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