sEphB4-HSA in Treating Patients With Metastatic Castration-Resistant Prostate Cancer

Inclusion Criteria:

* Patients must have a pathologically confirmed diagnosis of prostate adenocarcinoma
* Patients must have metastatic (M1) disease as evidenced by soft tissue and/or bony metastases on computed tomography (CT) or magnetic resonance imaging (MRI) scan or technetium bone scan
* Patients must have castration resistant disease with disease progression despite castrate levels of testosterone (testosterone =\< 50 ng/dL)
* Patients must have received and progressed on at least one second generation androgen receptor (AR) targeted therapy for castration resistant disease irrespective of prior chemotherapy. No more than 3 prior treatment therapies for castration resistant disease (life prolonging) are permitted. Prior therapy can include:

  * Second generation AR targeted therapy (i.e. abiraterone, enzalutamide, or other new antiandrogen \[ODM-201, apalutamide\])
  * Chemotherapy (docetaxel and/or cabazitaxel)
* Documented progressive mCRPC based on at least one of the following criteria:

  * PSA progression defined as 25% increase over baseline value with an increase in the absolute value of at least 2.0 ng/mL that is confirmed by another PSA level with a minimum of a 1 week interval and a minimum PSA of 2.0 ng/mL
  * Progression of bi-dimensionally measurable soft tissue or nodal metastasis assessed within one month prior to registration by a CT scan or MRI
  * Progression of bone disease (evaluable disease) (new bone lesion\[s\]) by bone scan
* Serum testosterone \< 50 ng/dL. Patients must continue primary androgen deprivation therapy (ADT) with a luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist) if they have not undergone orchiectomy
* Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Patients must have adequate organ and bone marrow function as defined below within 28 days of registration:
* Absolute neutrophil count \>= 1,000/mcL (within 28 days of registration)
* Hemoglobin \>= 9 g/dL\* (within 28 days of registration)

  * Transfusion is allowed as long as patients have not received prior transfusion =\< 28 days from registration
* Bilirubin =\< 1.5 x institutional upper limit of normal (ULN) except for unconjugated hyperbilirubinemia or Gilbert?s syndrome, who can have total bilirubin \< 3.0 mg/dL (within 28 days of registration)
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 3 x ULN (=\< 5 x ULN if liver metastases present) (within 28 days of registration)
* Serum creatinine =\< 2.0 X ULN (upper limit of normal) or creatinine clearance \>= 30 mL/minute (using Cockcroft/Gault formula) (within 28 days of registration)
* Platelet \>= 100,000 (within 28 days of registration)
* Patients must use a condom during treatment and for 3 months after the last dose of study treatment when having sexual intercourse. Female partners of male subjects should also use a highly effective form of contraception if they are of childbearing potential. Subjects should not donate sperm throughout the study and for 3 months following the last dose of treatment
* Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study

Exclusion Criteria:

* Patients who have received more than 3 prior treatment therapies (life prolonging) for mCRPC are not eligible
* Patients who have had radiotherapy =\< 14 days prior to entering the study are not eligible

  * Note: Palliative radiation therapy is allowed
* Patients who have had systemic therapy for prostate cancer =\< 21 days or 5-half lives (whichever is shorter) are not eligible

  * Note: Patients can receive a stable dose of bisphosphonates for bone metastases, including zoledronic acid, or denosumab before and during the study as deemed appropriate by the treating physician. Patients must continue androgen deprivation therapy
* Patients receiving any other investigational agents are not eligible
* Patients with small cell carcinoma of the prostate are not eligible

  * Note: Neuroendocrine differentiation is permitted. If there is doubt about this and it is clinically indicated then a biopsy should be obtained to document histological differentiation
* Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to sEphB4-HSA are not eligible. AND patients who have had prior exposure to compounds of similar chemical or biologic composition to sEphB4-HSA are not eligible
* Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible:

  * Ongoing or active infection requiring systemic treatment
  * Symptomatic congestive heart failure (New York Heart Association class III or IV congestive heart failure)
  * Unstable angina pectoris
  * Serious cardiac arrhythmia
* Patients with uncontrolled hypertension (defined as systolic blood pressure \[BP\] \>= 160 mmHg or diastolic BP \>= 95 mmHg) are not eligible

  * Note: Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
* Patients with electrocardiogram (ECG) with QT interval (corrected QT interval \[QTc\]) \> 480 msec are not eligible
* Patients with other malignancy that has progressed or has required active systemic treatment in the last 3 years

  * Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or carcinoma in situ or non-muscle invasive bladder cancer are not excluded
* Patients with known active central nervous system (CNS) metastases and/or carcinomatous meningitis are not eligible

  * Note: A scan to confirm the absence of brain metastases is not required. Subjects with previously treated brain metastases may participate provided they are stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), without requirement of steroid treatment for at least 4 weeks prior to randomization and with any neurologic symptoms resolved or have returned to baseline of prior treatment for brain metastasis
* Patients with spinal cord compression are not eligible unless considered to have received definitive treatment for this and evidence of stable disease for 28 days
* Patients who underwent major surgery =\< 14 days of starting study treatment or have not recovered from effects of surgery are not eligible