Supraphysiologic Testosterone Priming Induces Darolutamide Extended Response

This research is being done to determine if alternating high dose testosterone and prevent the development of resistance to hormone therapy. It is also being done to determine if this alternating therapy can decease the side effects of hormone therapy and improve the participant's quality of life.

Right now, patients who develop metastatic prostate cancer are treated with medications that block testosterone effects as first-line therapy. Eventually, the testosterone blocking therapies become ineffective and the tumor begins to grow. The investigaors call this phase of the disease castrater-resistant prostate cancer (CRPC). Previous research has shown that prostate cancer cells can eventually adapt to low testosterone conditions produced by hormone therapy and begin to grow again. The investigators have learned that these resistant prostate cancer cells can killed by high levels of testosterone followed by a rapid drop to low testosterone levels. The investigators call this treatment bipolar androgen therapy (BAT) because the investigators are going from the polar extremes of high and low testosterone in the blood every 28 days. The investigators have tested this idea in previous studies by giving injections of high doses of testosterone to patients with CRPC. In these trials, the investigators saw that BAT was safe. BAT produced decreases in PSA levels and decreases in tumor size in some patients. After treatment with BAT, many patients had an improved response to the testosterone-blocking drug enzalutamide. The drug used in this study, darolutamide, is similar to enzalutamide. Both drugs are considered to be antiandrogens that block effects of testosterone within the prostate cancer cells.

The investigators also did a study called the BATMAN study in patients with mHSPC. These patients received alternating therapy with high dose testosterone and ADT as first line therapy. In this study, alternating testosterone and ADT was found to be safe. In this study, more patients remained sensitive to hormone therapy after 18 months than the investigators would have expected with ADT alone.

In this study, the investigators would like to see if improvement on these results and decrease hormonal side effects when the investigators give testosterone in sequence with darolutamide.

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:

• Bilirubin < 2.5 times institutional upper limit of normal (ULN)
• AST (SGOT) and ALT (SGPT) < 2.5 times ULN
• Acceptable renal function:

a. Serum creatinine < 2.5 times ULN

• Acceptable hematologic status:

• Absolute neutrophil count (ANC) > 1000 cells/mm3 (1.0 ×109/L)
• Platelet count > 100,000 platelet/mm3 (100 ×109/L)
• 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.