A Trial Comparing Docetaxel 75 mg/m2 (3w) Versus Docetaxel 50 mg/m2 (2w) in Combination With Darolutamide + ADT in mHSPC Patients

Study Overview
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Brief Summary
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The purpose of this clinical phase 3 randomized trial is to compare two different dosing schedules of Docetaxel in combination with ADT and Darolutamide in subjects with mHSPC. The main question aims to compare grade 3-5 adverse events (AEs) in patients with mHSPC treated with 6 cycles of either Docetaxel 75 mg/m2 every 3 weeks in a 3 week cycle or 6 cycles of Docetaxel 50 mg/m2 every 2 weeks in a 4 week cycle in combination with Darolutamide + ADT. The primary endpoint are Grade 3-5 AEs, followed by neutropenia grade 3/4 + grade 5 AEs to be analysed 28 weeks after last patient first Docetaxel dose (LPFD).

Detailed Description
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This is a randomized, open, controlled, multicenter phase III clinical trial. Approximately 250 patients with mHSPC who are candidates for docetaxel, darolutamide and ADT will be randomized (1:1 ratio) to one of the following study arms: Arm 1: 6 x Docetaxel 75 mg/m2 every 3 weeks of a 3 week cycle Arm 2: 6 x Docetaxel 50 mg/ m2 every 2 weeks of a 4 week cycle Subjects will be stratified at randomization for the extent of disease and for Alkaline Phosphatase levels. All subjects must receive ADT of Investigator's choice (LHRH agonist/antagonists or orchiectomy) and darolutamide as standard therapy. Six cycles of docetaxel are be administered after randomization according to either Arm 1 or Arm 2. After completion of study drug treatment, subjects will continue with the observation period. During the observation period all subjects will continue with Darolutamide+ADT until occurrence of metastatic castration-resistant prostate cancer (mCRPC).

Official Title
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A Randomised, Phase 3 Trial Comparing 3-weekly Docetaxel 75 mg/m2 (in a 3 Week Cycle) Versus 2-weekly Docetaxel 50 mg/m2 (in a 4 Week Cycle) in Combination With Darolutamide + ADT in Patients With mHSPC

Conditions
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Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

Intervention / Treatment
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* Drug: Standard ADT (androgen deprivation therapy)
* Drug: Standard Darolutamide
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Males ≥18 years of age Histologically or cytologically confirmed adenocarcinoma of prostate Investigator assessed metastatic disease documented either by a positive bone scan, or for soft tissue or visceral metastases, either by contrast-enhanced abdominal/pelvic/chest computed tomography (CT) or magnetic resonance imaging (MRI) scan assessed. Metastatic disease is defined as either malignant lesions in bone scan or soft tissue/visceral lesions according to Response Evaluation Criteria In Solid Tumors (RECIST) 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. Subjects with lymph node metastases only (either below the aortic bifurcation (N1) or above the aortic bifurcation (M1a)) will not be eligible for the study. Subjects must be candidates for ADT, docetaxel and darolutamide therapy per Investigator's judgment Started ADT (LHRH agonist/antagonist or orchiectomy) with or without first generation anti-androgen, but no longer than 12 weeks before randomization. For subjects receiving LHRH agonists, treatment in combination with a first generation anti-androgen for at least 4 weeks, prior to randomization is recommended. First generation anti-androgen has to be stopped prior to randomization. An Eastern Cooperative Oncology Group performance status of 0 or 1 Blood counts at Screening: hemoglobin ≥9.0 g/dL, absolute neutrophil count ≥1.5x109/L, platelet count ≥100x109/L (subject 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 and/or aspartate transaminase ≤1.5x upper limit of normal (ULN), total bilirubin ≤ULN, creatinine ≤2.0x ULN Sexually active male subjects 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 darolutamide and for 3 months after the end of the treatment with darolutamide and 6 months after treatment with docetaxel. Exclusion Criteria: Exclusion criteria Prior treatment with: LHRH agonist/antagonists started more than 12 weeks before randomization Second-generation androgen receptor (AR) inhibitors such as enzalutamide, apalutamide, darolutamide, other investigational AR inhibitors Cytochrome P 17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as antineoplastic treatment for prostate cancer Chemotherapy, immunotherapy, radium or other therapeutic radiopharmaceuticals for prostate cancer (e.g. Lutetium177-PSMA) prior to randomization Treatment with radiotherapy (external beam radiation therapy, 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 both CT and MRI contrast agent 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 blood pressure (BP) ≥160 mmHg or diastolic BP ≥100 mmHg despite medical management Had a 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 treatment has been completed ≥5 years before randomization and from which the subject has been disease-free A gastrointestinal disorder or procedure which is expected to interfere significantly with absorption of study drug An active viral hepatitis, known human immunodeficiency virus infection with detectable viral load, or chronic liver disease with a need for treatment 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 subject and/or his/her compliance with study procedures, or may interfere with the subject's participation in the study or evaluation of the study results Inability to swallow oral medications Previous assignment to treatment in this study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1<br>6 x Docetaxel 75 mg/m2 every 3 weeks of a 3 week cycle Co-administration of docetaxel, darolutamide and standard ADT | Drug: Standard ADT (androgen deprivation therapy)<br>* as prescribed by the treating physician.<br>Drug: Standard Darolutamide<br>* 2x600 mg/d as prescribed by the treating physician<br>Drug: Docetaxel<br>* Docetaxel<br>|
| Experimental: Arm 2<br>6 x Docetaxel 50 mg/ m2 every 2 weeks of a 4 week cycle Co-administration of docetaxel, darolutamide and standard ADT | Drug: Standard ADT (androgen deprivation therapy)<br>* as prescribed by the treating physician.<br>Drug: Standard Darolutamide<br>* 2x600 mg/d as prescribed by the treating physician<br>Drug: Docetaxel<br>* Docetaxel<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of grade 3-5 AEs | Rate of grade 3-5 AEs, followed by rate of neutropenia grade 3/4 + grade 5 AEs t | 28 weeks after last patient first Docetaxel dose (LPFD) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA-response | PSA-response (PSA <=0.2, >0.2-4.0 und >4.0 ng/ml) determined at week 28 after LPFD | 28 after LPFD | 
| Time to castration-resistant prostate cancer | approx. every 90 days, defined as the time to PSA progression with serum testosterone being at castrate level <0.50 ng/mL, or the time to progression by soft tissue/visceral lesions or time to progression by bone lesions whatever comes first; | approximately 42 months | 
| Overall survival | defined as the time (in days) from date of randomization until death from any cause | approximately 42 months | 
| Time to initiation of subsequent antineoplastic therapy | approx. every 90 days up to the date of first subsequent antineoplastic therapy for prostate cancer | approximately 42 months | 
| Symptomatic skeletal event free survival (SSE) | approx. every 90 days up to the first occurence of SSE, symptomatic skeletal event free survival, defined as the time from randomization to the first occurrence of SSE or death from any cause, whichever comes first. An SSE is defined as EBRT to relieve skeletal symptoms, or new symptomatic pathologic bone fracture, or occurrence of spinal cord compression or tumor-related orthopedic surgical intervention, whichever comes first. | approximately 42 months | 
| Time to first symptomatic skeletal event (SSE) | approx. every 90 days up to the first occurence of SSE, defined as the time from randomization to the first occurrence of SSE. An SSE is defined as EBRT to relieve skeletal symptoms, or new symptomatic pathologic bone fracture, or occurrence of spinal cord compression or tumor-related orthopedic surgical intervention, whichever comes first. | approximately 42 months | 
| Time to pain progression | approx. every 90 days up to the first date a subject experiences a pain progression. Pain to be assessed with a patient reported questionaire | approximately 42 months | 
| Time to worsening of physical symptoms of disease | approx. every 90 days up to the first date a subject experiences an increase in physical symptoms based on the NCCN-FACT-FPSI-17 questionnaire | approximately 42 months | 
| Treatment emergent adverse events | all grade AEs until the end-of-study treatment visit (to be analysed 26 weeks after last patient first Docetaxel, all grade AEs until the discontinuation visit, all and Study drug-related SAEs until the end of Survival Follow-up | approximately 42 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostate cancer, metastatic prostate cancer, metastatic hormone-sensitive prostate cancer, docetaxel, darolutamide, safety