Testosterone and Olaparib in Treating Patients With Castration-Resistant Prostate Cancer
Condition: Castration-Resistant Prostate Carcinoma; Prostate Adenocarcinoma
MeSH terms: Prostatic Neoplasms; Adenocarcinoma
Intervention: Laboratory Biomarker Analysis; Olaparib; Quality-of-Life Assessment; Survey Administration; Testosterone Enanthate; Testosterone Cypionate
Intervention description: Correlative studies; Given PO; Ancillary studies; Ancillary studies; Given IM; Given IM
Intervention MeSH terms: Methyltestosterone; Olaparib; Poly(ADP-ribose) Polymerase Inhibitors; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 36.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well testosterone (enanthate or cypionate) and olaparib work
      in treating patients with prostate cancer that has progressed despite hormonal therapy.
      Hormonal therapy, such as leuprolide, may lessen the amount of male sex hormones made by the
      body. In patients that have developed progressive cancer in spite of standard hormonal
      treatment (i.e. castration-resistant prostate cancer), administering testosterone may result
      in regression of tumors by causing DNA damage in cancer cells that have adapted to low
      testosterone conditions. Olaparib may stop the growth of tumor cells by blocking some of the
      enzymes involved in repairing DNA damage. Therefore, giving testosterone and olaparib
      together may work better in treating castration-resistant prostate cancer by generating DNA
      damage that the cancer cell is unable to repair.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Must be willing to provide informed consent prior to any study specific procedures

          -  Documented histologically confirmed adenocarcinoma of the prostate

          -  Patient must have evidence of castration resistant prostate cancer as evidenced by PSA
             progression (per Prostate Cancer Working Group 3 [PCWG3] criteria) and a castrate
             serum testosterone level (i.e., ≤ 50 mg/dL)

          -  PSA must be at least 1 ng/ml and rising on two successive measurements at least two
             weeks apart

          -  Patients must have progressed on abiraterone and/or enzalutamide; there must be at
             least a 3-week washout period after stopping the most recent approved therapy for
             mCRPC (i.e., abiraterone, enzalutamide, Ra-223, sipuleucel-t); if applicable, patients
             should be weaned off steroids at least 1 week prior to starting treatment

          -  No prior chemotherapy for the treatment of mCRPC; patients may have received docetaxel
             for the treatment of hormone-sensitive prostate cancer

          -  Prior treatment with non-chemotherapy investigational agents is permitted; there must
             be at least a 3-week washout period after stopping any investigational cancer agent

          -  Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days (within 28 days
             prior to administration of study treatment)

          -  Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (within 28 days prior to administration
             of study treatment)

          -  Platelet count ≥ 100 x 10^9/L (within 28 days prior to administration of study
             treatment)

          -  Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (within 28 days
             prior to administration of study treatment)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) ≤
             2.5 x institutional upper limit of normal unless liver metastases are present in which
             case they must be ≤ 5 x ULN (within 28 days prior to administration of study
             treatment)

          -  Patients must have creatinine clearance estimated using the Cockcroft-Gault equation
             or based on a 24 hour urine test of ≥ 51 mL/min (within 28 days prior to
             administration of study treatment)

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Patients must have a life expectancy ≥ 16 weeks

          -  Male patients and their partners, who are sexually active and of childbearing
             potential, must agree to the use of two highly effective forms of contraception in
             combination throughout the period of taking study treatment and for 3 months after
             last dose of study drug(s) to prevent pregnancy in a partner

          -  Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations

          -  At least one lesion (measurable and/or non-measurable) that can be accurately assessed
             at baseline by computed tomography (CT), positron-emission tomography (PET), magnetic
             resonance imaging (MRI) and/or bone scan and is suitable for repeated assessment

          -  Must have archival tissue available, be willing to undergo metastatic biopsy or have a
             sufficient plasma circulating tumor DNA (ctDNA) concentration in order to perform
             next-generation DNA sequencing

          -  The study will require that 50% of enrolled subjects have homozygous deletions,
             deleterious mutations, or both in one or more of the DNA damage response (DDR) genes;
             the other 50% of patients must have an intact DDR pathway

        Exclusion Criteria:

          -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
             staff and/or staff at the study site)

          -  Previous enrollment in this study

          -  Participation in another clinical study with an investigational product during the
             last 3 weeks

          -  Any previous treatment with poly-adenosine diphosphate ribose polymerase (PARP)
             inhibitor, including olaparib

          -  Other malignancy unless curatively treated with no evidence of disease for ≥ 5 years
             except: adequately treated non-melanoma skin cancer

          -  Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible
             cardiac conditions, as judged by the investigator (e.g. unstable ischemia,
             uncontrolled symptomatic arrhythmia, congestive heart failure, Fridericia's corrected
             QT interval [QTcF] prolongation > 500 ms, electrolyte disturbances, etc.), or patients
             with congenital long QT syndrome

          -  Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
             reasons) within 3 weeks prior to study treatment

          -  Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil); the required washout
             period prior to starting olaparib is 2 weeks

          -  Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin,
             rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's wort) or
             moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil); the required washout
             period prior to starting olaparib is 3 weeks for enzalutamide, 5 weeks for
             phenobarbital and 3 weeks for other agents

          -  Persistent toxicities (> Common Terminology Criteria for Adverse Event [CTCAE] grade
             2) caused by previous cancer therapy, excluding alopecia

          -  Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
             suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)

          -  Patients with symptomatic uncontrolled brain metastases; a scan to confirm the absence
             of brain metastases is not required; the patient can receive a stable dose of
             corticosteroids before and during the study as long as these were started at least 4
             weeks prior to treatment; patients with spinal cord compression unless considered to
             have received definitive treatment for this and evidence of clinically stable disease
             for 28 days

          -  Major surgery within 2 weeks of starting study treatment and patients must have
             recovered from any effects of any 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, history of prior
             myocardial infarction, uncontrolled major seizure disorder, uncontrolled hypertension
             (blood pressure [BP] ≥ 160/100), history of prior stroke, uncontrolled diabetes
             (glycosylated hemoglobin [hgb A1C] > 7), 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, e.g., 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 a known hypersensitivity to the testosterone cypionate 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)

          -  Evidence of serious and/or unstable pre-existing medical, psychiatric or other
             condition (including laboratory abnormalities) that could interfere with patient
             safety or provision of informed consent to participate in this study

          -  Any psychological, familial, sociological, or geographical condition that could
             potentially interfere with compliance with the study protocol and follow-up schedule

          -  Evidence of disease that, in the opinion of the investigator, would put the patient at
             risk from testosterone therapy (e.g. femoral metastases with concern over fracture
             risk, spinal metastases with concern over spinal cord compression, lymph node disease
             with concern for ureteral obstruction)

          -  Patients with pain attributable to their prostate cancer

          -  Tumor causing urinary outlet obstruction that requires catheterization for voiding;
             patients that require catheterization to void secondary to benign strictures or other
             non-cancer causes will be permitted to enroll

          -  Prior history of deep venous thrombosis or pulmonary embolism within 5 years prior to
             enrollment in the study and not currently on systemic anticoagulation

          -  Patients with NYHA (New York Heart Association) class III or IV heart failure or
             history of a prior myocardial infarction (MI) prior to enrollment in the study