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Clinical Trial 19137

Cancer Type: Genitourinary
Study Type: Treatment
NCT#: NCT03012321

Phase: Phase II
Principal Investigator: Zhang, Jingsong

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Study Title

A Randomized Phase II Trial of Abiraterone, Olaparib, or Abiraterone + Olaparib in Patients with Metastatic Castration-Resistant Prostate Cancer with DNA Repair Defects


The purpose of this research is to study two U.S. Food and Drug Administration (FDA) approved drugs alone and in combination with each other in people who have mCRPC and DNA repair defects.


Primary Objective: 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. Secondary Objectives: To evaluate: - Measurable disease response rate by RECIST. - Whether noncanonical DNA repair defects in FANCA, PALB2, RAD51, ERCC3, MRE11, NBN, MLH3, CDK12, CHEK2, HDAC2, ATR, PMS2, GEN1, MSH2, MSH6, BRIP1, or FAM175A have clinical susceptibility to PARP inhibition alone. - The safety of the combination of abiraterone/prednisone and olaparib combination therapy. - The response rate and PFS with cross over to olaparib or abiraterone post progression on therapy with abiraterone or olaparib respectively. - The qualitative and quantitative toxicities. Correlative Objectives: - CTC number, morphology and possible DNA, RNA analyses will assess for heterogeneity, mutational load, DNA repair defects, and expression of key prostate cancer-related genes for potential use as biomarkers of response or failure and also as a potential surrogate for the metastatic biopsy. - ctDNA will be assessed for mutational load as a biomarker of response or failure and also as a means to identify DNA repair defects for use as a potential surrogate for the metastatic biopsy. - Correlation of mutational data, copy number alterations, and transcriptome profiling between liquid assays and tissue-based analyses. - Within the above data sets and also the sequencing of the metastatic biopsy, the predictive and prognostic role of AR mutations, amplifications, splice variants, expression regulation, and other androgen signaling pathway modulation. - IHC or other genetic/proteomic/methylomic analyses in the future may be pursued as excess samples will be banked.



Hormonal Therapy; Therapy (NOS)


Abiraterone acetate (); Olaparib (Lynparza); Zytiga (Abiraterone acetate); prednisone ()

Inclusion Criteria

  • 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.
  • Agree to undergo a biopsy of at least one metastatic site to determine DNA repair defects. However: 1.) 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. 2.) 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. 3.) 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 biopsy if there is clear local disease and no other metastatic (disease site or biopsiable bone lesion) disease biopsy to better define the scope of the DNA repair defects in the current disease context. 4.) Patients with known DNA damage repair defects based on priorstandard of care CLIA-certified cfDNA assays in lieu of new biopsy/analysis. Note: Eligibility by cfDNA will be reviewed on a case-by-case basis by the Sponsor-Investigator.
  • ECOG status of 0-2.
  • Adequate organ function within 14 days of registration.
  • Men must agree to use adequate contraception prior to study entry, for the duration of study participation and for at least 3 months thereafter.
  • Participants 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.
  • Serum testosterone > Able to take oral medication without crushing, dissolving or chewing tablets.
  • Must have a life expectancy ≥ 6 months.
  • May have received prior radiation therapy or surgery. However, at least 14 days must have elapsed since completion of radiation therapy or surgery and patient must have recovered from all side effects at the time of registration (e.g. back to baseline or grade 1) .
  • Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

  • Exclusion Criteria

  • Prior exposure to CYP-17 (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. 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.
  • A currently active second malignancy excluding non-melanomatous skin cancer or superficial transitional cell carcinoma. Not considered to have a "currently active" malignancy if have completed all therapy and now considered without evidence of disease for 1 year.
  • Receiving any other investigational agents. Any prior investigational agents must be stopped at least 14 days (2 week washout) prior to registration.
  • Have received itraconazole, ketoconazole, or fluconazole within 3 weeks prior to registration or those who have not recovered from AEs due to agents administered more than 3 weeks earlier.
  • History of active seizures (or a single confirmed seizure event) in the last 2 years from the time of registration.
  • History of pituitary or adrenal dysfunction or active or symptomatic viral hepatitis or chronic liver diseas.
  • Active brain metastases.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib or abiraterone.
  • Considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.
  • Prolonged pre-existing hematological toxicities including known indicators of bone marrow failure or abnormality.
  • Myelodysplastic syndrome / acute myeloid leukemia.
  • May continue on a daily Multi-Vitamin, calcium and Vitamin D, but all other herbal, alternative and food supplements must be stopped before registration. Hormonal-acting agents such as DES are forbidden during the trial and must be stopped prior to registration. No washout period required. Patients on megesterol acetate for hot flashes are allowed to continue therapy.
  • Must stop taking ritonavir, idinavir, saquinavir, telithromycin, clarithromycin and nelfinavir 1 week prior to registration. Note: topical ketoconazole is permitted.
  • Must stop taking phenytoin, rifampicin, rifapentine, rifabutin, carbamazepine, nevirapine, modafinil and St John's Wort 3 weeks prior to registration.
  • Must stop taking phenobarbitone 5 weeks prior to registration.
  • Must stop taking all strong CYP3A4 inhibitors, including clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, prior to registration.
  • Planned concurrent cytotoxic chemotherapy, surgery or radiation therapy during protocol treatment.
  • Use of prohibited concomitant medications within 7 days of registration.
  • HIV-positive on combination antiretroviral therapy.
  • Known active Hepatitis B or Hepatitis C.
  • Baseline moderate to severe hepatic impairment.
  • Persistent toxicities, with exception of alopecia, caused by previous cancer therapy.
  • Resting ECG with QTc > 470msec on 2 or more time points within a 24 hour period or of long QT syndrome.
  • Symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris
  • Blood transfusion within 30 days of registration.
  • Previous allogeneic bone marrow transplant.
  • Major surgery within 14 days of registration and must have recovered from any effects of any major surgery.

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