Testing the Use of High Dose Testosterone Followed by Darolutamide Compared to the Usual Care for Patients With Metastatic Prostate Cancer

NCT07852195 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: EA8251NCI-2026-04706U10CA180820
• Study Type: interventional
• Target: 432
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Stage IVB Prostate Cancer AJCC v8; Metastatic Castration-Resistant Prostate Adenocarcinoma

Outcome Measures

Primary Outcomes (3)

• 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.

  From randomization to disease progression or death, whichever occurs first after initiation of second treatment (standard of care [SOC]2 or darolutamide), assessed up to 60 months

• 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.

  From randomization until death from any cause or date last known alive, assessed up to 60 months

• 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).

  At randomization,12, 24 and 48 weeks after randomization

Secondary Outcomes (16)

• Progression-free survival (PFS)

  From randomization to disease progression or death, whichever occurs first prior to initiation of the second treatment of the study, assessed up to 60 months

• PFS

  From initiation of second treatment to disease progression, clinical progression, or death, whichever occurs first, assessed up to 60 months

• Radiographic response rate

  From initial randomization up to 60 months

• Radiographic response rate

  From initiation of second treatment up to 60 months

• Prostate-specific antigen (PSA) decline ≥ 50% from baseline (PSA50) response

  From initial randomization up to 60 months

Other Outcomes (3)

• Estimates of the primary outcome treatment effect by sex

  From randomization until death from any cause or date last known alive, assessed up to 60 months

• Estimates of the primary outcome treatment effect by race

  Up to 60 months

• Estimates of the primary outcome treatment effect by ethnicity

  Up to 60 months

Study Arms (2)

Arm A (SOC1, SOC2)

ACTIVE COMPARATOR

Patients receive an SOC1 treatment regimen per discretion of the patient and the treating provider: 1) Docetaxel IV every 21 days with or without prednisone; OR 2) Abiraterone acetate PO QD with prednisone or methylprednisolone or dexamethasone; OR 3) Enzalutamide PO QD. SOC1 treatment continues in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression then receive an SOC2 treatment regimen per discretion of the patient and the treating provider: 1) Docetaxel IV every 21 days with or without prednisone; OR 2) cabazitaxel IV every 21 days; OR 3) 177Lu-PSMA-617 IV every 6 weeks for 6 doses; OR 4) Abiraterone acetate PO QD with prednisone or methylprednisolone or dexamethasone; OR 5) Enzalutamide PO QD. SOC2 treatment continues in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI, bone imaging, and biospecimen collection throughout the study.

Drug: Abiraterone Acetate; Procedure: Biospecimen Collection; Procedure: Bone Scan; Drug: Cabazitaxel; Procedure: Computed Tomography; Drug: Dexamethasone; Drug: Docetaxel; Drug: Enzalutamide; Drug: Lutetium Lu 177 Vipivotide Tetraxetan; Procedure: Magnetic Resonance Imaging; Drug: Methylprednisolone; Drug: Prednisone; Other: Questionnaire Administration

Arm B (testosterone cypionate, darolutamide)

EXPERIMENTAL

Patients receive testosterone cypionate IM on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression then receive darolutamide PO BID in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI, bone imaging, and biospecimen collection throughout the study.

Procedure: Biospecimen Collection; Procedure: Bone Scan; Procedure: Computed Tomography; Drug: Darolutamide; Procedure: Magnetic Resonance Imaging; Other: Questionnaire Administration; Drug: Testosterone Cypionate

Interventions

Abiraterone Acetate DRUG

Given PO

Also known as: BR9004, BR9004-1, CB 7630, CB-7630, CB7630, JNJ-212082, Yonsa, Zytiga

Arm A (SOC1, SOC2)

Biospecimen Collection PROCEDURE

Undergo biospecimen collection

Also known as: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

Arm A (SOC1, SOC2); Arm B (testosterone cypionate, darolutamide)

Bone Scan PROCEDURE

Undergo bone imaging

Also known as: Bone Scintigraphy

Arm A (SOC1, SOC2); Arm B (testosterone cypionate, darolutamide)

Cabazitaxel DRUG

Given IV

Also known as: Jevtana, RPR 116258A, RPR-116258A, RPR116258A, Taxoid XRP6258, TXD 258, TXD-258, TXD258, XRP 6258, XRP-6258, XRP6258

Arm A (SOC1, SOC2)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Arm A (SOC1, SOC2); Arm B (testosterone cypionate, darolutamide)

Darolutamide DRUG

Given PO

Also known as: Antiandrogen ODM-201, BAY 1841788, BAY-1841788, BAY1841788, Nubeqa, ODM 201, ODM-201, ODM201

Arm B (testosterone cypionate, darolutamide)

Dexamethasone DRUG

Given dexamethasone

Also known as: Aacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycadron, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decadron DP, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasone Intensol, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Dxevo, Fluorodelta, Fortecortin, Gammacorten, Hemady, Hexadecadrol, Hexadrol, LenaDex, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDex

Arm A (SOC1, SOC2)

Docetaxel DRUG

Given IV

Also known as: Docecad, RP 56976, RP-56976, RP56976, Taxotere, Taxotere Injection Concentrate

Arm A (SOC1, SOC2)

Enzalutamide DRUG

Given PO

Also known as: ASP9785, MDV 3100, MDV-3100, MDV3100, Xtandi

Arm A (SOC1, SOC2)

Lutetium Lu 177 Vipivotide Tetraxetan DRUG

Given IV

Also known as: 177Lu-labeled PSMA-617, 177Lu-PSMA-617, AAA 617, AAA-617, AAA617, Lu177-PSMA-617, Lutetium Lu 177-PSMA-617, LUTETIUM LU-177 VIPIVOTIDE TETRAXETAN, Lutetium-177-PSMA-617, Pluvicto

Arm A (SOC1, SOC2)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Arm A (SOC1, SOC2); Arm B (testosterone cypionate, darolutamide)

Methylprednisolone DRUG

Given methylprednisolone

Also known as: Adlone, Caberdelta M, DepMedalone, Depo Moderin, Depo-Nisolone, Duralone, Emmetipi, Esametone, Firmacort, Medlone 21, Medrate, Medrol, Medrol Veriderm, Medrone, Mega-Star, Meprolone, Methylprednisolonum, Metilbetasone Solubile, Metrocort, Metypresol, Metysolon, Predni-M-Tablinen, Prednilen, Radilem, Sieropresol, Solpredone, Summicort, Urbason, Veriderm Medrol, Wyacort

Arm A (SOC1, SOC2)

Prednisone DRUG

Given prednisone

Also known as: .delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, Perrigo Prednisone, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisone Intensol, Prednisonum, Prednitone, Promifen, Rayos, Servisone, SK-Prednisone

Arm A (SOC1, SOC2)

Questionnaire Administration OTHER

Ancillary studies

Arm A (SOC1, SOC2); Arm B (testosterone cypionate, darolutamide)

Testosterone Cypionate DRUG

Given IM

Also known as: depAndro, Depo-Testosterone, Depotest, Depovirin, Pertestis, Virilon

Arm B (testosterone cypionate, darolutamide)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Patient must have evidence of metastatic castration resistant prostate cancer (mCRPC) defined by Prostate Cancer Working Group 3 criteria as follows:
• 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
• Castrate serum testosterone level ≤ 50 ng/dL
• Patient must not be on systemic immunosuppressive medication, including steroids (if doses exceed the equivalent of prednisone 10 mg daily). Short courses of steroids, e.g., "burst", which are discontinued prior to randomization are acceptable. Patients on inhaled, intranasal, intra-articular and/or topical steroids are eligible
• Patients must have progressed on prior androgen receptor pathway inhibitors (ARPI) including, but not limited to, abiraterone, enzalutamide, apalutamide, or darolutamide. There must be at least a 2-week washout period after stopping ARPI prior to randomization
• NOTE: Prior bicalutamide is allowed and does not count as an ARPI
• Patient must not have prior chemotherapy for the treatment of mCRPC. Patient may have received docetaxel for the treatment of hormone-sensitive prostate cancer
• NOTE: This includes high dose testosterone therapy for prostate cancer
• Patient must have at least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by CT, MRI and/or bone scan and is suitable for repeated assessment. Baseline imaging must be obtained within 28 days prior to randomization
• Patient must not have current cancer-related pain requiring the use of opiates at the time of randomization
• Patient must not have received any systemic therapy or radiotherapy within 14 days prior to randomization
• NOTE: Luteinizing hormone-releasing hormone (LHRH) agonist/antagonist treatment is allowed

Sponsors & Collaborators

• ECOG-ACRIN Cancer Research Group: lead
• National Cancer Institute (NCI): collaborator

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

Abiraterone Acetate; Specimen Handling; cabazitaxel; XRP6258; TXD 258; darolutamide; Dexamethasone; Calcium Dobesilate; auricularum; dexamethasone acetate; dexamethasone 21-phosphate; Docetaxel; enzalutamide; Pluvicto; Magnetic Resonance Spectroscopy; Methylprednisolone; exifone; Medrol Veriderm; Prednisone; deltacortene; prednylidene; testosterone 17 beta-cypionate; Testosterone Propionate; Methyltestosterone

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Diterpenes; Terpenes; Spectrum Analysis; Chemistry Techniques, Analytical; Prednisolone; Pregnadienediols; Testosterone; Androstenols; Testosterone Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Michael Schweizer

  ECOG-ACRIN Cancer Research Group

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 13, 2026
• First Posted: October 1, 2026
• Study Start (Estimated): January 6, 2027
• Primary Completion (Estimated): March 31, 2029
• Study Completion (Estimated): March 31, 2030
• Last Updated: October 1, 2026

Record last verified: 2026-08