Evaluation of Darolutamide and Stereotactic Dose-Escalated Radiotherapy in High-Risk Localized Prostate Cancer: A Phase III Randomized Trial
- Trial ID
- 2023-509787-15-00
- Protocol
- UC-GTG-2310
- Sponsor
- Unicancer
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of **darolutamide** and stereotactic dose escalated radiotherapy, in combination with androgen deprivation therapy (ADT) and pelvic nodal radiotherapy, in terms of metastasis-free survival (MFS) in patients with localized prostate cancer and high-risk features of relapse. This is clinically relevant as it aims to improve outcomes in patients with a high likelihood of disease progression, thereby potentially reducing the incidence of metastasis and improving long-term survival.
Secondary objectives include:
- Assessing the efficacy of the treatments in terms of clinical progression-free survival (cPFS).
- Evaluating biochemical progression-free survival.
- Determining the time to local relapse.
- Assessing overall survival (OS).
- Evaluating prostate cancer-specific survival (PCSS).
- Assessing the safety of the treatments in terms of acute and long-term toxicity.
- Determining the impact of treatments on patients' quality of life.
Participants
The clinical trial involves **male** participants aged between 18 and 80 years, diagnosed with **localized prostate cancer** and possessing high-risk features of relapse, as defined by the National Comprehensive Cancer Network (NCCN) classification. The study population is characterized by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating that participants are fully active or restricted in physically strenuous activity but ambulatory. Participants must have histologically confirmed adenocarcinoma of the prostate and meet at least two high-risk criteria from the NCCN classification. The trial excludes individuals with significant co-morbidities that might prevent long-term follow-up. Participants are required to have adequate hematologic and hepatic function, as well as a creatinine level within specified limits. The trial does not include female subjects or vulnerable populations. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **randomized**, double-blind, controlled study with a factorial design, aimed at evaluating the efficacy and safety of **darolutamide** and stereotactic dose escalated radiotherapy in patients with localized **prostate cancer** and high-risk features of relapse. The trial will assess the primary endpoint of metastasis-free survival (MFS) and secondary endpoints including clinical progression-free survival, biochemical progression-free survival, time to local relapse, overall survival, prostate cancer-specific survival, severity of adverse events and toxicities, long-term toxicity, and quality of life. The trial is expected to commence recruitment on June 10, 2024, and conclude by December 30, 2044, with a maximum treatment period of 24 months for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed adenocarcinoma of the prostate, specific laboratory values, and an ECOG performance status of 0 or 1. Following randomization, participants will attend regular follow-up visits to monitor treatment effects, adherence, and safety. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. Conditions that may lead to early termination include significant adverse events, withdrawal of consent, or non-compliance with the study protocol.
Participant involvement is expected to last up to 24 months, with the possibility of early termination based on predefined criteria. The trial will utilize **triptorelin** administered via intramuscular or subcutaneous routes and **darolutamide** in the form of film-coated tablets taken orally. The study aims to provide comprehensive data on the efficacy and safety of the treatment regimen in the specified patient population, contributing valuable insights into the management of high-risk localized prostate cancer.
Treatment
The clinical trial involves the administration of **TRIPTORELIN**, an experimental medication formulated as a **powder and solvent for prolonged-release suspension for injection**. The active substance, triptorelin, is administered either intramuscularly or subcutaneously. The maximum daily dose is 11.25 mg, with a total maximum dose of 90 mg over a treatment period of 24 months. This formulation is not a pediatric formulation and is not classified as an orphan drug. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.
In addition to triptorelin, the trial includes the administration of **BAY 1841788**, known by its active substance name **DAROLUTAMIDE**. This medication is provided in the form of a **film-coated tablet** and is taken orally. The maximum daily dose is 1200 mg, with a total maximum dose of 876 g over a 24-month treatment period. Darolutamide is a chemical substance and is not a pediatric formulation or an orphan drug. The trial ensures that participants adhere to the oral dosing schedule through regular compliance monitoring.
The study also incorporates standard-of-care therapy, including androgen deprivation therapy (ADT) and pelvic nodal radiotherapy, as part of the treatment regimen. These non-experimental treatments are used in combination with the experimental medications to evaluate their efficacy and safety in patients with localized prostate cancer and high-risk features of relapse. The trial employs a 2 by 2 factorial design to assess the impact of these treatments on metastasis-free survival.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **metastasis-free survival (MFS)** in patients with localized prostate cancer and high-risk features of relapse. This primary endpoint will evaluate the time from randomization to the occurrence of distant metastasis or death from any cause, whichever occurs first. Secondary endpoints include Clinical Progression-Free Survival (cPFS), Biochemical Progression-Free Survival, Time to Local Relapse, Overall Survival (OS), Prostate Cancer-Specific Survival (PCSS), Severity of Adverse Events and Toxicities, Long-term Toxicity, and Quality of Life. These parameters will provide a comprehensive assessment of the treatment's impact on disease progression and patient well-being.
The trial employs a 2 by 2 factorial design to evaluate the efficacy of **darolutamide** and stereotactic dose-escalated radiotherapy in combination with androgen deprivation therapy (ADT) and pelvic nodal radiotherapy. The efficacy parameters will be collected and analyzed at specified time points throughout the trial duration, which is estimated to conclude by December 2044. The trial will utilize validated scales and laboratory tests to ensure accurate and reliable data collection. The analysis will focus on comparing the outcomes between the different treatment arms to determine the effectiveness of the interventions in improving survival and reducing relapse in the target patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed a written informed consent form prior to any trial specific procedures
- Men, 18 years ≤ Age ≤ 80 years
- ECOG performance status of 0 or 1
- No significant co-morbidities that might prevent long-term follow-up
- Histologically confirmed adenocarcinoma of the prostate
- Meet at least 2 of the following criteria from NCCN classification
- Prostate size on MRI < 100 cc
- Absolute neutrophil count ≥ 1.5 x 10^9/L
- Platelet count ≥ 100 x 10^9/L
- Haemoglobin ≥ 90 g/L (in absence of red blood cell transfusion within 4 weeks prior to randomisation)
- Hepatic function: serum alanine aminotransferase (ALT) and/or aspartate transaminase (AST) ≤ 2.5 x upper limit of normal (ULN), total bilirubin ≤ 1.5 x ULN
- Creatinine ≤ 2.0 x ULN
- Sexually active patients must agree to use an effective contraceptive method while on treatment and for 1 week after the final dose of investigational product
- Patient must be affiliated to a Social Security System or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials)
- Patient must be willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow- up
Exclusion Criteria
- Clinically or radiologically detectable metastasis, defined as: - Any bone or visceral disease on PSMA PET/CT or conventional imaging - Any non-pelvic nodal metastasis on PSMA PET/CT or conventional imaging - Any enlarged pelvic lymph node (≥ 1 cm in small diameter) on conventional imaging (CT scan or MRI). Note: Patients with infra-centimetric pelvic nodal disease (< 1 cm in small diameter) on conventional imaging can be included even if they have PSMA PET/CT suggestive of pelvic nodal metastasis.
- Recent history of TURP or prostate enucleation (less than 6 months)
- Prior treatment for prostate cancer except lymph node dissection (i.e. patients with PN- disease only can be included) or ADT (started more than 6 weeks before randomisation).
- Patient with other known concurrent severe and/or uncontrolled concurrent medical disease or infection (such as active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease) or co-morbidity, which could compromise participation in the study.
- Cardiac disease such as uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg; 3 consecutive measures taken 5 minutes apart), stroke, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infarction within one year, coronary/peripheral artery bypass graft, LVEF > grade 2,
- Uncontrolled diabetes mellitus
- Current active hepatic or biliary disease (with exception of subjects with Gilbert's syndrome, asymptomatic gallstones, stable chronic liver disease per investigator assessment)
- Gastrointestinal disorder or procedure, which expects to interfere significantly with absorption of study treatment. Severe GI disorders precluding pelvic irradiation
- Known severely impaired lung function (spirometry and DLCO 70% or less of normal and O2 saturation of 88% or less at rest on room air)
- Other prior malignancies within the last 3 years, except basal cell skin cancer
- Known hypersensitivity to the study treatment or any of its ingredients
- Physical or psychological condition or any condition that in the opinion of the investigator would impair the patients' ability to comply with the study procedures
- Previous treatment for prostate cancer (surgery or radiotherapy) or previous pelvic irradiation that would make prostate/pelvis radiotherapy impossible
- Concomitant prohibited treatment. Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5. A one-week washout period is necessary for patients who are already on these treatments
- Prior treatment with second generation androgen receptor (AR) inhibitors, other investigational AR inhibitors, or CYP17 enzyme inhibitor
- Use of oestrogens or 5-α reductase inhibitors or AR inhibitors
- Acute toxicities of prior treatments and procedures not resolved to grade ≤ 1 or baseline before randomisation.
- Prior chemotherapy or immunotherapy for prostate cancer.
- Major surgery within 28 days before randomisation
- Participation in another therapeutic trial within 30 days prior to inclusion
- Persons deprived of their liberty or under protective custody or guardianship
- Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 10 Jun 2024 | 550 |
 Spain | Recruiting | 10 Jun 2024 | 50 |
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 |
|---|---|---|---|---|---|---|
NUBEQA 300 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 1200 | 24 | PRD7991449 |
TRIPTORELIN | Other | — | INTRAMUSCULAR OR SUBCUTANEOUS | 11.25 | 24 | SUB11324MIG |
BAY 1841788 | Test | FILM-COATED TABLET | ORAL | 1200 | 24 | PRD1849573 |