Olaparib for the Treatment of Castration Resistant Prostate Adenocarcinoma

Inclusion Criteria:

* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
* Subject must be \>= 18 years of age at the time of signing the informed consent form
* Individuals who have documented histologically confirmed adenocarcinoma of the prostate
* Subject 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 2 ng/mL and rising on two successive measurements at least two weeks apart
* At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by computed tomography (CT) scan, magnetic resonance imaging (MRI), or positron emission tomography (PET) and is suitable for repeated assessment
* Must have progressed on abiraterone and/or a second-generation androgen receptor (AR) antagonist (i.e. enzalutamide, apalutamide, or darolutamide). If these were given in the hormone sensitive setting, patients must also have progressed on at least one prior approved therapy for CRPC
* Must have archival tissue available or be willing to undergo metastatic biopsy in order to perform next-generation deoxyribonucleic acid (DNA) sequencing and undergo whole exome sequencing
* Patient must have a positive LOH score on prior University of Washington (UW) OncoPlex testing
* 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 of \>= 51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test (within 28 days prior to administration of study treatment)
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
* Patients must have an estimated life expectancy \>= 16 weeks
* Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential

Exclusion Criteria:

* As judged by the investigator, any evidence of serious and/or unstable pre-existing medical or psychiatric condition which in the investigator's opinion makes it undesirable for the patient to participate in the trial
* Other malignancy unless curatively treated with no evidence of disease for \>= 5 years except: adequately treated non-melanoma skin cancer and non-muscle invasive bladder cancer
* Resting electrocardiography (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT interval by Fridericia's formula \[QTcF\] prolongation \> 500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome
* 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
* 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, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are not receiving active treatment or have a detectable viral load
* Patients with known active hepatitis (i.e. hepatitis B or C).

  * Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible
  * Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
* Any previous treatment with PARP inhibitor, including olaparib
* Any previous treatment with platinum chemotherapy in the metastatic castration-resistant setting
* 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 (eg. 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 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
* Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
* Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
* Patients with a known hypersensitivity to olaparib or any of the excipients of the product
* Involvement in the planning and/or conduct of the study
* Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements