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.
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.
Study Type
Intermittent intramuscular testosterone cypionate (T) at a dose of 400 mg every 4 weeks.
Eligible patients will initiate combined androgen deprivation therapy (ADT) with an LHRH agonist or antagonist (e.g. Eligard, Zoladex, Lupron, Orgovyx) in combination with standard dose darolutamide (600 mg twice daily) for a total of 6 months.
600 mg twice daily during the lead-in phase and on darolutamide cycle.
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
Baltimore, Maryland, United States
RECRUITINGPercent of subjects free of Clinical or radiographic free progression
Percent of subjects are free of clinical or radiographic progression at 24 months from initiation of treatment
Time frame: 24 months from Day 1 (start of treatment)
Percent of patients who achieve Complete PSA response at end of in lead-in phase
Percent of patients who achieve a complete PSA response (i.e. serum PSA \<0.2 ng/ml) at end of in lead-in phase.
Time frame: 6 months from Day 1 (start of treatment)
Percent of patients who achieve Complete PSA response with darolutamide treatment
Percent of patients who achieve a complete PSA response (i.e. serum PSA \<0.2 ng/ml) over the course of treatment with darolutamide.
Time frame: 36 months from Day 1 (start of treatment)
Number of patients with Clinical or Radiographic progression free survival
Number of patients with clinical or radiographic progression free survival while on the study.
Time frame: 6 years from Day 1 (start of treatment)
Overall Survival
Number of months from the start of study treatment in the lead-in phase to death due to any cause, will be summarized using Kaplan-Meier method
Time frame: 6 years from Day 1 (start of treatment)
Objective Response to darolutamide
Number of patients who have complete response or partial response according to RECIST 1.1 criteria, among those with measurable disease at baseline, with darolutamide treatment following BAT.
Time frame: 1 year from Day 1 (start of treatment)
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INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
60
Response in patients with high volume (CHAARTED criteria) vs. low volume disease
Number of patients who have complete response or partial response according to RECIST 1.1 criteria, among those with measurable disease at baseline, with high volume disease vs those with low volume disease.
Time frame: 3 years from Day 1 (start of treatment)