This phase II/II trial compares the effect of high dose testosterone followed by darolutamide with the usual care in treating patients with prostate cancer that has spread from where it first started (primary site) to other places in the body (metastatic) and keeps growing even when the amount of testosterone in the body is reduced to very low levels (castration-resistant). Usual care treatment for patients with metastatic prostate cancer includes surgery or medical castration which involves drugs to suppress the function of the testes. After receiving this therapy, a period of disease stability occurs, followed typically by cancer regrowth and castration-resistant disease. Castration-resistant prostate cancer occurs because the tumor cells are eventually able to adapt to the very low levels of testosterone in the body. A new type of therapy called Bipolar Androgen Therapy (BAT) involves giving patients very high doses of testosterone every 28 days. This results in a cycle of higher than normal testosterone levels (i.e., "supraphysiologic") to near castrate levels over the 28 days. BAT may be able to stop prostate tumor cells from becoming castrate-resistant. In this trial, patients who receive BAT with high dose testosterone and experience disease progression then receive darolutamide. Darolutamide is in a class of medications called androgen receptor inhibitors. It works by blocking the effects of androgen (a male reproductive hormone) to stop the growth and spread of tumor cells. Adding BAT with high dose testosterone prior to darolutamide after disease progression may help shrink or stabilize metastatic castration-resistant prostate cancer better than usual treatments alone.
Patient must be ≥ 18 years of age
Patient must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
Patient must have documented histologically confirmed adenocarcinoma of the prostate
Prostate-specific antigen (PSA) progression defined as PSA ≥ 2 ng/mL and rising on two successive measurements at least 14 days apart (most recent PSA value must be within 28 days prior to randomization) AND
None
Parallel
Abiraterone Acetate
DrugGiven PO
Biospecimen Collection
Procedure/SurgeryUndergo biospecimen collection
Bone Scan
Procedure/SurgeryUndergo bone imaging
Cabazitaxel
DrugGiven IV
Computed Tomography
Procedure/SurgeryUndergo CT
Darolutamide
DrugGiven PO
Dexamethasone
DrugGiven dexamethasone
Docetaxel
DrugGiven IV
Enzalutamide
DrugGiven PO
Lutetium Lu 177 Vipivotide Tetraxetan
DrugGiven IV
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Methylprednisolone
DrugGiven methylprednisolone
Prednisone
DrugGiven prednisone
Questionnaire Administration
Other interventionAncillary studies
Testosterone Cypionate
DrugGiven IM
Second progression-free survival (PFS2) (Phase II)
Definition of progression includes radiographic progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or Prostate Cancer Working Group 3 (PCWG3) for bone lesions, and clinical progression determined by treating physician. The phase II part will be conducted first and only if the treatment of Bipolar Androgen Therapy (BAT) followed by darolutamide significantly improves PFS2 compared to the SOC (SOC1 followed by SOC2) arm, then the study will continue to the phase III part. The primary comparisons will be an intention-to-treat analysis including all randomized patients. The phase II part of the study will have 89.5% power to detect the above difference in PFS2 using a one-sided 0.15 level stratified log-rank test.
Overall survival (OS) (Phase III)
The phase II part will be conducted first and only if the treatment of BAT followed by darolutamide significantly improves PFS2 compared to the SOC (SOC1 followed by SOC2) arm, then the study will continue to the phase III part. The primary comparisons will be an intention-to-treat analysis including all randomized patients.
Overall quality of life (QOL)
Will compare overall QOL, measured by Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score, between the two arms. Mixed-effects models will be constructed, utilizing all available data, with fixed effects for treatment arm, assessment time, and the treatment-by-time interactions. A random intercept per patient will be included to account for within-subject correlations. Patients will rate physical, social/family, emotional, and functional well-being along with additional concerns on a scale from "not at all" to "very much". Interpretation of higher vs. lower scores being better is dependent on which subsection is being scored (i.e."I am able to work" rated as very much is not comparable to "I feel sad" rated as very much).
Progression-free survival (PFS)
Will be determined using RECIST 1.1 criteria (for soft tissue metastases) and PCWG3 criteria (for bone metastases). Will be evaluated for each of the two treatments in a given arm.
PFS
Will be determined using RECIST 1.1 criteria (for soft tissue metastases) and PCWG3 criteria (for bone metastases). Will be evaluated for each of the two treatments in a given arm.
Radiographic response rate
Will be determined using RECIST 1.1 criteria. Will be evaluated for each of the two treatments in a given arm.
Radiographic response rate
Will be determined using RECIST 1.1 criteria. Will be evaluated for each of the two treatments in a given arm.
Estimates of the primary outcome treatment effect by sex
Will estimate the primary outcome treatment effect and the corresponding 95% confidence intervals (CIs) by sex.
Estimates of the primary outcome treatment effect by race
Will estimate the primary outcome treatment effect and the corresponding 95% CIs by race.
Estimates of the primary outcome treatment effect by ethnicity
Will estimate the primary outcome treatment effect and the corresponding 95% CIs by ethnicity.
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ECOG-ACRIN Cancer Research Group
Lead sponsor
National Cancer Institute (NCI)
Collaborator
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