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Testing the Safety of Different Doses of Olaparib Given Radium-223 for Men With Advanced Prostate Cancer With Bone Metastasis

Primary Purpose

Castration-Resistant Prostate Carcinoma, Metastatic Prostate Adenocarcinoma, Stage IVB Prostate Cancer AJCC v8

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Biopsy
Biospecimen Collection
Computed Tomography
Laboratory Biomarker Analysis
Magnetic Resonance Imaging
Olaparib
Quality-of-Life Assessment
Radium Ra 223 Dichloride
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Castration-Resistant Prostate Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

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 (LHRH) agonist/antagonist; participants receiving prior docetaxel abiraterone, or next generation AR antagonist (enzalutamide, apalutamide, or darolutamide) for hormone sensitive disease are permitted
  • Participants must have progressive disease as defined by any of 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 >= 2 bone metastases by radiographic imaging and at least 1 lesion which has not been treated with prior radiation therapy
  • Participants must have tumor accessible for biopsy and be agreeable to baseline tumor biopsy; a metastatic focus is preferred but if not available and prostate is still intact prostate biopsy can be performed
  • Availability at the study site of formalin-fixed, paraffin-embedded (FFPE) archival tumor specimens, when available
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 80%)
  • White blood cell count (WBC) >= 3,000/mcL (within 28 days prior to administration of study treatment)
  • Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 days prior to administration of study treatment)
  • Platelets >= 100,000/mcL (within 28 days prior to administration of study treatment)
  • Hemoglobin >= 10 g/dL (transfusions permitted) (within 28 days prior to administration of study treatment)
  • Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN) (within 28 days prior to administration of study treatment); for subjects with Gilbert's disease =< 3.0 mg/dL
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x institutional ULN (within 28 days prior to administration of study treatment)
  • Creatinine clearance >= 51 ml/min as defined by Cockcroft-Gault equation (within 28 days prior to administration of study treatment)
  • Participants should be receiving an osteoclast targeting agent including either bisphosphonates or denosumab except in patients with contraindications as determined by the treating investigator including:

    • Hypocalcemia
    • Hypophosphatemia
    • Renal impairment including those with a glomerular filtration rate < 35 mL/min using the Cockcroft-Gault equation
    • Hypersensitivity to drug formulation
    • Dental condition or need for dental intervention that per the investigator would increase the risk of osteonecrosis of the jaw
  • 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
  • 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 abiraterone, apalutamide, or darolutamide within 2 weeks of treatment initiation; treatment with cytotoxic chemotherapy within 3 weeks of treatment initiation; treatment with investigational prostate cancer directed therapy within 4 weeks of treatment initiation; treatment with enzalutamide 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 (as determined on 2 or more time points within a 24 hour period if the first ECG demonstrates a prolonged corrected QT interval) or family history of long QT syndrome
    • 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
  • Patient unable to swallow orally administered medication
  • 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 or radium-223
  • Participants receiving strong 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 4 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

Sites / Locations

  • UC San Diego Moores Cancer CenterRecruiting
  • University of California Davis Comprehensive Cancer CenterRecruiting
  • Smilow Cancer Center/Yale-New Haven Hospital
  • Yale University
  • University of Kansas Clinical Research CenterRecruiting
  • University of Kansas Cancer CenterRecruiting
  • University of Kansas Cancer Center-Overland ParkRecruiting
  • University of Kansas Hospital-Westwood Cancer CenterRecruiting
  • University of Maryland/Greenebaum Cancer CenterRecruiting
  • Wayne State University/Karmanos Cancer Institute
  • Siteman Cancer Center at West County HospitalRecruiting
  • University of Kansas Cancer Center - NorthRecruiting
  • University of Kansas Cancer Center - Lee's SummitRecruiting
  • University of Kansas Cancer Center at North Kansas City HospitalRecruiting
  • Washington University School of MedicineRecruiting
  • Siteman Cancer Center-South CountyRecruiting
  • Siteman Cancer Center at Saint Peters HospitalRecruiting
  • Rutgers Cancer Institute of New JerseyRecruiting
  • Duke University Medical Center
  • Ohio State University Comprehensive Cancer CenterRecruiting
  • University of Pittsburgh Cancer Institute (UPCI)Recruiting
  • University of Wisconsin Carbone Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm I (radium Ra 223 dichloride, olaparib)

Arm II (radium Ra 223 dichloride)

Arm Description

Patients receive radium Ra 223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.

Patients receive radium Ra 223 dichloride as in Arm I. Patients with radiographic progression may crossover to Arm I. If patients have already completed all 6 infusions of radium, they will receive monotherapy with olaparib. If they have not yet completed all 6 radium-223 infusion, they will continue radium-223 infusion until completion and receive concurrent treatment with olaparib. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.

Outcomes

Primary Outcome Measures

Maximum tolerated dose of olaparib and radium Ra 223 dichloride
Radiographic progression-free survival (rPFS)
Will be estimated using the Kaplan-Meier method by treatment arm. A stratified Cox proportional hazards regression model will estimate the rPFS treatment hazard ratio with 80% 2-sided confidence intervals (CIs).

Secondary Outcome Measures

Radiographic progression free survival (rPFS)
Treatment comparison in rPFS will be conducted in pre-defined subgroups, including homologous recombination deficiency status (yes/no), disease extent (=< 20 or > 20 bone lesions) and prior docetaxel (yes or no). Cox regression hazard ratios (for treatment comparison) along two-sided 80% CI will be provided for each subgroup.
Prostate specific antigen (PSA) response
Will be defined by 50% decline in PSA from baseline. Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Response rate by different criteria will be summarized as number and percentage of participants by treatment arm with two-sided 80% CI and compared between groups using Fisher's exact tests.
Alkaline phosphatase (ALP) response
Will be defined as >= 30% reduction of the blood level, compared to the baseline value. Will be assessed by RECIST 1.1. Response rate by different criteria will be summarized as number and percentage of participants by treatment arm with two-sided 80% CI and compared between groups using Fisher's exact tests.
Tumor response
Will be assessed by RECIST 1.1. Response rate by different criteria will be summarized as number and percentage of participants by treatment arm with two-sided 80% CI and compared between groups using Fisher's exact tests.
Prostate specific antigen (PSA) progression
Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
ALP progression
Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
Symptomatic skeletal event (SSE)
Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
Overall survival (OS)
Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
Incidence of adverse events
Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5. Adverse events will be summarized according to grade, overall and by treatment arm, as number and percentage of participants. All adverse events resulting in discontinuation, dose modification, and/or dosing interruption, and/or treatment delay of drug will also be summarized by treatment arm.

Full Information

First Posted
October 20, 2017
Last Updated
September 12, 2023
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT03317392
Brief Title
Testing the Safety of Different Doses of Olaparib Given Radium-223 for Men With Advanced Prostate Cancer With Bone Metastasis
Official Title
A Phase 1/2 Study of Combination Olaparib and Radium-223 in Men With Metastatic Castration-Resistant Prostate Cancer With Bone Metastases (COMRADE)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 4, 2019 (Actual)
Primary Completion Date
November 30, 2023 (Anticipated)
Study Completion Date
November 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This phase I/II trial studies the best dose and side effects of olaparib and how well it works with radium Ra 223 dichloride in treating patients with castration-resistant prostate cancer that has spread to the bone and other places in the body (metastatic). PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Radioactive drugs, such as radium Ra 223 dichloride, may carry radiation directly to tumor cells and not harm normal cells. Giving olaparib and radium Ra 223 dichloride may help treat patients with castration-resistant prostate cancer.
Detailed Description
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 next generation androgen receptor (AR) antagonist (enzalutamide, apalutamide, darolutamide or other agent) use (yes versus no) for either hormone sensitive or castration resistant prostate cancer (CRPC). 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 first subsequent anti-cancer therapy (including AR signaling agents, cytotoxic chemotherapy, immunotherapy, or investigational agents) or death. 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. Correlate presence or absence of RAD51 with somatic and germline homologous recombination gene mutation status, PSA response, and PFS between treatment arms. X. 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. XI. 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 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) as well as blood sample collection and a tissue biopsy during screening and on study. 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 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study. ARM II: Patients receive radium Ra 223 dichloride as in Arm I. Patients with radiographic progression may crossover to Arm I. If patients have already completed all 6 infusions of radium, they will receive monotherapy with olaparib. If they have not yet completed all 6 radium-223 infusion, they will continue radium-223 infusion until completion and receive concurrent treatment with olaparib. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study. After completion of study treatment, patients are followed up every 6 months for 2 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Castration-Resistant Prostate Carcinoma, Metastatic Prostate Adenocarcinoma, Stage IVB Prostate Cancer AJCC v8

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
133 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm I (radium Ra 223 dichloride, olaparib)
Arm Type
Experimental
Arm Description
Patients receive radium Ra 223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Arm Title
Arm II (radium Ra 223 dichloride)
Arm Type
Experimental
Arm Description
Patients receive radium Ra 223 dichloride as in Arm I. Patients with radiographic progression may crossover to Arm I. If patients have already completed all 6 infusions of radium, they will receive monotherapy with olaparib. If they have not yet completed all 6 radium-223 infusion, they will continue radium-223 infusion until completion and receive concurrent treatment with olaparib. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.
Intervention Type
Procedure
Intervention Name(s)
Biopsy
Other Intervention Name(s)
BIOPSY_TYPE, Bx
Intervention Description
Undergo tissue biopsy
Intervention Type
Procedure
Intervention Name(s)
Biospecimen Collection
Other Intervention Name(s)
Biological Sample Collection, Biospecimen Collected, Specimen Collection
Intervention Description
Undergo blood sample collection
Intervention Type
Procedure
Intervention Name(s)
Computed Tomography
Other Intervention Name(s)
CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, CT, CT Scan, tomography
Intervention Description
Undergo CT
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Procedure
Intervention Name(s)
Magnetic Resonance Imaging
Other Intervention Name(s)
Magnetic Resonance, Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging
Intervention Description
Undergo MRI
Intervention Type
Drug
Intervention Name(s)
Olaparib
Other Intervention Name(s)
AZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, Olanib, Olaparix, PARP Inhibitor AZD2281
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Quality-of-Life Assessment
Other Intervention Name(s)
Quality of Life Assessment
Intervention Description
Ancillary studies
Intervention Type
Radiation
Intervention Name(s)
Radium Ra 223 Dichloride
Other Intervention Name(s)
Alpharadin, BAY 88-8223, BAY88-8223, Radium 223 Dichloride, RADIUM RA-223 DICHLORIDE, Radium-223 Chloride, Radium-223 Dichloride, Xofigo
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Maximum tolerated dose of olaparib and radium Ra 223 dichloride
Time Frame
Up to 2 years
Title
Radiographic progression-free survival (rPFS)
Description
Will be estimated using the Kaplan-Meier method by treatment arm. A stratified Cox proportional hazards regression model will estimate the rPFS treatment hazard ratio with 80% 2-sided confidence intervals (CIs).
Time Frame
Up to 2 years
Secondary Outcome Measure Information:
Title
Radiographic progression free survival (rPFS)
Description
Treatment comparison in rPFS will be conducted in pre-defined subgroups, including homologous recombination deficiency status (yes/no), disease extent (=< 20 or > 20 bone lesions) and prior docetaxel (yes or no). Cox regression hazard ratios (for treatment comparison) along two-sided 80% CI will be provided for each subgroup.
Time Frame
Up to 2 years
Title
Prostate specific antigen (PSA) response
Description
Will be defined by 50% decline in PSA from baseline. Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Response rate by different criteria will be summarized as number and percentage of participants by treatment arm with two-sided 80% CI and compared between groups using Fisher's exact tests.
Time Frame
Up to 2 years
Title
Alkaline phosphatase (ALP) response
Description
Will be defined as >= 30% reduction of the blood level, compared to the baseline value. Will be assessed by RECIST 1.1. Response rate by different criteria will be summarized as number and percentage of participants by treatment arm with two-sided 80% CI and compared between groups using Fisher's exact tests.
Time Frame
Up to 2 years
Title
Tumor response
Description
Will be assessed by RECIST 1.1. Response rate by different criteria will be summarized as number and percentage of participants by treatment arm with two-sided 80% CI and compared between groups using Fisher's exact tests.
Time Frame
Up to 2 years
Title
Prostate specific antigen (PSA) progression
Description
Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
Time Frame
From randomization to PSA progression by Prostate Cancer Working Group (PCWG) 3 criteria, assessed up to 2 years
Title
ALP progression
Description
Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
Time Frame
From randomization to the date of first ALP progression, assessed up to 2 years
Title
Symptomatic skeletal event (SSE)
Description
Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
Time Frame
From randomization to occurrence of the first SSE, such as pathologic bone fracture, spinal cord compression, hypercalcemia of malignancy or radiation therapy or surgery to bone, described by the US Food and Drug Administration, assessed up to 2 years
Title
Overall survival (OS)
Description
Will be estimated using the method of Kaplan-Meier and compared between treatment arms using the stratified log-rank test.
Time Frame
From randomization to the date of death due to any cause, assessed up to 2 years
Title
Incidence of adverse events
Description
Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5. Adverse events will be summarized according to grade, overall and by treatment arm, as number and percentage of participants. All adverse events resulting in discontinuation, dose modification, and/or dosing interruption, and/or treatment delay of drug will also be summarized by treatment arm.
Time Frame
Up to 2 years
Other Pre-specified Outcome Measures:
Title
Change in levels of serum lactate dehydrogenase (LDH)
Description
Will be summarized at baseline and each cycle with descriptive statistics. Percent change from baseline or status change (e.g. from normal to abnormal defined by institution upper limit level) will be reported and compared between treatment arms at selected timepoints using Wilcoxon rank sum test or Fisher's exact test as appropriate.
Time Frame
Baseline up to 2 years
Title
Frequency of mutations in the deoxyribonucleic acid (DNA) repair pathway
Description
Will be determined by Oncopanel testing. Gene mutation frequencies and mean +/- standard deviation of quantitative biomarkers will be summarized by arm and in overall population at baseline and/or at time of progression.
Time Frame
Up to 2 years
Title
Homologous recombination deficiency
Description
Cox regression or logistic regression will be conducted to explore the association of rPFS or treatment response (PSA or tumor response) with homologous recombination gene mutation status.
Time Frame
Up to 2 years
Title
Prevalence of germline mutations in homologous recombination genes
Description
Their correlation with family history of cancers as determined by the Family History Questionnaire and PSA response will be evaluated using Fisher's exact test or logistic regression as appropriate in all patients and/or by treatment arm as exploratory analyses.
Time Frame
Up to 2 years
Title
Quality of life (QOL)
Description
Will be measured using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and Brief Pain Inventory (BPI). For each treatment group, calculated QOL scores will be summarized at baseline and each time point. Changes from baseline will be graphically presented. The effect of treatment will be evaluated using a repeated measures model to incorporate assessments across time into a single analysis, using model contrasts to compare treatment groups at selected time points.
Time Frame
Baseline up to 2 years

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participants must be male aged >= 18 years of age 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 (LHRH) agonist/antagonist; participants receiving prior docetaxel abiraterone, or next generation AR antagonist (enzalutamide, apalutamide, or darolutamide) for hormone sensitive disease are permitted Participants must have progressive disease as defined by any of 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 >= 2 bone metastases by radiographic imaging and at least 1 lesion which has not been treated with prior radiation therapy Participants must have tumor accessible for biopsy and be agreeable to baseline tumor biopsy; a metastatic focus is preferred but if not available and prostate is still intact prostate biopsy can be performed Availability at the study site of formalin-fixed, paraffin-embedded (FFPE) archival tumor specimens, when available Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 80%) White blood cell count (WBC) >= 3,000/mcL (within 28 days prior to administration of study treatment) Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 days prior to administration of study treatment) Platelets >= 100,000/mcL (within 28 days prior to administration of study treatment) Hemoglobin >= 10 g/dL (transfusions permitted) (within 28 days prior to administration of study treatment) Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN) (within 28 days prior to administration of study treatment); for subjects with Gilbert's disease =< 3.0 mg/dL Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x institutional ULN (within 28 days prior to administration of study treatment) Creatinine clearance >= 51 ml/min as defined by Cockcroft-Gault equation (within 28 days prior to administration of study treatment) Participants should be receiving an osteoclast targeting agent including either bisphosphonates or denosumab except in patients with contraindications as determined by the treating investigator including: Hypocalcemia Hypophosphatemia Renal impairment including those with a glomerular filtration rate < 35 mL/min using the Cockcroft-Gault equation Hypersensitivity to drug formulation Dental condition or need for dental intervention that per the investigator would increase the risk of osteonecrosis of the jaw 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 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 abiraterone, apalutamide, or darolutamide within 2 weeks of treatment initiation; treatment with cytotoxic chemotherapy within 3 weeks of treatment initiation; treatment with investigational prostate cancer directed therapy within 4 weeks of treatment initiation; treatment with enzalutamide 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 (as determined on 2 or more time points within a 24 hour period if the first ECG demonstrates a prolonged corrected QT interval) or family history of long QT syndrome 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 Patient unable to swallow orally administered medication 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 or radium-223 Participants receiving strong 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 4 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rana R McKay
Organizational Affiliation
Yale University Cancer Center LAO
Official's Role
Principal Investigator
Facility Information:
Facility Name
UC San Diego Moores Cancer Center
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
858-822-5354
Email
cancercto@ucsd.edu
First Name & Middle Initial & Last Name & Degree
Rana R. McKay
Facility Name
University of California Davis Comprehensive Cancer Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
916-734-3089
First Name & Middle Initial & Last Name & Degree
Mamta Parikh
Facility Name
Smilow Cancer Center/Yale-New Haven Hospital
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
Individual Site Status
Active, not recruiting
Facility Name
Yale University
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520
Country
United States
Individual Site Status
Active, not recruiting
Facility Name
University of Kansas Clinical Research Center
City
Fairway
State/Province
Kansas
ZIP/Postal Code
66205
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
913-588-3671
Email
KUCC_Navigation@kumc.edu
First Name & Middle Initial & Last Name & Degree
Rahul A. Parikh
Facility Name
University of Kansas Cancer Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
913-588-3671
Email
KUCC_Navigation@kumc.edu
First Name & Middle Initial & Last Name & Degree
Rahul A. Parikh
Facility Name
University of Kansas Cancer Center-Overland Park
City
Overland Park
State/Province
Kansas
ZIP/Postal Code
66210
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
913-588-3671
Email
KUCC_Navigation@kumc.edu
First Name & Middle Initial & Last Name & Degree
Rahul A. Parikh
Facility Name
University of Kansas Hospital-Westwood Cancer Center
City
Westwood
State/Province
Kansas
ZIP/Postal Code
66205
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
913-588-3671
Email
KUCC_Navigation@kumc.edu
First Name & Middle Initial & Last Name & Degree
Rahul A. Parikh
Facility Name
University of Maryland/Greenebaum Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
800-888-8823
First Name & Middle Initial & Last Name & Degree
Arif Hussain
Facility Name
Wayne State University/Karmanos Cancer Institute
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Individual Site Status
Active, not recruiting
Facility Name
Siteman Cancer Center at West County Hospital
City
Creve Coeur
State/Province
Missouri
ZIP/Postal Code
63141
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
800-600-3606
Email
info@siteman.wustl.edu
First Name & Middle Initial & Last Name & Degree
Hiram A. Gay
Facility Name
University of Kansas Cancer Center - North
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64154
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
913-588-3671
Email
KUCC_Navigation@kumc.edu
First Name & Middle Initial & Last Name & Degree
Rahul A. Parikh
Facility Name
University of Kansas Cancer Center - Lee's Summit
City
Lee's Summit
State/Province
Missouri
ZIP/Postal Code
64064
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
913-588-3671
Email
KUCC_Navigation@kumc.edu
First Name & Middle Initial & Last Name & Degree
Rahul A. Parikh
Facility Name
University of Kansas Cancer Center at North Kansas City Hospital
City
North Kansas City
State/Province
Missouri
ZIP/Postal Code
64116
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
913-588-3671
Email
KUCC_Navigation@kumc.edu
First Name & Middle Initial & Last Name & Degree
Rahul A. Parikh
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
800-600-3606
Email
info@siteman.wustl.edu
First Name & Middle Initial & Last Name & Degree
Hiram A. Gay
Facility Name
Siteman Cancer Center-South County
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63129
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
800-600-3606
Email
info@siteman.wustl.edu
First Name & Middle Initial & Last Name & Degree
Hiram A. Gay
Facility Name
Siteman Cancer Center at Saint Peters Hospital
City
Saint Peters
State/Province
Missouri
ZIP/Postal Code
63376
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
800-600-3606
Email
info@siteman.wustl.edu
First Name & Middle Initial & Last Name & Degree
Hiram A. Gay
Facility Name
Rutgers Cancer Institute of New Jersey
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08903
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
732-235-7356
First Name & Middle Initial & Last Name & Degree
Biren Saraiya
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Individual Site Status
Active, not recruiting
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
800-293-5066
Email
Jamesline@osumc.edu
First Name & Middle Initial & Last Name & Degree
Edmund Folefac
Facility Name
University of Pittsburgh Cancer Institute (UPCI)
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
412-647-8073
First Name & Middle Initial & Last Name & Degree
Adam Olson
Facility Name
University of Wisconsin Carbone Cancer Center
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Site Public Contact
Phone
800-622-8922
First Name & Middle Initial & Last Name & Degree
Christos Kyriakopoulos

12. IPD Sharing Statement

Learn more about this trial

Testing the Safety of Different Doses of Olaparib Given Radium-223 for Men With Advanced Prostate Cancer With Bone Metastasis

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