Combining CRLX101, a Nanoparticle Camptothecin, With Enzalutamide in People With Progressive Metastatic Castration Resistant Prostate Cancer Following Prior Enzalutamide Treatment

* INCLUSION CRITERIA: * Patients must have histologically or cytologically confirmed prostate cancer confirmed by either the Laboratory of Pathology at the national Institutes of Health (NIH) Clinical Center or Walter Reed National Military Medical Center at Bethesda prior to starting this study. If no pathological specimen is available, patients may enroll with a pathologist's report showing a histological diagnosis of prostate cancer and clinical course consistent with the disease. * Patients must have progressive metastatic castration-resistant prostate cancer mCRPC. There must be radiographic evidence of disease progression or biochemically (rising prostate-specific antigen (PSA) levels on successive measurements) recurring disease despite adequate testosterone suppression. * Progression must be evidenced and documented by any of the following parameters: * PSA progression defined by a minimum of two rising PSA levels with an interval of greater than or equal to 1 week between each determination * Appearance of one or more new lesions consistent with prostate cancer on bone scan * New or growing lesions on computed tomography (CT) scan * Patients must have metastatic disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1(64). * Patients must have received treatment with prior enzalutamide for two or more cycles and must have had evidence of disease progression while on enzalutamide. * Patients who have received antiandrogens such as flutamide, bicalutamide, or nilutamide for \>6 months immediately before enrollment on this study must be off treatment for 4 weeks (6 weeks for bicalutamide) and demonstrate a continued rise in PSA. Patients on antiandrogens for \<6 months must be off medication for 2 weeks. * Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of enzalutamide and CRLX101 in patients \<18 years of age and prostate cancer is not common in children \<18 years of age, children are excluded from this study. * Patients must have adequate organ and marrow function as defined below: * leukocytes greater than or equal to 3,000/mcL * absolute neutrophil count greater than or equal to 1,500/mcL * platelets greater than or equal to 100,000/mcL * total bilirubin within normal institutional limits; for patients with Gilberts syndrome, total bilirubin less than or equal to 3.0 mg/dL * hemoglobin greater than or equal to 9g/dL * serum albumin greater than or equal to 2.8 g/dL * Aspartate aminotransferase (AST) Serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT)Serum glutamic-pyruvic transaminase (SGPT) less than or equal to 2.5 times institutional upper limit of normal (\<5 times institutional ULN for liver metastases) * creatinine within 1.5 times normal institutional limits OR --creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal. * Patients must have castrate levels of testosterone (\<50 ng/dL \[1.74 nmol/L\]). * Patients must have undergone bilateral surgical castration or must continue on gonadotropin-releasing hormone (GnRH) agonists/antagonists for the duration of the study. * Patients on 5-alpha reductase inhibitors such as finasteride or dutasteride must stop medication at least 28 days prior to study entry. * The effects of enzalutamide and CRLX101 (formerly IT-101) on the developing human fetus are unknown. For this reason and because androgen receptor antagonists and topoisomerase I inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, all study subjects must agree to use a condom during the study treatment period and for 120 days following the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately. * Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky greater than or equal to 60%). * Ability of subject to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: * Patients who are receiving any other investigational agents. A minimum washout period of 28 days is required prior to the initiation of on study treatment unless the patient is receiving immunotherapy, for which the minimum washout period will be 14 days. This is because Immune-related toxicities are distinct and unlikely to synergize with this protocol therapy, a shorter washout period is reasonable and customary in clinical trials. * Patients who have been treated with prior secondary hormonal manipulations with proposed investigational rationale for having efficacy against androgen receptor variant 7 (AR-V7) splice variants. This includes but is not limited to Ralaniten (EPI-002) and AZD5312 (IONIS-AR-2.5Rx). (Note: patients previously treated with abiraterone, orteronel (TAK-700), apalutamide (ARN-509), galeterone, or VT-464 (formerly INO-464) will be eligible for this study. Patients who have received prior chemotherapy will also be eligible for this study). * Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. * Patients with a recent (within 1 year) history of seizure or any condition that, in the opinion of the investigator, significantly increases seizure risk. Also, current or prior treatment with anti-epileptic medications for the treatment of seizures. Transient ischemic attack within 12 months prior to study enrollment will not be permitted. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to enzalutamide, CRLX101, or other agents used in study. * Patients with a history within the last 3 years of another invasive malignancy (localized non-melanoma skin and bladder cancers are allowed). * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension (systolic blood pressure (SBP)\>170/diastolic blood pressure (DBP)\>105), or psychiatric illness/social situations within 6 months that would limit compliance with study requirements. * Patients who have received palliative radiotherapy within 2 weeks of study entry and have not recovered to Grade 1 or baseline from associated toxicities. Note: Patients may receive palliative radiation once enrolled on study. The subject has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) less than or equal to Grade 1 from toxicity due to all prior therapies, including surgery, except alopecia and other non-clinically significant adverse events (AEs). * Patients who are unable to swallow tablets or have a gastrointestinal disease that could hinder the absorption of enzalutamide * The use of any herbal products that may lower prostate-specific antigen (PSA) levels (e.g., saw palmetto). * Patients with microscopic hematuria (defined as \>100 red blood cells (RBCs) on urinalysis) or worsening urinary symptoms within 7 days prior to the initiation of study treatment. * Known human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy are ineligible because of potential pharmacokinetic interactions with study drugs. However, patients with long-standing (\>5 years) HIV on antiretroviral therapy \>1 month (undetectable HIV viral load and cluster of differentiation 4 (CD4) count \> 150 cells/micro L) may be eligible if the Principal Investigator or designee determines no anticipated clinically significant drug-drug interactions. INCLUSION OF MINORITIES AND WOMEN: -Men of all races and ethnic groups are eligible for this trial. Women are excluded as prostate cancer does not exist in this population.