Abiraterone/Prednisone, Olaparib, or Abiraterone/Prednisone + Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer With DNA Repair Defects

NCT03012321 | Active Not Recruiting Phase 2 DMC

• 4 other identifiers: NU_16U05STU00203960NCI-2016-01834PCCTC #: c16-168
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 18

Brief Summary

This is a biomarker preselected, randomized, open-label, multicenter, phase II study in men with metastatic castration resistant prostate cancer (mCRPC). Patients with tumors that have ATM, BRCA1 and/or BRCA2 mutations/deletions/loss of heterozygosity will be randomized in a 1:1:1 fashion to each arm. Patients with mutations in noncanonical DNA repair genes including FANCA, PALB2, RAD51, ERCC3, MRE11, NBN, MLH3, CDK12, CHEK2, HDAC2, ATR, PMS2, GEN1, MSH2, MSH6, BRIP1, or FAM175A defects will be assigned to Arm IV with single agent olaparib.

Conditions

Prostate Cancer Metastatic Castration-Resistant; Abnormal DNA Repair; Metastatic Prostate Carcinoma; Stage IV Prostate Cancer

Outcome Measures

Primary Outcomes (1)

• Objective Progression Free Survival (PFS)

  Evaluate the objective PFS of abiraterone/prednisone, olaparib or the combination abiraterone/prednisone + olaparib in mCRPC patients with canonical DNA repair defects in BRCA1, BRCA2, or ATM.

  Up to 2 years

Secondary Outcomes (9)

• Measurable disease response rate by RECIST

  Up to 2 years

• PSA response rate

  Up to 2 years

• Rate of undetectable PSA

  Up to 2 years

• Poly[ADP-ribose] polymerase (PARP) inhibition

  Up to 2 years

• Incidence of Adverse Events

  Up to 2 years

Study Arms (4)

Arm I: Abiraterone + Prednisone

ACTIVE COMPARATOR

Abiraterone 1000 mg orally once daily and prednisone 5 mg orally twice daily, days 1-28 in 28 day cycles.

Drug: Abiraterone Acetate; Drug: Prednisone

Arm II: Olaparib

ACTIVE COMPARATOR

Olaparib 300 mg orally twice daily for days 1-28 in 28 day cycles.

Drug: Olaparib

Arm III: Abiraterone + Prednisone + Olaparib

ACTIVE COMPARATOR

Abiraterone 1000 mg orally once daily, prednisone 5 mg orally twice daily, olaparib 300 mg orally twice daily for days 1-28 in 28 day cycles.

Drug: Olaparib; Drug: Abiraterone Acetate; Drug: Prednisone

Olaparib

ACTIVE COMPARATOR

Olaparib 300 mg orally twice daily for days 1-28 in 28 day cycles.

Drug: Olaparib

Interventions

Olaparib DRUG

Also known as: Lynparza

Arm II: Olaparib; Arm III: Abiraterone + Prednisone + Olaparib; Olaparib

Abiraterone Acetate DRUG

Arm I: Abiraterone + Prednisone; Arm III: Abiraterone + Prednisone + Olaparib

Prednisone DRUG

Arm I: Abiraterone + Prednisone; Arm III: Abiraterone + Prednisone + Olaparib

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability to understand and the willingness to sign a written informed consent document that is approved by the local institutional review board and HIPAA authorization for the release of personal health information.
• Histological or cytological proof of prostate adenocarcinoma (Note: small-cell carcinoma of the prostate is not permitted)
• Documented progressive mCRPC based on at least one of the following criteria:
• PSA progression defined as 25% increase over baseline value with an increase in the absolute value of at least 2.0 ng/mL that is confirmed by another PSA level with a minimum of a 1 week interval and a minimum PSA of 2.0 ng/mL.
• Progression of bidimensionally measurable soft tissue or nodal metastasis assessed within one month prior to registration by a CT scan or MRI.
• Progression of bone disease (evaluable disease) (new bone lesion(s)) by bone scan.
• Agree to undergo a biopsy of at least one metastatic site (fresh biopsy of primary prostate only allowed if there is clear local disease and no other measurable disease site or biopsiable bone lesion.) to determine DNA repair defects. (Please refer to the Laboratory Manual for specific procedures). However:
• Adequate archival metastatic or primary disease tumor tissue can be used if available in lieu of a new biopsy. These patients will only be eligible for protocol therapy if the biopsy has tumor that is positive for DNA repair defects.
• Patients with known DNA damage repair defects based on prior appropriately validated metastatic or prostate tissue analysis may be used in lieu of new biopsy/analysis based on central site evaluation of quality of the biopsy and analysis.
• Patients with known germline DNA repair defects are eligible without a biopsy. However it will be highly desirable that they undergo a metastatic (or fresh prostate biopsy if there is clear local disease and no other measurable disease site or biopsiable bone lesion) disease biopsy to better define the scope of the DNA repair defects in the current disease context.
• ECOG status of 0-2 (Appendix A: Performance Status Criteria).
• Adequate organ function as defined below obtained within 14 days of registration:
• ANC \> or = 1500/µl Hemoglobin ≥ 10.0 g/dL WBC \> 3x10\^9/L Platelet count 100,000/µl Creatinine ≥51 mL/min estimated using the Cockcroft-Gault equation Potassium ≥ 3.5 mmol/L (within institutional normal range) Bilirubin within normal institutional limits (or \<2X the upper limit of normal (ULN) in those with Gilbert's disease) AST (SGOT) / ALT (SGPT) ≤ 1.5x institutional ULN unless liver metastases are present in which case it must be ≤ 5x ULN
• The effects of abiraterone, olaparib or the combination of both on the developing human fetus at the recommended therapeutic dose are unknown. Men must agree to use adequate contraception prior to study entry, for the duration of study participation and for at least 3 months thereafter.
• Patients must discontinue antiandrogen therapy (i.e., flutamide, bicalutamide, nilutamide) for at least 4 weeks prior to registration with no evidence of a falling PSA after washout.

You may not qualify if:

• Prior exposure to CYP17 (other than ketoconazole) or PARP inhibitors for prostate cancer. Patients with prior exposure to ketoconazole are eligible.
• Prior chemotherapy for castration resistant disease. Chemotherapy given in the hormone-sensitive setting is permissible if stopped at least 4 weeks prior to registration.
• Note: Patients can receive a stable dose of bisphosphonates for bone metastases, including zoledronic acid, or denosumab before and during the study as deemed appropriate by the treating physician.
• Prior exposure to enzalutamide, ARN-509 or other investigational AR-directed therapy in the setting of mCRPC.
• Patients with a currently active second malignancy excluding non-melanomatous skin cancer or superficial transitional cell carcinoma.
• Note: Patients are not considered to have a "currently active" malignancy if they have completed all therapy and are now considered without evidence of disease for 1 year.
• Patients receiving any other investigational agents. Any prior investigational agents must be stopped at least 14 days (2 week washout) prior to registration.
• Patients who have received itraconazole, ketoconazole, or fluconazole within 3 weeks prior to registration or those who have not recovered (i.e., back to baseline or Grade 1) from AEs due to agents administered more than 3 weeks earlier.
• Patients with a history of active seizures (or a single confirmed seizure event) in the last 2 years from the time of registration.
• Patients with a history of pituitary or adrenal dysfunction or active or symptomatic viral hepatitis or chronic liver disease are not eligible.
• Patients with active brain metastases. A scan to confirm the absence of brain metastases is not required for asymptomatic patients.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib or abiraterone.
• Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord compression (untreated or unstable within at least 28 days prior to registration), superior vena cava syndrome, and extensive bilateral lung disease on HRCT scan or any psychiatric disorder that prohibits obtaining informed consent.
• Patients with prolonged pre-existing hematological toxicities including known indicators of bone marrow failure or abnormality.
• Patients with myelodysplastic syndrome / acute myeloid leukemia.

Sponsors & Collaborators

• Northwestern University: lead
• AstraZeneca: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (18)

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

University of California Los Angeles

Los Angeles, California, 90073, United States

Location

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

Northwestern Medicine

Chicago, Illinois, 60611, United States

Location

Rush University Cancer Center

Chicago, Illinois, 60612, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Kellogg Cancer Center - NorthShore University

Evanston, Illinois, 60201, United States

Location

Indiana University/ Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

University of Michigan Health System

Ann Arbor, Michigan, 48109-5946, United States

Location

Karmanos Cancer Center

Detroit, Michigan, 48201, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08903, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27514, United States

Location

Huntsman Cancer Institute - University of Utah

Salt Lake City, Utah, 84112, United States

Location

University of Virginia

Charlottesville, Virginia, 22903, United States

Location

Related Publications (1)

• Collins K, Cheng L. Reprint of: morphologic spectrum of treatment-related changes in prostate tissue and prostate cancer: an updated review. Hum Pathol. 2023 Mar;133:92-101. doi: 10.1016/j.humpath.2023.02.007. Epub 2023 Mar 8.

  PMID: 36898948 DERIVED

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

olaparib; Abiraterone Acetate; Prednisone

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienediols; Pregnadienes; Pregnanes

Study Officials

• Maha Hussain, MD, FACP, FASCO

  Northwestern University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 3, 2017
• First Posted: January 6, 2017
• Study Start: January 12, 2017
• Primary Completion: October 21, 2023
• Study Completion (Estimated): January 16, 2027
• Last Updated: October 21, 2025

Record last verified: 2025-10

Locations

US (18)