ESK981 and Nivolumab for the Treatment of Metastatic Castration Resistant Prostate Cancer

This phase II trial studies the side effects of ESK981 and nivolumab and to see how well they work for the treatment of castration resistant prostate cancer that has spread to other places in the body (metastatic). ESK981 is an investigational drug that targets several important pathways that are believed to play a role in the spread of cancer. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This study is being done to see if giving ESK981 and nivolumab together works better in treating metastatic castration resistant prostate cancer compared to usual treatments.

PRIMARY OBJECTIVES:

I. To determine the prostate specific antigen (PSA) \>= 50% response rate (PSA50) from baseline using the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria to pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981 (ESK981) plus nivolumab in men with metastatic castration resistant prostate cancer (mCRPC) who have progressed on enzalutamide (an oral androgen-receptor inhibitor) and/or abiraterone acetate (an androgen synthesis inhibitor) and chemotherapy (docetaxel and/or cabazitaxel).

II. To assess the safety and tolerability of ESK981 plus nivolumab.

SECONDARY OBJECTIVES:

I. To determine the time to PSA response (TTPR) in patients with mCRPC. II. To determine the duration of PSA response (PRD) in patients with mCRPC. III. To determine PSA progression rates as defined by the PCWG3 criteria. IV. To determine PSA progression free survival (PPFS) as defined by the PCWG3 criteria.

CORRELATIVE/EXPLORATORY/TERTIARY OBJECTIVE:

I. To assess exploratory biomarkers from blood and tumor biopsies.

OUTLINE:

Patients receive ESK981 orally (PO) once daily (QD) for 5 consecutive days per week, followed by a 2-day break. Patients also receive nivolumab intravenously (IV) on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 5 years.

Eligibility Criteria:
Inclusion Criteria:

* Eastern Cooperative Group (ECOG) performance status =\< 1
* Recovery to baseline or =\< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v.)5 from toxicities related to any prior treatments, unless adverse event (AE)(s) are clinically non-significant and/or stable on supportive therapy
* Absolute neutrophil count (ANC) \>= 1.5 K/mm\^3
* Hemoglobin (Hgb) \>= 9 g/dL
* Platelets (Plt) \>= 100,000/mm\^3
* Serum creatinine =\< 1.5 times the upper limit of normal OR creatinine clearance \> 30 mL/min by Cockcroft-Gault formula
* Total bilirubin =\< 1.5 x upper limit of normal (ULN)
* Aspartate aminotransferase (AST) =\< 2.5 x ULN (=\< 5 x ULN with known hepatic metastases)
* Alanine aminotransferase (ALT) =\< 2.5 x ULN (=\< 5 x ULN with known hepatic metastases)
* Prothrombin time (PT) and activated partial thromboplastin time (aPTT) levels =\< 1.5 x ULN (If patient is receiving anticoagulation that is expected to alter these levels, should be in targeted therapeutic range for that agent)
* Patient must have progressive disease while receiving androgen deprivation therapy (ADT) defined by any one of the following as per the PCWG3 criteria for PSA, measurable or non-measurable (bone) disease and must have a castrate serum testosterone level (i.e. =\< 50 ng/dL) at screening:

  * PSA: At least two consecutive rises in serum PSA, obtained at a minimum of 1-week intervals, with the final value \>= 2.0 ng/mL
  * Measurable disease (by Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1): \>= 20% increase (with an absolute increase of at least 5 mm) in the sum of diameters of all measurable lesions or the development of one or more new lesions. The short axis of a target lymph node must be more than 15 mm to be assessed for change in size
  * Non-measurable (bone) disease: The appearance of two or more new areas of uptake on bone scan consistent with metastatic disease compared to previous imaging during castration therapy. The increased uptake of pre-existing lesions on bone scan will not be taken to constitute progression, and ambiguous results must be confirmed by other imaging modalities (e.g. X-ray, computed tomography \[CT\] or magnetic resonance imaging \[MRI\])
* Metastatic prostate cancer (M1) as documented by appropriate medical imaging (i.e. CT-Scan, positron emission tomography \[PET\] scan or bone scan)
* Progression on a hormonal agent (abiraterone/enzalutamide) and on a chemotherapy agent (docetaxel and/or cabazitaxel) in the metastatic castration resistant setting as per PCWG3 criteria
* Progression on chemotherapy (e.g. docetaxel, cabazitaxel) in the metastatic castration resistant setting. Progression of disease within 6 months of completing docetaxel in the metastatic castrate-sensitive setting is acceptable
* Have signed an informed consent document indicating that the subject understands the purpose of and procedures required for the study and are willing to participate in the study
* Be willing and able to adhere to the prohibitions and restrictions specified in this protocol
* Willingness to use contraception by a method that is deemed effective by the investigator throughout the treatment period and for at least 30 days following the last dose of therapy
* Willingness and ability to comply with study procedures and follow-up examination
* Able to swallow and retain oral medication
* Willingness and ability to undergo mandatory tumor biopsy at baseline and at the cycle 3 visit
* Willingness and ability to undergo mandatory whole blood sample collections at baseline, weeks 2-4 in the first cycle, and then monthly

Exclusion Criteria:

* Systemic therapy (other than a gonadotrophin releasing hormone \[GnRH\] agonist/antagonist) for CRPC within the past two weeks from cycle 1/day 1 including:

  * CYP-17 inhibitors (e.g. ketoconazole, abiraterone)
  * Antiandrogens (e.g. bicalutamide, nilutamide)
  * Second generation antiandrogens (e.g. enzalutamide, ARN-509, galeterone)
  * Immunotherapy (e.g. sipuleucel-T, ipilimumab)
  * Chemotherapy (e.g. docetaxel, cabazitaxel)
* Prior radiopharmaceutical therapy (e.g. radium-223, strontium-89, samarium-153, etc.) within the past year
* Have any condition that, in the opinion of the investigator, would compromise the well-being of the subject or the study or prevent the subject from meeting or performing study requirements
* The patient is currently on warfarin or heparin therapy
* The patient has any pre-existing coagulopathy, recent hemoptysis, gross hematuria or gastrointestinal bleeding
* The patient has a history of a clinically significant cardiovascular or cerebrovascular event within 3 months prior to study entry
* The patient has uncontrolled hypertension defined as a blood pressure measurement greater than 150 mm Hg systolic or 90 mm Hg diastolic with medication
* The patient has previously been enrolled in the study or received ESK981
* The patient has known hypersensitivity to gelatin or lactose monohydrate
* The patient has taken a medication known to be a potent inducer of CYP1A2, CYP2C8, or CYP3A4 within 4 weeks prior to the first dose of study drug
* Prior treatment with anti-PD/PD-L1/CTLA4/IDO antibody
* Untreated brain metastases or spinal cord compression
* Major surgical procedure or significant traumatic injury within 6 weeks prior to study registration. (\> 6 weeks prior to registration is permitted as long as they have fully recovered from any such procedure)
* History of another primary malignancy except for: malignancy treated with curative intent and no known active disease for \>= 5 years, adequately treated non-melanoma skin cancer without evidence of disease, adequately treated carcinoma in situ without evidence of disease
* Angina, myocardial infarction symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, percutaneous angioplasty or Coronary arterial bypass surgery within the past 3 months
* The patient has received any investigational drug within 28 days prior to registration or 5 half-lives of the investigational drug, whichever is sooner