Selinexor in Treating Patients With Abiraterone Acetate and/or Enzalutamide Refractory Metastatic Castration-Resistant Prostate Cancer

Inclusion Criteria:

* Histologically confirmed adenocarcinoma of the prostate
* Patients must have castrate levels of testosterone (\< 50 ng/dL) on gonadotropin-releasing hormone (GnRH) analogues or have had prior orchiectomy; GnRH analogues must be continued while on study
* Tumor tissue submitted for molecular and genetic analysis through the companion Stand-up 2 Cancer (SU2C) radiologically guided biopsy of abiraterone and/or enzalutamide refractory mCRPC protocol

  * Patients who consent to participate in the companion biopsy protocol and are subsequently determined to be ineligible for biopsy are eligible to participate in the current protocol
* Progressive disease as demonstrated by a rising PSA (at least two determinations) prior to study entry, and/or radiographic evidence of tumor progression in soft tissue according to modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria or identification of new lesions by bone scan (i.e., \>= 2 new lesions)
* Primary resistance or acquired resistance (i.e., acquired resistance will be defined as disease progression following a period of response defined as \>= 50% decline in PSA within 12 weeks of starting therapy and not otherwise meeting criteria for primary resistance) to any of the following agents/combinations of therapy:
* Abiraterone acetate; primary resistance to abiraterone will be defined as:

  * No PSA decline
  * PSA decline less than 50% after 12 weeks of abiraterone therapy
  * PSA progression within 12 weeks of abiraterone acetate (AA) treatment (by Prostate Cancer Working Group-2 \[PCWG2\] criteria), after initial response to therapy
  * Objective progression, by RECIST criteria for soft tissue lesions and by modified PCWG2 criteria for bone lesions within 12 weeks of starting abiraterone treatment
  * Unequivocal clinical progression (per the treating provider's discretion) within 12 weeks of starting abiraterone treatment
* Enzalutamide; primary resistance to enzalutamide will be defined as:

  * No PSA decline
  * PSA decline less than 50% after 12 weeks of enzalutamide therapy
  * PSA progression within 12 weeks of enzalutamide treatment (by PCWG2 criteria), after initial response to therapy
  * Objective progression, by RECIST criteria for soft tissue lesions and by modified PCWG2 criteria for bone lesions within 12 weeks of starting enzalutamide treatment
  * Unequivocal clinical progression (per the treating provider's discretion) within 12 weeks of starting enzalutamide treatment
* Other second-generation investigational anti-androgen/androgen-receptor targeted therapies, including apalutamide (ARN-509); primary resistance will be defined as:

  * No PSA decline
  * PSA decline less than 50% after 12 weeks of enzalutamide therapy
  * PSA progression within 12 weeks of enzalutamide treatment (by PCWG2 criteria), after initial response to therapy
  * Objective progression, by RECIST criteria for soft tissue lesions and by modified PCWG2 criteria for bone lesions within 12 weeks of starting enzalutamide treatment
  * Unequivocal clinical progression (per the treating provider's discretion) within 12 weeks of starting enzalutamide treatment
* Combination therapy with abiraterone, enzalutamide and/or other second- generation investigational anti-androgen/androgen-receptor targeted therapies, including ARN-509; primary resistance to combination therapy will be defined as:

  * No PSA decline
  * PSA decline less than 50% after 12 weeks of abiraterone and enzalutamide therapy
  * PSA progression within 12 weeks of abiraterone and enzalutamide treatment (by PCWG2 criteria), after initial response to therapy
  * Objective progression, by RECIST criteria for soft tissue lesions and by modified PCWG2 criteria for bone lesions within 12 weeks of starting abiraterone and enzalutamide treatment
  * Unequivocal clinical progression (per the treating provider?s discretion) within 12 weeks of starting abiraterone and enzalutamide treatment
* Sequenced therapy, including any of the following:

  * Abiraterone acetate followed by enzalutamide

    * Primary resistance will be defined per criteria for abiraterone monotherapy primary resistance
  * Enzalutamide followed by abiraterone acetate

    * Primary resistance will be defined per criteria for enzalutamide monotherapy primary resistance
  * Other second-generation investigational anti-androgen/androgen- receptor targeted therapies, including ARN-509

    * Primary resistance will be defined per criteria for other investigational anti-androgen monotherapy primary resistance
* Presence of 1 or more bone metastasis
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* Prior and ongoing zoledronic acid or denosumab therapy is allowed
* Prior therapy with radium-223 is allowed
* Discontinuation of prior therapy for mCRPC: a washout period of 28 days for the following therapies is required: abiraterone, enzalutamide, fluconazole, itraconazole, flutamide, bicalutamide, nilutamide, and other experimental hormonal agents (ARN509, orteronel \[TAK-700\], etc.), sipuleucel-T (Provenge), other experimental vaccines (PROSTVAC-V/F, etc.), strontium-89, samarium, and radium-223 chloride
* Leukocytes \> 3,000/mcL
* Absolute neutrophil count \> 1,500/mcL
* Platelets \> 125,000/mcL
* Hemoglobin \>= 5.59 mmol/L or 9 g/dL; up to 5% deviation is tolerated; transfusions and growth factors are allowed
* Total bilirubin within normal institutional limits
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\]) \< 3 X institutional upper limit of normal
* Alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) \< 3 X institutional upper limit of normal
* Creatinine within normal institutional limits OR creatinine clearance \> 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
* Ability to understand a written informed consent document, and the willingness to sign it
* Life expectancy of at least 12 weeks
* Able to swallow and retain oral medication

Exclusion Criteria:

* Untreated brain metastases; brain metastases =\< 1 cm and not associated with any focal neurologic deficits are allowed
* Prior docetaxel or other chemotherapy for mCRPC; patients who have received docetaxel for metastatic hormone-sensitive prostate cancer are eligible
* Active or symptomatic viral hepatitis or chronic liver disease
* Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) class II-IV heart disease or known cardiac ejection fraction measurement of \< 50 % at baseline
* Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea or other gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agents
* Pure small cell carcinoma of the prostate or any mixed histology cancer of the prostate (eg: neuroendocrine) that contains \< 50% adenocarcinoma, as observed on biopsy obtained at the time of diagnosis or on any subsequent biopsies
* Any ?currently active? second malignancy, other than non-melanoma skin cancer; patients are not considered to have a "currently active? malignancy, if they have completed therapy and are considered by their physician to be at least less than 30% risk of relapse over next year
* Any condition, which in the opinion of the investigator, would preclude participation in this trial
* Active psychiatric illnesses/social situations that would limit compliance with protocol requirements
* Patients in whom urgent treatment with docetaxel is indicated, per clinician discretion; this includes, but is not limited to patients with symptomatic visceral metastatic disease
* Uncontrolled infection or concomitant medical illness that is not adequately controlled with current medical management, as determined per clinician discretion
* Active bleeding disorders or evidence of evidence of chronic or acute disseminated intravascular coagulation (DIC)
* Severely compromised immunological state, including known human immunodeficiency virus (HIV)
* Any acute toxicities due to prior anti-cancer treatments and/or radiotherapy that have not resolved to a National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade of =\< 1 (except alopecia)
* Prior radiation therapy completed \< 3 weeks or single fraction of palliative radiotherapy \< 14 days prior to first dose of KPT-330 (selinexor)
* Initiation of bisphosphonate therapy \< 4 weeks prior to first dose of KPT-330; patients receiving bisphosphonate or denosumab therapy must be on stable doses for at least 4 weeks prior to first dose of KPT-330
* Men unable or unwilling to employ 2 forms of highly effective contraception throughout the study and for 8 weeks after the end of study treatment