Supraphysiologic Testosterone Priming Induces Darolutamide Extended Response

NCT07142551 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: J2564IRB00509292
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Metastatic Castration-resistant Prostate Cancer

Keywords

Prostate Cancer

Outcome Measures

Primary Outcomes (1)

• Percent 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

  24 months from Day 1 (start of treatment)

Secondary Outcomes (6)

• Percent of patients who achieve Complete PSA response at end of in lead-in phase

  6 months from Day 1 (start of treatment)

• Percent of patients who achieve Complete PSA response with darolutamide treatment

  36 months from Day 1 (start of treatment)

• Number of patients with Clinical or Radiographic progression free survival

  6 years from Day 1 (start of treatment)

• Overall Survival

  6 years from Day 1 (start of treatment)

• Objective Response to darolutamide

  1 year from Day 1 (start of treatment)

Other Outcomes (4)

• Number of participants with treatment-related adverse events

  3 years from Day 1 (start of treatment)

• Quality of Life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale

  2.5 years from Day 1 (start of treatment)

• Quality of Life as assessed by the Short Form-36 (SF-36)

  2.5 years from Day 1 (start of treatment)

Study Arms (3)

Lead-In Phase - ADT with an LHRH agonist or antagonist

EXPERIMENTAL

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. After this initial "lead-in" phase, patients who have clinical or radiographic progression or do not have at least a ≥50% decline in PSA will remain on combined androgen deprivation and discontinue study.

Drug: Luteinizing hormone-releasing hormone (LHRH) analogue; Drug: Darolutamide

Bipolar Androgen-based Therapy (BAT) Cycle

EXPERIMENTAL

Patients with ≥50% decline in PSA will discontinue combined androgen deprivation and will receive intermittent intramuscular testosterone cypionate (T) at a dose of 400 mg every 4 weeks for a total of 3 injections while on a BAT cycle (12 weeks).

Drug: Testosterone cypionate

Darolutamide Cycle

EXPERIMENTAL

Patient will proceed to a cycle off BAT and start darolutamide alone at 600 mg twice daily for 12 weeks. Patients will continue with alternating cycles of BAT or darolutamide (without ADT) until clinical or radiographic progression.

Drug: Darolutamide

Interventions

Testosterone cypionate DRUG

Intermittent intramuscular testosterone cypionate (T) at a dose of 400 mg every 4 weeks.

Also known as: Depo-Testosterone

Bipolar Androgen-based Therapy (BAT) Cycle

Luteinizing hormone-releasing hormone (LHRH) analogue DRUG

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.

Also known as: Trelstar, Eligard, Lupron, Degarelix, Relugolix

Lead-In Phase - ADT with an LHRH agonist or antagonist

Darolutamide DRUG

600 mg twice daily during the lead-in phase and on darolutamide cycle.

Also known as: Nubeqa

Darolutamide Cycle; Lead-In Phase - ADT with an LHRH agonist or antagonist

Eligibility Criteria

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

You may qualify if:

• 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:

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• Bayer: collaborator

Study Sites (1)

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21205, United States

RECRUITING

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

testosterone 17 beta-cypionate; Gonadotropin-Releasing Hormone; Triptorelin Pamoate; luprolide acetate gel depot; Leuprolide; acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; relugolix; darolutamide

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)

Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Study Officials

• Samuel Denmeade, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rana Sullivan, RN

CONTACT

410-614-6337; tomalra@jhmi.edu

Donna Bieg, RN

CONTACT

410-502-7625; dbieg2@jh.edu

Study Design

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

Study Record Dates

• First Submitted: August 19, 2025
• First Posted: August 26, 2025
• Study Start: March 9, 2026
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): June 1, 2034
• Last Updated: March 11, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)