(21140 ARANOTE) A randomized, double-blind, placebo-controlled Phase 3 study of darolutamide in addition to androgen deprivation therapy (ADT) versus placebo plus ADT in men with metastatic hormone-sensitive prostate cancer (mHSPC).
- Trial ID
- 2022-502244-12-00
- Protocol
- 21140
- Sponsor
- Bayer Consumer Care AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3 study is to determine if **darolutamide** in addition to androgen deprivation therapy (ADT) is superior to placebo plus ADT by improving radiographic progression-free survival (rPFS) in participants with metastatic hormone-sensitive prostate cancer (mHSPC). This is clinically relevant as improving rPFS can potentially delay disease progression and improve patient outcomes in mHSPC, a condition where the cancer has spread but remains sensitive to hormonal therapy.
Secondary objectives include:
- Evaluating the efficacy of darolutamide in addition to ADT compared to placebo plus ADT by improving overall survival (OS), time to progression to castration-resistant prostate cancer (CRPC), time to initiation of subsequent anti-cancer therapy, time to prostate-specific antigen (PSA) progression, and undetectable PSA rates.
- Estimating the participant’s quality of life benefit of darolutamide in addition to ADT compared to placebo plus ADT by improving symptomatic time to pain progression.
- Assessing the safety of darolutamide in addition to ADT compared to placebo plus ADT in participants with mHSPC.
Participants
The clinical trial involves a total of **537 participants** diagnosed with **metastatic hormone-sensitive prostate cancer (mHSPC)**. The study population consists exclusively of male subjects, aged 18 years and older, who have histologically or cytologically confirmed adenocarcinoma of the prostate. Participants were selected based on documented metastatic disease, as confirmed by conventional imaging methods, and must have started androgen deprivation therapy (ADT) within 12 weeks prior to randomization. The trial excludes female subjects and does not involve a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2, indicating they are in relatively good health despite their cancer diagnosis. Lifestyle considerations include the requirement for sexually active male participants to use condoms and refrain from sperm donation during and after the treatment period. The trial aims to evaluate the efficacy of darolutamide in combination with ADT compared to placebo plus ADT in improving radiographic progression-free survival (rPFS) in this specific patient population.
Plans and Procedures
The clinical trial is a **randomized, double-blind, placebo-controlled Phase 3 study** designed to evaluate the efficacy of **darolutamide** in combination with androgen deprivation therapy (ADT) compared to placebo plus ADT in men with **metastatic hormone-sensitive prostate cancer (mHSPC)**. The primary objective is to assess whether darolutamide plus ADT improves radiological progression-free survival (rPFS) compared to the placebo group. Secondary endpoints include overall survival, time to castration-resistant prostate cancer, and time to PSA progression, among others. The trial is expected to run from February 2021 to September 2025, with a maximum treatment period of 36 months for participants.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, histological confirmation of prostate adenocarcinoma, and documented metastatic disease. Following successful screening, participants will be randomized to receive either darolutamide or placebo, both administered orally in the form of film-coated tablets. Regular follow-up visits will be scheduled to monitor treatment efficacy and safety, including assessments of PSA levels and imaging studies to evaluate disease progression. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.
Participant involvement is anticipated to last up to 36 months, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. The trial is conducted under strict adherence to ethical guidelines, ensuring informed consent and compliance with study protocols. The study aims to provide valuable insights into the treatment of mHSPC, potentially improving therapeutic strategies for this patient population.
Treatment
The clinical trial involves the administration of **darolutamide**, marketed under the product name **BAY 1841788**. This experimental medication is provided in the form of a **film-coated tablet**. The active substance, darolutamide, is of chemical origin and is administered orally. The maximum daily dose is 1200 mg, with a total maximum dose of 1296 g over a treatment period of up to 36 months. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.
A **placebo** is used as a comparator in this study, specifically designed to match the appearance of BAY 1841788. The placebo is administered in the same pharmaceutical form and via the same oral route as the experimental medication. This ensures blinding and maintains the integrity of the double-blind study design. The placebo is administered with the same frequency and under the same conditions as the active treatment to provide a valid comparison.
Additionally, the trial includes the use of a non-experimental treatment, **androgen deprivation therapy (ADT)**, which is standard-of-care for men with metastatic hormone-sensitive prostate cancer (mHSPC). ADT is administered according to established clinical guidelines and is used in combination with either darolutamide or placebo. The combination of ADT with the investigational or placebo treatment is intended to evaluate the efficacy of darolutamide in improving radiographic progression-free survival (rPFS) in the target patient population.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is **radiological progression-free survival** (rPFS), which will be used to determine if darolutamide in addition to androgen deprivation therapy (ADT) is superior to placebo plus ADT in men with metastatic hormone-sensitive prostate cancer (mHSPC). Secondary endpoints include overall survival (OS), time to castration-resistant prostate cancer (CRPC), time to initiation of subsequent anti-cancer therapy, time to PSA progression, percentage of participants with detectable PSA values (≥0.2 ng/mL) at baseline which become undetectable (<0.2 ng/mL), time to pain progression, and the number of participants with treatment-emergent adverse events.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent obtained. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
- Males ≥18 years of age.
- Histologically or cytologically confirmed adenocarcinoma of prostate.
- Documented metastatic disease by conventional imaging method either by a positive 99mTc-phosphonate bone scan, or soft tissue or visceral metastases, either by contrastenhanced abdominal/pelvic/chest CT or MRI scan assessed by central review. Note: Metastatic disease is defined as either malignant lesions in bone scan or measurable lymph nodes above the aortic bifurcation or soft tissue/visceral lesions according to RECIST version 1.1. Lymph nodes are measurable if the short axis diameter is ≥15 mm, soft tissue/visceral lesions are measurable if the long axis diameter is ≥10 mm. Regional lymph node metastases only (N1, below the aortic bifurcation) will not be considered as metastases eligible for the study. Only participants with non-regional lymph node metastases (M1a) and/or bone metastases (M1b) and/or other sites of metastases with or without bone disease (M1c), assessed according to National Comprehensive Cancer Network (NCCN) classification, will be eligible.
- Started ADT (LHRH agonist/antagonist or orchiectomy) with or without first generation anti–androgen, but no longer than 12 weeks before randomization. For participants receiving LHRH agonists, treatment in combination with a first generation anti–androgen for at least 14 days prior to randomization is recommended.
- First generation anti–androgen must be discontinued at least 1 day before study treatment start.
- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1 or 2.
- Blood counts at Screening: hemoglobin ≥9.0 g/dL, absolute neutrophil count ≥1.5x10^9/L, platelet count ≥100x10^9/L (participant must not have received any growth factor within 4 weeks or a blood transfusion within 7 days of the hematology laboratory sample obtained at Screening).
- Screening values of serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤1.5 x ULN, total bilirubin ≤1.5 x ULN, creatinine ≤2.0 x ULN.
- Sexually active male participants must agree to use condoms as an effective barrier method and refrain from sperm donation, and/or their female partners of reproductive potential to use a method of effective birth control, during the treatment with study drug/placebo and for 4 weeks after treatment with study drug/placebo.
Exclusion Criteria
- Pathological finding consistent with small cell, ductal or neuroendocrine carcinoma of the prostate
- Known brain/ leptomeningeal metastases Note: Brain CT/MRI scan should be performed only in case of symptoms.
- "Prior treatment with: - LHRH agonist/antagonists started >12 weeks before randomization starts except neoadjuvant and /or adjuvant therapy for a duration ≤ 24 months and completed ≥ 12 months prior to randomization - Second–generation androgen receptor (AR) inhibitors such as enzalutamide, darolutamide, apalutamide or other investigational AR inhibitors - Cytochrome P 17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as anti-cancer treatment for prostate cancer - Chemotherapy including docetaxel or immunotherapy for prostate cancer - Use of systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/day within 28 days prior to randomization - radiopharmaceuticals - Any other anti-cancer treatment for prostate cancer, excluding local therapies and ADT"
- Treatment with radiotherapy (external beam radiation therapy [EBRT], brachytherapy) within 2 weeks before randomization.
- Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs.
- Contraindication to iodinated CT and gadolinium chelate MRI intravenous contrast agent(s).
- Any prior malignancy (other than adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) within 5 years prior to randomization.
- An active viral hepatitis (defined as Hepatitis B surface antigen [HBsAg] reactive or detectable [qualitative] hepatitis B virus [HBV] DNA or defined as hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected), known human immunodeficiency virus (HIV) infection with detectable viral load, or chronic liver disease with a need of treatment. Note: No testing for Hepatitis B and/or Hepatitis C is required unless mandated by local authority. No HIV testing is required unless mandated by local authority.
- Had any of the following within 6 months before randomization: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure (New York Heart Association Class III or IV).
- Uncontrolled hypertension as indicated by a resting systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg despite medical management.
- A gastrointestinal (GI) disorder or procedure which is expected to interfere significantly with absorption of study drug.
- Previous (within 28 days before the start of study drug or 5 half–lives of the investigational treatment of the previous study, whichever is longer) or concomitant participation in another clinical study with investigational medicinal product(s).
- Any other serious or unstable illness, or medical, social, or psychological condition, that could jeopardize the safety of the participant and/or his/her compliance with study procedures or may interfere with the participant’s participation in the study or evaluation of the study results.
- Inability to swallow oral medications.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Latvia | Not Recruiting | 01 Feb 2021 | 71 |
 Lithuania | Not Recruiting | 01 Feb 2021 | 40 |
 Spain | Not Recruiting | 01 Feb 2021 | 21 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
- | Other | PHF00243MIG | SUBCUTANEOUS INJECTION | 0.23 | 36 | L02AE |
BAY 1841788 | Test | FILM-COATED TABLET | ORAL USE | 1200 | 36 | PRD1849573 |
Placebo of BAY 1841788 | Placebo | N/A | — | — | — | N/A |