Evaluation of dAroLutamide Addition to anDrogen Deprivation Therapy and radIatioN Therapy in Newly Diagnosed Prostate Cancer With Pelvic Lymph Nodes Metastases

Study Overview
=================
Brief Summary
-----------------
Prospective, multicenter, comparative, randomized placebo-controlled Phase III trial - patients with hormone-naïve prostate cancer and pelvic lymph nodes metastases

Detailed Description
-----------------
Standard of care for patients with prostate cancer (PC) with pelvic lymph nodes metastases is radiotherapy (RT) with long-term androgen deprivation therapy (ADT). . Darolutamide improves survival in men with castration-refractory non metastatic prostate cancer. We hypothesize that adding Darolutamide to ADT and RT could improve FFS for these high-risk patients.

Official Title
-----------------
Evaluation of dAroLutamide Addition to anDrogen Deprivation Therapy and radIatioN Therapy in Newly Diagnosed Prostate Cancer With Pelvic Lymph Nodes Metastases

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Darolutamide 300 mg
* Drug: Placebo of Darolutamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Newly diagnosed, histologically confirmed prostate adenocarcinoma ≥ 18 years old. Initial staging with Pelvic MRI, CT-scan and or Choline or PSMA PET-CT Any T stage 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 LH-RH agonist or antagonist is allowed up to 2-months prior to randomization. Able to receive either protocol therapy and 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. Exclusion Criteria: Lymph nodes metastases outside of the pelvis Bone or visceral metastases Prior systemic therapy for locally-advanced prostate cancer. Prior treatment with: Second generation AR inhibitors such as enzalutamide, ARN-509, ODM-201, other investigational AR inhibitors, CYP17 enzyme inhibitor such as abiraterone acetate, TAK-700 or Oral ketoconazole longer than for 28 days. Use of estrogens, 5-α reductase inhibitors (finasteride, dutasteride) or AR inhibitors (bicalutamide, flutamide, nilutamide, cyproterone acetate) within 28 days before randomization. Prior chemotherapy or immunotherapy for prostate cancer, except adjuvant/neoadjuvant treatment, completed > 2 years before randomization. Use of systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/day within 28 days before randomization. Severe or uncontrolled concurrent disease, infection or co-morbidity that, in the opinion of the investigator, would make the patient inappropriate for enrolment. Initiation of treatment with bisphosphonate or denosumab within 12 weeks before randomization. Patients receiving bone loss prevention treatment on a stable dose of e.g. bisphosphonate or denosumab for at least 28 days before randomization 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 randomization. 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 (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 within 28 days before randomization. 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 tutorship and incapable to give informed consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Arm A: ADT + Intensity-Modulated Image-Guided Radiation Therapy + Darolutamide ADT will be associated with LHRH agonists or antagonists for 24 months4. Darolutamide regimen will be of 2 tablets of 300 mg orally twice daily for 24 months. | Drug: Darolutamide 300 mg<br>* Darolutamide regimen will be of 2 tablets of 300 mg orally twice daily for 24 months.<br>|
| Placebo Comparator: Arm B<br>Arm B: ADT + Intensity-Modulated Image-Guided Radiation Therapy + Placebo of Darolutamide ADT will be associated with LHRH agonists or antagonists for 24 months4. Darolutamide regimen will be of 2 tablets of 300 mg orally twice daily for 24 months. | Drug: Placebo of Darolutamide<br>* Placebo of Darolutamide regimen will be of 2 tablets of 300 mg orally twice daily for 24 months.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure-free survival FFS | The failure-free survival is defined as the time from the date of randomization to clinical (new cancer-related symptoms), biochemical (PSA rising) or radiological (local relapse or new metastases) progression, death, end of 3-year follow-up period or lost to follow-up, whichever occurs first. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metastasis-free survival rates | To evaluate the metastasis-free survival rates | 3 years | 
| PSA response levels | PSA response is defined by the rate of patients having a decrease of > 50% of their PSA level, as measured every 3 months from the date of randomization to the date of a documented biochemical relapse. | 3 years | 
| Overall survival rates | Overall survival is defined as the time from the date of randomization to the date of documented death from any cause, end of 3-year follow-up period or lost to follow-up, whichever occurs first | 3 years | 
| Cancer-specific survival rates | Cancer-specific survival is defined as the time from the date of randomization to the date of documented death from prostate cancer or complication from the treatment, end of 3-year follow-up period or lost to follow-up, whichever occurs first | 3 years | 
| Time to pain progression | Time to pain progression is defined as the time from the date of randomization to the date of documented pain, end of 3-year follow-up period or lost to follow-up, whichever occurs first | 3 years | 
| Toxicities | To evaluate toxicities (CTCAE v5.0) due to treatements | 3 years | 
| Quality of life of the patient | Quality of life will be assessed using self-administered questionnaires (EORTC QLQ-C302) | 3 years | 
| Quality of life of the participants | Quality of life will be assessed using self-administered questionnaires (EORTC QLQ-PR253) by patients | 3 years |