Evaluation of Darolutamide Addition to Androgen Deprivation and Radiation Therapy in Hormone-Naïve Prostate Cancer with Pelvic Lymph Node Metastases
- Trial ID
- 2024-517285-41-00
- Sponsor
- ARTIC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the impact of **darolutamide** in addition to androgen deprivation therapy (ADT) and radiotherapy on failure-free survival (FFS) in patients with hormone-naïve prostate cancer and pelvic lymph nodes metastases. This is clinically relevant as it aims to improve the management and outcomes of patients with newly diagnosed prostate cancer, potentially enhancing survival rates and delaying disease progression.
Secondary objectives include:
- Failure-free survival rates at 3 years.
- Metastasis-free survival and metastasis-free survival rates at 3 years.
- Progression-free survival and progression-free survival rates at 3 years.
- Time to PSA response, time to PSA progression, and PSA response rate (30%, 50%, 90%, undetectable = 0.2 ng/mL), PSA at 6 months after completion of radiotherapy, and PSA ≥0.1 ng/mL at 6 months after completion of radiotherapy.
- Overall survival and survival rates at 3 years.
- Cancer-specific survival and cancer-specific survival rates.
- Time to pain progression (EVA scale).
- Toxicities (CTCAE v5.0).
- Quality of life (EORTC QLQ-C30 and QLQ-PR25).
Participants
The clinical trial involves a study population of **male** participants who are newly diagnosed with **prostate cancer** with pelvic lymph nodes metastases. The age range of the participants is 18 years and older. The trial does not include female subjects, and the population is not considered vulnerable. Participants were selected based on specific inclusion criteria, including a histologically confirmed diagnosis of prostate adenocarcinoma, an ECOG Performance Status of 0-2, and a life expectancy of at least 36 months. The trial does not provide information on the total number of participants. Relevant lifestyle considerations include the requirement for sexually active patients to use condoms as an effective barrier method during the study treatment and for three months after its conclusion. Participants must also be willing to comply with the follow-up schedule and be affiliated with the social security system. The sponsor has not provided data on the total number of participants.
Plans and Procedures
The clinical trial is designed to evaluate the impact of **darolutamide** in addition to androgen deprivation therapy (ADT) and radiotherapy on failure-free survival in patients with newly diagnosed prostate cancer with pelvic lymph nodes metastases. This study is a randomized, double-blind, controlled trial, with an estimated duration from August 2022 to December 2028. Participants will be randomly assigned to receive either the investigational product or a placebo, alongside standard ADT and radiotherapy. The trial will include several key phases, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as histologically confirmed prostate adenocarcinoma and specific laboratory values.
Following the screening, eligible participants will undergo a baseline visit where initial assessments and randomization will occur. The treatment phase will last up to 24 months, during which participants will receive the study medication and undergo regular follow-up visits. These visits are scheduled to monitor the participants' health, assess treatment efficacy, and record any adverse events. The primary endpoint is failure-free survival, defined as the time from randomization to clinical, biochemical, or radiological progression, death, or the end of the 3-year follow-up period, whichever occurs first.
Secondary endpoints include metastasis-free survival, progression-free survival, overall survival, and quality of life assessments. Participants are expected to be involved in the study for a minimum of 36 months, with regular assessments every three months. The study will conclude with an end-of-study visit, where final evaluations will be conducted. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial aims to provide comprehensive data on the efficacy and safety of darolutamide in combination with ADT and radiotherapy for this patient population.
Treatment
The clinical trial involves the administration of several treatments, including the experimental medication **BAY 1841788**, also known as **darolutamide**. This medication is provided in the form of a 300 mg film-coated tablet. The route of administration is oral, with a maximum daily dose of 1200 mg. The treatment period is set for a maximum of 24 months. Darolutamide is classified as an antiandrogen and is chemically derived. Participant compliance with the dosing schedule will be monitored throughout the trial.
In addition to the experimental medication, a **placebo** is used as a comparator. The placebo is designed to mimic the BAY 1841788 300 mg film-coated tablet in appearance but contains no active substance. The placebo is administered orally, following the same dosing schedule as the experimental medication, to maintain blinding in the study.
**Leuprorelin acetate** is included as an auxiliary treatment in the trial. It is administered via injection, with a maximum daily dose of 30 mg. The pharmaceutical form is identified as PHF00231MIG, and the treatment period is also set for a maximum of 24 months. Leuprorelin acetate is a protein-derived substance used in hormonotherapy.
Another auxiliary treatment is **degarelix**, which is also administered by injection. The maximum daily dose is 22.5 mg, and the treatment period is up to 24 months. Degarelix is a protein-derived substance used in hormonotherapy, with the pharmaceutical form designated as PHF00231MIG.
**Triptorelin acetate** is similarly used as an auxiliary treatment, administered via injection with a maximum daily dose of 22.5 mg. The treatment period is set for a maximum of 24 months. Triptorelin acetate is a protein-derived substance used in hormonotherapy, with the pharmaceutical form identified as PHF00231MIG.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is **failure-free survival**, defined as the time from randomization to clinical progression, biochemical progression (PSA rising above nadir + 2 ng/mL, according to the Phoenix criteria), radiological progression, death, end of the 3-year follow-up period, or loss to follow-up, whichever occurs first. Secondary endpoints include failure-free survival rates at 3 years, metastasis-free survival and rates at 3 years, progression-free survival and rates at 3 years, time to PSA response, time to PSA progression, overall survival and rates at 3 years, cancer-specific survival and rates, time to pain progression using the EVA scale, toxicities assessed by CTCAE v5.0, and quality of life measured by EORTC QLQ-C30 and QLQ-PR25.
Measurements for these endpoints will be collected at specified intervals throughout the trial. PSA levels will be measured every 3 months to assess PSA response and progression. The time to PSA progression is defined from baseline to the date of biochemical relapse as per the Phoenix criteria. Overall survival is calculated from treatment initiation to documented death from any cause, while cancer-specific survival is from treatment initiation to death from prostate cancer or treatment complications. Quality of life assessments will be conducted using validated questionnaires, EORTC QLQ-C30 and QLQ-PR25, to evaluate the impact of treatment on patients' daily living and well-being.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Newly diagnosed, histologically confirmed prostate adenocarcinoma
- ≥ 18 years old.
- Initial staging with Pelvic MRI + (contrast-enhanced body CT-scan + bone scan or Choline or PSMA PET-CT)
- Any T stage
- N stage: N1 - Pelvis lymph nodes metastases (upper limit defined as the L4/L5 interspace).
- Intention to treat with long-term androgen deprivation therapy (24 months).
- Hormonal therapy with LHRH agonist or antagonist is allowed up to 3 months prior to treatment initiation
- Able to receive protocol therapy and have life expectancy of at least 36 months, ECOG Performance Status (PS) 0-2.
- Blood counts at screening: hemoglobin ≥ 9.0 g/dl, absolute neutrophil count ≥ 1500/μl (1.5x109/l), platelet count ≥ 100,000/μl (100x109/l ) (patient must not have received any growth factor or blood transfusion within 7 days of the hematology laboratory obtained at screening).
- Screening values of serum alanine aminotransferase (ALT) and/or aspartate transaminase (AST) < 2.5 x upper limit of normal (ULN), total bilirubin < 1.5 x ULN (except patients with a diagnosis of Gilbert’s disease), creatinine < 2.0 x ULN.
- Sexually active patients, unless surgically sterile, must agree to use condoms as an effective barrier method during the study treatment and for 3 months after the end of the study treatment.
- Written informed consent.
- Willing and expected to comply with follow-up schedule.
- Affiliated to the social security system.
- Use of 5-α reductase inhibitors (finasteride, dutasteride) is allowed
Exclusion Criteria
- Lymph nodes metastases outside of the pelvis
- Bone or visceral metastases
- Prior systemic therapy for locally-advanced prostate cancer except for LHRH agonist or antagonist up to 3 months before treatment initiation
- Prior treatment with: - Second generation AR inhibitors such as enzalutamide, apalutamide (ARN-509), darolutamide (ODM-201) other investigational AR inhibitors - CYP17 enzyme inhibitor such as abiraterone acetate, TAK-700 or - Oral ketoconazole - Use of estrogens, or AR inhibitors (bicalutamide = Casodex©, flutamide, nilutamide, cyproterone acetate) within 28 days before treatment initiation.
- Use of systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/day within 28 days before treatment initiation
- Patients with QTor QTc interval > 450 ms on the ECG
- Initiation of treatment with bisphosphonate or denosumab within 12 weeks before treatment initiation. Patients receiving bone loss prevention treatment on a stable dose of e.g. bisphosphonate or denosumab for at least 28 days before treatment initiation can continue the treatment during the study.
- Known hypersensitivity to the study treatment (RT, ADT, darolutamide/placebo) or any of its ingredients.
- Major surgery within 28 days before treatment initiation.
- Any of the following within 6 months before treatment initiation: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft; congestive heart failure New York Heart Association (NYHA) Class III or IV or arterial thromboembolic event.
- Uncontrolled hypertension as indicated by a resting systolic BP > 160 mmHg or diastolic BP > 100 mmHg at screening. Patients may be re-screened after adjustments of anti- hypertensive medications.
- Prior malignancy. Adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder cancer that has not spread behind the connective tissue layer (i.e. pTis, pTa, and pT1) is allowed, as well as any other cancer for which chemotherapy has been completed > 5 years ago and from which the patient has been disease-free.
- Gastrointestinal disorder or procedure which expects to interfere significantly with absorption of study treatment.
- Active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease.
- Participation in another interventional clinical trial and any concurrent treatment with any investigational drug
- Any condition that in the opinion of the investigator would impair the patients’ ability to comply with the study procedures.
- Unable to swallow study medications and comply with study requirements
- Galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
- History of bilateral hip replacements making IMRT impossible
- Contra-indications for the administration of any of the study treatments (RT, ADT, darolutamide/placebo) or any of its ingredients.
- Patient under guardianship, administrative curatorship and not able to give informed consent
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 30 Aug 2022 | 152 |
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 |
|---|---|---|---|---|---|---|
LEUPRORELIN | Other | PHF00231MIG | INJECTION | 30 | 24 | SCP151923 |
BAY 1841788 | Test | FILM-COATED TABLET | ORAL | 1200 | 24 | PRD1849573 |
DEGARELIX | Other | PHF00231MIG | INJECTION | 22.5 | 24 | SCP8252543 |
Placebo to BAY 1841788 300 mg film-coated tablet | Placebo | N/A | — | — | — | N/A |
TRIPTORELIN | Other | PHF00231MIG | INJECTION | 22.5 | 24 | SCP1035124 |