Hormone blockers join forces against Treatment-Resistant endometrial cancer

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

Inclusion Criteria: * Age greater than or equal to 18 years old * Histologically confirmed diagnosis of endometrial cancer with ER and/or PR expression \>= 1% by IHC on archival tissue taken within the prior 3 years or new biopsy if no archival tissue is available. IHC results do not have to be from Thomas Jefferson University * Patients who have failed one prior treatment with a platinum/taxane chemotherapy regimen for management of disease \* Patients cannot have treatment with more than 2 prior lines of therapy (one line must be platinum/taxane regimen) * Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v.)1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension. Each lesion must be \>= 10 mm when measured by computed tomography (CT) or magnetic resonance imaging (MRI). Lymph nodes must be \>= 15 mm in short axis when measured by CT or MRI * Patients with the following histologic epithelial cell types are eligible: * Endometrioid adenocarcinoma * Serous adenocarcinoma * Undifferentiated carcinoma * Clear cell adenocarcinoma * Mixed epithelial carcinoma * Adenocarcinoma not otherwise specified (NOS) * Please note: patients with carcinosarcoma are ineligible for this trial * Patients must have had one prior treatment with a platinum/taxane chemotherapy regimen for management of disease * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Must have a life expectancy of at least 12 weeks as judged by the treating physician * Females are only eligible for this study if they are postmenopausal. This is defined as meeting one of the following criteria: * S/p total abdominal hysterectomy and bilateral salpingo-oopherectomy * Patients who are in menopause is defined clinically as 12 consecutive months of amenorrhea in a woman over 55 in the absence of other biological or physiological causes OR women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL. * Body weight \> 30 kg * Absolute neutrophil count 1500/ul or more * Platelets 100,000/ul or more * Hemoglobin 9 g/dl or more * Bilirubin less than or equal to 1.5 x the upper limit of normal (except subjects with Gilbert syndrome, who can have total bilirubin \< 3 mg/dl) * Endocrine and targeted therapy protocols usually enroll patients with aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \< 2.5 x upper limit of normal (ULN) in patients without underlying liver metastasis and \< 5.0 x ULN in patients with underlying liver metastasis * Glomerular filtration rate (GFR) greater than or equal to 40 ml/min using the Cockcroft-Gault formula or measured creatinine clearance using 24 hours urine collection * International normalized ratio (INR) OR prothrombin time (PT) and activated partial thromboplastin time (aPTT) =\< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants * All subjects must be able to comprehend and sign a written informed consent document * Resolution of all acute toxic effects of prior therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0) grade =\< 1, with the exception of unresolved grade 2 neuropathy and grade 2 alopecia, which are allowed * Patient has recovered from any prior radiotherapy * Patients must be able to swallow tablets whole, without crushing * Be able to read and speak English Exclusion Criteria: * Concurrent or recent chemotherapy, radiotherapy, immunotherapy, or general anesthesia/major surgery within 3 weeks * History of prior hormonal therapy (i.e., megestrol acetate, tamoxifen or aromatase inhibitors) for treatment cancer within the past 2 months. Other concurrent hormonal therapy will not be allowed on this trial * Patient has a concurrent malignancy or history of invasive malignancy within 3 years of enrollment, with the exception of basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix that has completed curative therapy * If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment * Has received prior systemic anti-cancer therapy including investigational agents within 3 weeks prior to randomization * Known brain metastasis which have not been treated or showed stability for \>= 6 months * Proteinuria \> 1+ on urinalysis or \> 1 gm/24 hours (hr) * Known history of New York Heart Association stage 3 or 4 cardiac disease * A pleural or pericardial effusion of greater than or equal to grade 3 severity * Women who are pregnant or nursing * Has an active infection requiring systemic therapy * Use of any prescription medication during the prior 28 days of first onapristone dosing that the investigator judges is likely to interfere with onapristone activity; specifically strong inhibitors or inducers, or sensitive substrates of cytochrome P450 CYP3A4 * Patients may not be on a concurrent clinical trial, unless approved by investigator