Testing Olaparib in Patients With Advanced or Metastatic (Cancer That Has Spread) Bladder Cancer and Other Genitourinary Tumors With DNA-Repair Genetic Changes

Inclusion Criteria:

• Patients must have a histologically confirmed diagnosis non-prostate GU cancer

• Patients with the presence of cancer-associated genetic mutations in one or morepathogenic or likely pathogenic gene alterations tested in the FoundationOneFoundationOne®CDx (F1CDx) panel will be enrolled in cohorts 1 or 2 as follows:

• Cohort 1: BRCA1, BRCA2, ATM, BAP1, PALB2, and BRIP1, or tumor mutational burden (TMB) where 10 or greater mutations/megabase

• ABL1, FANCE, POLD1, ATR, FANCG, POLE, ATRX, FANCL, RAD51, BARD1, IKBKE,SMARCB1, BRD4, MEN1, STK11, CCND1, MLH1, TP53, CHEK1, MSH2, CHEK2, MSH6, DOT1L,MUTYH, FANCA, NPM1, FANCC, PMS2

• Patients with benign or variants of unknown significance as determined byFoundationOne FoundationOne®CDx (F1CDx) panel and Genetics Review Panel review willbe enrolled in Cohort 3 to be followed for survival

• Foundation One mutation analysis results performed prior to enrollment on this studymay be accepted for eligibility review and in the event that a patient cannotundergo a biopsy and tumor is not available, Foundation Medicine liquid biopsy maybe performed

• Patients must have measurable disease, defined as at least one lesion that can beaccurately measured in at least one dimension (longest diameter to be recorded fornon-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chestx-ray or as >= 10 mm (>= 1 cm) with CT scan, MRI, or calipers by clinical exam

• Evidence of disease progression as defined by Response Evaluation Criteria in SolidTumors (RECIST) (version 1.1) during treatment or after the most recent dose oftherapy with at least one platinum-based regimen of chemotherapy and/or animmune-checkpoint inhibitor (atezolizumab, pembrolizumab, nivolumab, avelumab ordurvalumab) (2-week washout from chemotherapy and 4-weeks washout from monoclonalantibodies is required)

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of olaparib in patients < 18 years of age, children are excluded from thisstudy, but will be eligible for future pediatric trials

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (or Karnofsky >= 70%)

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin =< 1.5 x upper limit of normal (ULN) (for subjects with documentedGilbert's disease total bilirubin =< 3.0 mg/dL)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (for subjects with livermetastasis AST/ALT =< 5 x ULN)

• Creatinine clearance >= 50 mL/min/1.73 m^2

• Hemoglobin >= 9 g/dL; transfusions are allowed

• Prothrombin time (PT)/international normalized ratio (INR) and activated partialthromboplastin time (aPTT) within 1.25 x ULN institutional limits, except where alupus anti-coagulant has been confirmed or the patient is on direct oralanticoagulant (DOA)

• Patients must be able to tolerate oral medications and not have gastrointestinalillnesses that would preclude absorption of olaparib

• Pre-clinical data indicate that olaparib adversely affects embryofetal survival anddevelopment. Therefore, women of child-bearing potential and their partners shouldagree to use two (2) highly effective forms of contraception throughout studyparticipation and for at least six (6) months after the last dose of olaparib. Malestudy participants should avoid fathering a child or donating sperm during the studyand for three (3) months after the last dose of olaparib.

• Note: Olaparib is a PARP inhibitor with the potential for teratogenic orabortifacient effects. Because there is a potential risk for adverse events innursing infants secondary to treatment of the mother with olaparib,breastfeeding should be discontinued if the mother is treated with olaparib

• Ability to understand and the willingness to sign a written informed consentdocument or patients with impaired decision making capacity (IDMC) if they arerepresented by a legally authorized representative (LAR)

• Patients must provide archival tumor sample for mutation analysis or be willing toundergo mandatory screening biopsy. In the event that the patient cannot undergobiopsy and tumor is not available, Foundation Medicine liquid biopsy will beperformed

• Postmenopausal or evidence of non-childbearing status for women of childbearingpotential: negative urine or serum pregnancy test within 28 days of study treatmentat screening. Note: This will also need to be confirmed within 3 days prior totreatment on day 1. Postmenopausal is defined as at least one (1) of the following:

• Amenorrheic for 1 year or more following cessation of exogenous hormonaltreatments

• Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in thepost menopausal range for women under 50

• Radiation-induced oophorectomy with last menses > 1 year ago

• Chemotherapy-induced menopause with > 1 year interval since last menses

• Surgical sterilization (bilateral oophorectomy or hysterectomy)

• Patients is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations

Exclusion Criteria:

• Patients who have had prior treatment with olaparib or any other PARP inhibitor (PARPi)

• Patients with myelodysplastic syndrome/acute myeloid leukemia; or baseline featuressuggestive of myelodysplastic syndrome or acute myelogenous leukemia on peripheralblood smear or bone marrow biopsy, if clinically indicated

• Persistent toxicities (>= Common Terminology Criteria for Adverse Events [CTCAE]grade 2) with the exception of alopecia or peripheral neuropathy, caused by previouscancer therapy

• Patients who are receiving any other investigational agents. Patients may be onother clinical trials or treatment during screening to determine eligibility

• Patients with known brain metastases should be excluded from this clinical trialbecause of their poor prognosis and because they often develop progressiveneurologic dysfunction that would confound the evaluation of neurologic and otheradverse events. A scan to confirm the absence of brain metastases is not required.Patients with spinal cord compression unless considered to have received definitivetreatment for this and evidence of clinically stable disease for 28 days

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition of olaparib

• Patients receiving strong or moderate CYP3A inhibitors or inducers are ineligible. Awashout period prior to the first dose of olaparib for patients on CYP3Ainhibitors/inducers is 5 half-lives or 3 weeks , whichever is shorter. Medicationswith limited systemic absorption (e.g., ophthalmic, otic) do not require a washoutand are permitted.

• Because the lists of these agents are constantly changing, it is important toregularly consult a frequently-updated medical reference texts such as thePhysicians' Desk Reference. As part of the enrollment/informed consentprocedures, the patient will be counseled on the risk of interactions withother agents, and what to do if new medications need to be prescribed or if thepatient is considering a new over-the-counter medicine or herbal product

• Pregnant women are excluded from this study because olaparib is a PARP inhibitoragent with the potential for teratogenic or abortifacient effects

• Any chronic or concurrent acute liver disease

• History of stroke, transient ischemic attack (TIA), or myocardial infarction, within 6 months prior to enrollment

• Uncontrolled concurrent disease or illness including but not limited to:

• Ongoing or active infection

• Symptomatic congestive heart failure, unstable angina pectoris, clinicallysignificant cardiac arrhythmia

• Unstable or untreated cardiac conditions or ejection fraction of < 50% asdetermined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)

• Uncontrolled diabetes mellitus

• Psychiatric illness/social situations that would limit compliance with studyrequirements

• Other severe, acute, or chronic medical or psychiatric condition or laboratoryabnormality that may increase the risk associated with study participation or studydrug administration or that may interfere with the interpretation of study resultsand, in the judgment of the investigator, would make the patient inappropriate forthe study

• Immunocompromised patients, e.g., those with known HIV not on highly activeantiretroviral therapy (HAART) with detectable levels of virus

• Patients with known active hepatitis (i.e., hepatitis B or C)

• Other malignancy within the last two (2) years except: adequately treatednon-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductalcarcinoma in situ (DCIS), stage 1, grade 1 endometrial carcinoma, or other solidtumors including lymphomas (without bone marrow involvement) curatively treated withno evidence of disease for >= 5 years. Patients with a history of localized triplenegative breast cancer or localized resected prostate cancer may be eligible,provided they completed their adjuvant chemotherapy more than two (2) years prior toregistration, and that the patient remains free of recurrent or metastatic disease

• Patients receiving any systemic chemotherapy or radiotherapy (except for palliativereasons) within 2 weeks prior to study treatment

• Major surgery within 2 weeks of starting study treatment and patients must haverecovered from any effects of any major surgery

• Previous allogenic bone marrow transplant or double umbilical cord bloodtransplantation (dUCBT)