Overview

The objective of this study is to determine the safety and clinical effects of alternating pharmacologic (i.e. supraphysiologic) testosterone therapy with darolutamide in men with metastatic prostate cancer as first line hormonal therapy. Correlative studies will be conducted to assess the effect of alternating therapy on quality of life, gene expression and metabolic changes associated with alternating therapy.

Eligibility

Inclusion Criteria:

• Age ≥ 18 years
• Performance status ≤2.
• Documented histologically confirmed adenocarcinoma of the prostate.
• Baseline PSA ≥1.0 ng/ml.
• No prior androgen deprivation therapy (i.e. surgical castration LHRH agonist, LHRH antagonist) as treatment for biochemically recurrent or metastatic disease (may have received neoadjuvant, concurrent and/or adjuvant AD therapy in the context of definitive radiation therapy if it was administered ≥ 1 year prior to recurrence).
• No prior treatment with ARPI (abiraterone, enzalutamide, darolutamide) for biochemically recurrent or metastatic prostate cancer. Neoadjuvant, concurrent and/or adjuvant ARPI +/- ADT is permitted if given in the context of definitive radiation therapy if it was administered ≥ 1 year prior to development of metastatic disease.
• Prior focal radiation treatment (e.g. SABR, Cyberknife) for oligometastatic disease is permitted if \> 6 months. Patients must have evidence of metastatic disease in non-irradiated sites to be eligible for study.
• Evidence of rising PSA on two successive dates \> 2 weeks apart.
• Evidence of metastatic disease on CT scan or bone scan performed with six weeks of screening.
• Patients with bone pain due to prostate cancer are eligible for trial but must be pain free at the end of the 6-month lead-in phase to be eligible to receive subsequent BAT.
• Patients with soft tissue lesions amenable to biopsy must agree to baseline and 6 months tumor biopsies to enroll in study.
• Acceptable liver function:
  1. Bilirubin \< 2.5 times institutional upper limit of normal (ULN)
  2. AST (SGOT) and ALT (SGPT) \< 2.5 times ULN
• Acceptable renal function:
  1. Serum creatinine \< 2.5 times ULN
• Acceptable hematologic status:
  1. Absolute neutrophil count (ANC) \> 1000 cells/mm3 (1.0 ×109/L)
  2. Platelet count \> 100,000 platelet/mm3 (100 ×109/L)
  3. Hemoglobin \> 9 g/dL.
• Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

• No prior treatment with chemotherapeutic regimens allowed.
• No prior treatment with Pluvicto or other PSMA-targeted agents is allowed.
• No prior treatment with Androgen Receptor targeted investigational agents is permitted.
• Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition (including laboratory abnormalities) that could interfere with patient safety or provision of informed consent to participate in this study.
• Evidence of disease that, in the opinion of the investigator, would put the patient at risk from testosterone therapy (e.g. femoral metastases with concern over fracture risk, spinal metastases with concern over spinal cord compression, lymph node disease with concern for ureteral obstruction).
• Requires urinary self-catheterization for voiding due to obstruction secondary to prostatic enlargement well-documented to be due to prostate cancer or benign prostatic hyperplasia (BPH). Patients with indwelling Foley or suprapubic catheter for obstructive symptoms are eligible.
• Active uncontrolled infection.
• Any condition or mental impairment that may compromise the ability to give informed consent, patient's safety or compliance with study requirements as determined by the investigator.
• Patients receiving anticoagulation therapy with Warfarin or Coumadin are not eligible for study. Patients on non-coumadin anticoagulants (Lovenox, Eliqis, Xarelto, etc.) are eligible for study. Patients on Coumadin who can be transitioned to non-coumadin anticoagulants prior to starting study treatments will be eligible.
• Hematocrit \>51%, untreated severe obstructive sleep apnea, uncontrolled or poorly controlled heart failure \[per Endocrine Society Clinical Practice Guidelines (34)\]
• Patients allergic to sesame seed oil or cottonseed oil are excluded.
• Major surgery as determined by the treating physician within 3 weeks before screening, or has not fully recovered from prior surgery (i.e., unhealed wound). Note: subjects with planned procedures (minor surgery with local anesthesia), colonoscopy under anesthesia may participate.
• Abnormal cardiac function as manifested by NYHA (New York Heart Association) class III or IV heart failure or history of a prior myocardial infarction (MI) within the last five years prior to enrollment in the study.
• Inability to provide informed consent.