COMbination of Bipolar Androgen Therapy and Nivolumab

Inclusion Criteria

• Willing and able to provide signed informed consent.
• Males aged 18 years of age and above.
• Histological or cytologic proof of adenocarcinoma of the prostate.
• Known castration-resistant disease, defined according to Prostate Cancer Working Group 3 (PCWG3) criteria as:
• Castrate serum testosterone level: ≤ 50 ng/dL (≤ 1.7 nmol/L).
• Subjects who have failed initial hormonal therapy, either by orchiectomy or by using a gonadotropin-releasing hormone (GnRH) agonist in combination with an anti-androgen, must first progress through anti-androgen withdrawal prior to being eligible. The minimum time frame to document failure of anti-androgen withdrawal will be four weeks.
• Serum Prostate Specific Antigen (PSA) progression defined as two consecutive increases in PSA over a previous reference value within 6 months of first study treatment, each measurement at least one week apart.

Or

• Documented bone lesions by the appearance of ≥ 2 new lesions by bone scintigraphy or dimensionally-measureable soft tissue metastatic lesion assessed by CT or MRI.
• Absolute PSA ≥ 2.0 ng/mL at screening.
• Must have PSA and/or radiographic progression on AT LEAST 1 novel AR targeted therapy (abiraterone acetate, enzalutamide). One prior chemotherapy agent for metastatic castration-resistant prostate cancer (mCRPC) will be allowed.
• Prior treatment with abiraterone, enzalutamide, bicalutamide, and/or ketoconazole is allowed. There is no limit on the maximum number or types of prior hormonal therapies received.
• Must be maintained on a GnRH analogue or have undergone orchiectomy.
• Radiographic evidence of metastatic disease by CT scan and bone scan, performed within the prior 4 weeks.
• Must have a soft tissue metastatic lesion available for biopsy collection to perform tumor tissue analysis.
• Karnofsky Performance Status (KPS): ≥ 70% within 14 days before start of study treatment (ECOG ≤ 2).
• Participants must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
• Hemoglobin ≥ 9.0 g/dL with no blood transfusion in the past 28 days.
• Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L
• Platelet count ≥ 100 x 10^9/L
• Total bilirubin within institutional upper limit of normal (ULN) (In patients with Gilbert's syndrome, total bilirubin 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
• Patients should be excluded if they have an active, known or suspected autoimmune disease (e.g. inflammatory bowel disease, rheumatoid arthritis, autoimmune hepatitis, lupus, celiac disease). Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Permitted therapies include topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g. contrast dye allergy) or for treatment of non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
• As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition to hepatotoxicity should be used with caution in patients treated with nivolumab-containing regimen.
• Patients should