BrUOG 337: Olaparib Prior to Radical Prostatectomy For Advanced Prostate Cancer Defects in DNA Repair Genes
Condition: Prostate Cancer; Adenocarcinoma of the Prostate
MeSH terms: Prostatic Neoplasms
Intervention: Olaparib Pill; Prostatectomy
Intervention description: 300 mg BID; 22-42 days post Olaparib patients will undergo surgery
Intervention MeSH terms: Olaparib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: High risk; Defects; prostate

Summary:

      This study will evaluate approximately 3 months of treatment with the drug olaparib in
      patients with prostate cancer. A capsule formulation of olaparib (tradename Lynparza™) is
      approved by the United States Food and Drug Administration (FDA) for the treatment of women
      with advanced BRCA-mutated ovarian cancer. Olaparib is an investigational drug in prostate
      cancer. A tablet formulation of olaparib is being tested in this study. It is a new
      formulation which is more convenient for patients than the approved capsule formulation
      because fewer tablets of olaparib need to be taken daily than with capsules.

      The purpose of the study is to evaluate whether olaparib can reduce prostate cancer with
      defects in DNA repair genes when olaparib is given for approximately 3 months before surgery.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Biopsy confirmed adenocarcinoma of the prostate.

          -  High risk for recurrence after prostatectomy including any of the following

               -  Lymph node involvement by radiographic criteria

               -  T3 or T4 disease by radiographic criteria

               -  T2 disease and either PSA > 20 or Gleason 8,9 or 10

          -  Defects in any of the following genes:BRCA1, BRCA 2, ATM, CHEK1, CHEK2, FANCONIS
             ANEMIA (FANCL), HDAC2, PALB2, BARD1, BRIP1, CDK12, PPP2R2A, RAD51B, RAD51C, RAD51D, or
             RAD54L as assessed by Foundation Medicine FoundationOne assay on tumor tissue or
             cell-free DNA from peripheral blood via the FoundationACT assay.

          -  No distant visceral metastases.

          -  No prior chemotherapy or radiation for prostate cancer or PARP inhibitor. Prior and
             current hormone therapy (< 6 months from start date on study) for prostate cancer is
             allowed. Patients are allowed to remain on hormone therapy on study.

          -  ECOG performance status 0-1.

          -  Age>18.

          -  Required entry laboratory parameters

               -  ANC≥ 1,500 cells/mm3;

               -  Hemoglobin > 10.0g/dL with no blood transfusion in the last 14 days

               -  Platelet count ≥100 x 109/L,

               -  Total bilirubin ≤ 1.5 x ULN,

               -  AST and ALT ≤ 2.5 x ULN

               -  Patients must have creatinine clearance estimated using the Cockcroft-Gault
                  equation of ≥51 mL/min

          -  Life expectancy of at least 1 year as documented by treating physician.

          -  All Men must be willing to consent to using two highly effective contraception while
             on treatment and for at least 4 months (120 days) after last treatment on study

          -  Signed study-specific consent form prior to study entry.

          -  Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations- to be documented
             and submitted to BrUOG.

          -  Formalin fixed, paraffin embedded (FFPE) tumor sample from the primary cancer must be
             available for central testing coordinated by Rhode Island Hospital pathology. If there
             is not written confirmation of the availability of an archived tumor sample prior to
             enrollment the patient is not eligible for the study. Submit this written
             certification to BrUOG

          -  Patient agreed to not receiving any live virus and live bacterial vaccines while
             receiving study medication and during the 30 day follow up period. Patient should be
             made aware of this and it should be documented to BrUOG.

          -  Patient agreed to not consume grapefruit juice while on study treatment. Submit
             documentation patient was instructed and agreed.

        Exclusion Criteria:

          -  Participation in another clinical study with an investigational anticancer product
             during the last 2 months (from day 1 of treatment on this trial). This pertains to
             treatment no trials the patient may only be seen in follow-up.

          -  Any previous treatment with PARP inhibitor for this or another cancer, 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)
             which was curatively treated with no evidence of disease for ≥5 years. Diagnosis date
             and treatment confirmation required to be sent to BrUOG. Certification from treating
             physician that patient is disease free is required.

          -  Resting ECG with QTc > 470 msec on 2 time-points within a 24 hour period or known
             family history of long QT syndrome

          -  Patients receiving any systemic chemotherapy or radiotherapy within 3 weeks prior to
             study treatment

          -  Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
             period prior to starting olaparib is 2 weeks.

          -  Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,
             rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ) or
             moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout
             period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3
             weeks for other agents.

          -  Concomitant use of the substrates of CYP3A4, CYP1A2, 2B6, 2C9, 2C19 and P-gp should be
             cautioned while on study.

        CYP3A4 - hormonal contraceptive, simvastatin, cisapride, cyclosporine, ergot alkaloids,
        fentanyl, pimozide, sirolimus, tacrolimus and quetiapine CYP1A2 - duloxetine, melatonin
        CYP2B6 - bupropion, efavirenz CYP2C9 - warfarin CYP2C19 - lansoprazole, omeprazole,
        S-mephenytoin P-gp - simvastatin, pravastatin, digoxin, dabigatran, colchicine OATP1B1 -
        bosentan, glibenclamide, repaglinide, statins and valsartan OCT1, MATE1, MATE2K - metformin
        OCT2 - serum creatinine OAT3 -furosemide, methotrexate

          -  Persistent toxicities deemed related to previous cancer therapy, excluding alopecia.

          -  Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
             suggestive of MDS/AML.

          -  Patients with brain metastases.

          -  Major surgery within 2 weeks of starting study treatment and patients must have
             recovered from any effects of any prior 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 3
             months) myocardial infarction, uncontrolled major seizure disorder, 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 that according to treating investigator would increase
             their risk to protocol treatment, or 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 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 as long as not within 28 days
             from study registration).

          -  Major medical or psychiatric illness which, in the investigator's opinion, would
             prevent completion of treatment and would interfere with follow-up.