acid (RNA) expression of DNA repair genes and immune
markers by whole transcriptome sequencing (WTS) in each arm.

IV. Characterize changes in immune cell, T-cell receptor (TCR), and B-cell (BCR) receptor
repertoire at baseline, during treatment, and at progression in each arm.

V. Evaluate changes in lactate dehydrogenase (LDH) in patients each treatment arm.

VI. Assess the prevalence of germline mutations in homologous recombination genes in all
enrolled patients.

VII. Correlate homologous recombination gene germline mutation status with PSA response by
treatment arm.

VIII. Evaluate family history of cancers in the study population and correlate family cancer
history with germline mutation status.

IX. Evaluate the changes in whole genome sequencing (WGS) of plasma cell-free circulating DNA
(cfDNA) based patient-tumor specific signature at baseline, on treatment, and at progression.

X. Evaluate tumor mutation burden (TMB) and tumor mutational signature in plasma cfDNA at
baseline and correlate to tumor tissue TMB and mutational signature.

OUTLINE: This is a phase I, dose-escalation study of olaparib followed by a phase II study.

PHASE I: Patients receive radium Ra 223 dichloride intravenously (IV) over 1 minute on day 1.
Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity. Patients also receive olaparib orally (PO) twice daily (BID) on days
1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity.

PHASE II: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive radium Ra 223 dichloride IV over 1 minute on day 1. Treatment repeats
every 28 days for up to 6 courses in the absence of disease progression or unacceptable
toxicity. Patients also continue to receive olaparib as in Phase I.

ARM II: Patients receive radium Ra 223 dichloride as in Arm I.

After completion of study treatment, patients are followed up every 6 months for 2 years.

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed adenocarcinoma of the
prostate

- Participants must have castrate levels of serum testosterone < 50 ng/dL

- Participants without orchiectomy must be maintained on luteinizing hormone releasing
hormone agonist/antagonist; participants receiving prior docetaxel or abiraterone for
hormone sensitive disease are permitted

- Participants must have progressive disease as defined by the following:

- Castrate resistant disease as defined by PCWG-3 criteria; participants must have
a rise in PSA on two successive determination at least one week apart and PSA
levels >= 2 ng/mL (only the screening PS needs to be >= 2 ng/mL) and serum
testosterone < 50 ng/dL

- Soft tissue progression as defined by RECIST version 1.1

- Bone disease progression as defined by PCWG-3 criteria including the development
of two or more new lesions on bone scan

- Participants must have any number of bone metastases by radiographic imaging

- Participants must have tumor accessible for biopsy and be agreeable to baseline tumor
biopsy

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- White blood cell count (WBC) >= 3,000/mcL (within 28 prior to administration of study
treatment)

- Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 prior to administration of
study treatment)

- Platelets >= 100,000/mcL (within 28 prior to administration of study treatment)

- Hemoglobin >= 10 g/dL (transfusions permitted) (within 28 prior to administration of
study treatment)

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

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x institutional
ULN (within 28 prior to administration of study treatment)

- Creatinine clearance >= 51 ml/min/1.73 m^2 as defined by Cockcroft-Gault equation
(within 28 prior to administration of study treatment)

- The effects of olaparib and radium-223 on the developing human fetus are unknown; for
this reason, men treated or enrolled on this protocol must agree to use adequate
contraception and avoid sperm donation prior to the study, for the duration of study
participation, and three months after discontinuation of olaparib and radium-223
administration

- Human immunodeficiency virus (HIV)-positive with negative viral loads on stable
antiretroviral regimen and CD4 count > 250 are eligible

- Ability to understand and the willingness to sign a written informed consent document;
patients with impaired decision-making who have a legal guardian (e.g., spouse) able
to make informed decisions on behalf of the patient are eligible

- Patients must be able to tolerate oral medications by mouth and not have a
gastrointestinal illness that would preclude absorption of olaparib

Exclusion Criteria:

- Pathology consistent with small cell carcinoma of the prostate

- Persistent grade > 1 CTCAE version 5.0 adverse events (except alopecia)

- Presence of visceral metastases (liver, lung, brain, etc.) or malignant
lymphadenopathy exceeding 4 centimeters (cm) in short diameter

- Prior treatment with radium-223

- Prior treatment with olaparib or other PARPi

- Treatment with cytotoxic chemotherapy, hormonal therapies (including but not limited
to abiraterone, enzalutamide), investigational prostate cancer directed therapy within
4 weeks of treatment initiation

- Prior hemibody external radiotherapy

- Palliative radiation therapy to the bone or other sites within 2 weeks of treatment
initiation

- Participants who are receiving any other investigational agents

- Imminent or established spinal cord compression based on clinical and/or imaging
findings

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring need for intravenous anti-microbials, symptomatic congestive heart
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements

- Clinically significant medical condition defined as:

- Cerebral infarction within 6 months of study treatment

- Transient ischemic attack within 3 months of study treatment

- Myocardial infarction within 6 months of study treatment

- Uncontrolled angina within 3 months of study treatment

- Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or
subjects with history of congestive heart failure NYHA class 3 or 4 in the past,
or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless a
screening echocardiogram or multi‐gated acquisition scan performed within 3
months of the screening visit results in a left ventricular ejection fraction
that is >= 45%

- History of clinically significant ventricular arrhythmias (e.g., ventricular
tachycardia, ventricular fibrillation, torsade de pointes)

- Prolonged corrected QT interval by the Fridericia correction formula on the
screening electrocardiogram (ECG) > 470 msec

- History of Mobitz II second degree or third degree heart block without a
permanent pacemaker in place

- Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170
mmHg or diastolic blood pressure > 105 mmHg at the screening visit

- History of hypertensive emergency or encephalopathy within 6 months of study
treatment

- Deep venous thrombosis or pulmonary embolism within 3 months of study treatment

- Major surgery within 4 weeks of study treatment; subjects with clinically relevant
ongoing complications from prior surgery are not eligible

- History of gastrointestinal disorders (medical disorders or extensive surgery) which
may interfere with the absorption of the study drug

- History of bowel obstruction within 1 month of study treatment

- History of abdominal fistula, intra-abdominal abscess, or gastrointestinal perforation
within the 3 months of study treatment

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to olaparib

- Participants receiving strong or moderate CYP3A4/5 inducers or inhibitors are
ineligible; dihydropyridine calcium-channel blockers are permitted for management of
hypertension; the required washout period prior to starting olaparib is 2 weeks for
CYP3A inhibitors; the required washout period prior to starting olaparib is 5 weeks
for enzalutamide or phenobarbital and 3 weeks for other CYP3A inducers

- Patients with known active hepatitis (i.e. hepatitis B or C) infection

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

- Patient having received prior allogenic bone marrow transplant or double umbilical
cord blood transplantation

- Individuals with a history of a different malignancy are ineligible except for the
following circumstances:

- Individuals with a history of other malignancies are eligible if they have been
disease-free for at least 3 years and are deemed by the investigator to be at low
risk for recurrence of that malignancy, or

- Individuals with the following cancers are eligible if diagnosed and treated
within the past 5 years: superficial bladder cancer, basal cell or squamous cell
carcinoma of the skin