A Study Called ARAMON to Learn to What Extent Does Study Treatment With Darolutamide Affects Testosterone Levels in Men With Prostate Cancer That Had Not Been Treated With Hormonal Therapy Compared to Treatment With Enzalutamide

Study Overview
=================
Brief Summary
-----------------
Researchers are looking for a better way to treat men who have biochemically recurrent hormone-naïve prostate cancer. Hormone-naïve prostate cancer is a prostate cancer that has not yet been treated with hormonal therapy including androgen deprivation therapy (ADT). Biochemically recurrence (BCR) means that patients who received local treatment (surgery or radiation therapy) for prostate cancer now present with a rise in the blood level of a specific protein called PSA (prostate-specific antigen) but no detectable cancer or cancer spreading after a treatment that aimed to cure their prostate cancer (e.g. surgery and radiation). This may mean that the cancer has come back as the PSA level can be taken as a marker for prostate cancer development. Although men with BCR may not have symptoms for many years, proper treatment for BCR is important as the cancer may spread to other parts of the body in 7-8 years. In prostate cancer patients, male sex hormones like testosterone (also called androgens) can sometimes help the cancer spread and grow. To reduce androgen levels in these patients, androgen deprivation therapy (ADT) is often used. Second generation androgen receptor inhibitors including Darolutamide and Enzalutamide are available for the treatment of prostate cancer in addition to ADT. These inhibitors work by blocking androgen receptors and preventing it from attaching to proteins in cancer cells in the prostate. It is already known that men with prostate cancer benefit from these treatments. But besides benefits, Darolutamide and Enzalutamide are not without side effects. Clinical studies have shown that treatment with Enzalutamide increase testosterone level in serum, probably because it can pass blood brain barrier and goes into the central nervous system (CNS). The increased testosterone levels are thought to cause some specific side effects including so called feminizing side effects like overdevelopment of the breast tissue in men, and breast tenderness. Darolutamide has a distinct chemical structure and reduced ability to enter the CNS compared with Enzalutamide. That means that Darolutamide potentially leads to fewer and less severe side effects than Enzalutamide. In this study researchers will collect more data to learn to what extent Darolutamide affects serum testosterone levels in men with BCR in hormone-naïve prostate cancer. This study will consist of 2 stages. In stage 1 (also called lead-in phase) all participants will take Darolutamide by mouth twice a day. The study team will monitor and measure testosterone levels in the blood after: 12 weeks 24 weeks and 52 weeks of treatment. The second stage (also called randomized phase) is conditional and depends on the results from the stage 1. It will be conducted if after 24 weeks of treatment with Darolutamide in stage 1: a mean change in blood testosterone levels is below 45% and if the feminizing side effects (including overdevelopment of the breast tissue in men, and breast tenderness) will occur less frequently than previously reported. In the second stage of this study all participants will be randomly (by chance) assigned into two treatment groups, taking either Darolutamide twice daily or Enzalutamide once daily by mouth for a minimum of 12 and a maximum of 52 weeks. During both stages of this study the study team will: do physical examinations take blood and urine samples examine heart health using ECG examine heart and lung health using CPET check bone density using x-ray scan (DEXA) check vital signs check if the participants' cancer has grown and/or spread using CT (computed tomography) or MRI (magnetic resonance imaging) and, if needed, bone scan ask the participants questions about how they are feeling and what adverse events they are having. An adverse event is any medical problem that a participant has during a study. Doctors keep track of all adverse events that happen in studies, even if they do not think the adverse events might be related to the study treatments. The study participants who receive Darolutamide in stage 2 can continue to receive their treatments as long as they benefit from the treatment. The participants from the Enzalutamide group can also switch to treatment with Darolutamide after finishing stage 2. The study team will continue to check the participants' health and collect information about medical problems that might be related to Darolutamide until up to 30 days of last dose for those participants who continue on treatment with Darolutamide.

Official Title
-----------------
A 2-stage, Lead-in and Randomized, Phase 2, Open-label Study of Darolutamide Versus Enzalutamide as Monotherapy on Testosterone Levels Change in Men With Hormone-Naïve Prostate Cancer

Conditions
-----------------
Biochemically Recurrent Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Darolutamide(BAY1841788, Nubeqa)
* Drug: Enzalutamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male of ≥ 18 years of age. Patients must have histologically or cytologically confirmed adenocarcinoma of the prostate. Prior treatment with primary radical prostatectomy or definitive RT for localized prostate cancer Patients must have PSA rise ≥2 ng/ml at screening The presence of 5 or less asymptomatic metastatic lesions on conventional or PSMA-PET based imaging methods permitted. Lesions that need treatment with any opioid based analgetic are considered symptomatic Rising PSA as confirmed by at least 3 consecutive PSA values, AND Interval between first and last PSA values of >8 weeks but <12 months PSA doubling time (PSADT) ≥6, ≤ 20 months calculated per PCWG3 and MSKCC nomogram Eastern Cooperative Oncology Group ECOG (PS) of 0 - 1. Baseline serum testosterone >150 ng/dl Patients must have adequate organ function within 4 weeks prior to enrollment Exclusion Criteria: Current or prior use of androgen deprivation therapy (ADT) during the prior 6 months (prolonged use of ADT not allowed to prevent suboptimal T rise); plan to initiate ADT during the trial period is not allowed Radiation therapy (RT) or major surgery within 4 weeks of trial enrollment Baseline testosterone level < 150 ng/dL Systemic glucocorticoids within 3 months prior to enrollment or was expected to require systemic glucocorticoids during the study period 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 A GI disorder or procedure which is expected to interfere significantly with absorption of study drug Prior history of a clinically significant malignancy with the exception of basal cell and squamous cell carcinoma of the skin Prior treatment with: Second-generation androgen receptor (AR) inhibitors such as enzalutamide, apalutamide, darolutamide other investigational AR inhibitors or Cytochrome P17 enzyme inhibitor such as abiraterone acetate as antineoplastic treatment for prostate cancer

Ages Eligible for Study
-----------------
Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lead-in phase: Darolutamide treatment<br>Darolutamide treatment arm is single cohort in lead-in phase. | Drug: Darolutamide(BAY1841788, Nubeqa)<br>* tablet, oral<br>|
| Experimental: Randomized phase: Darolutamide treatment<br>The conduct of the randomized phase is dependent on the results of the lead-in phase. | Drug: Darolutamide(BAY1841788, Nubeqa)<br>* tablet, oral<br>|
| Active Comparator: Randomized phase: Enzalutamide treatment<br>The conduct of the randomized phase is dependent on the results of the lead-in phase. | Drug: Enzalutamide<br>* tablet, oral<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lead-in phase: Change in serum testosterone |  | From baseline to week 12 | 
| Randomized Phase: Change in serum testosterone |  | From baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lead-in phase: Change in serum testosterone |  | From baseline to week 24 and 52 | 
| Lead-in phase: Serum Prostate-specific antigen (PSA) |  | At week 4, 12, 24, 36, 52 | 
| Lead-in phase: Number of participants with Adverse Event (AE) | AE assessments using National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE) v.5.0 | From the signing of Informed Consent Form (ICF) up to 30 days after last dose administration, up to 13 months | 
| Randomized Phase: Change in serum testosterone |  | From baseline to week 24 and 52 | 
| Randomized Phase: Serum PSA |  | At week 4, 12, 24, 36, 52 | 
| Randomized Phase: Number of participants with Adverse Event (AE) | AE assessments using National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE) v.5.0 | From the signing of Informed Consent Form (ICF) up to 30 days after last dose administration, up to 13 months | 
| Randomized Phase: Quality of life (QoL) assessments | QoL assessment using Functional Assessment of Cancer Therapy - Prostate Cancer (FACT-P) questionnaire. FACT-P is a multidimension, selfreport QoL instrument specifically designed for patients with prostate cancer. It consists of 39 questions items, made up by 2 parts: the 27 questions for functional assessment of cancer therapy general (FACT-G) and 12 prostate cancer subscale questions. It assesses 4 main domains which are: physical (n=7), social/family (n=7), emotional (n=6) and functional wellbeing (n=7). | From the signing of Informed Consent Form (ICF) up to 30 days after last dose administration, up to 13 months | 
| Randomized Phase: Changes in the blood levels of dihydrotestosterone (DHT) |  | At week 4, 12, 24, 36 and 52 | 
| Randomized Phase: Changes in the blood levels of dehydroepiandrosterone (DHEA), sex hormone-binding globulin (SHBG), Androstenedione and Prolactin |  | At week 4, 12, 24, 36 and 52 | 
| Randomized Phase: Changes in the blood levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) |  | At week 4, 12, 24, 36 and 52 | 
| Randomized Phase: Changes in the blood levels of Estradiol |  | At week 4, 12, 24, 36 and 52 | 
| Randomized Phase: Changes in the blood levels of Total cholesterol, High-density and low-density lipoproteins, Triglycerides and Fasting glucose |  | At week 4, 12, 24, 36 and 52 | 
| Randomized Phase: Changes in the blood levels of Haemoglobin A1c |  | At week 4, 12, 24, 36 and 52 | 
| Randomized Phase: Changes in the blood levels of Fat body mass and Lean body mass |  | At week 4, 12, 24, 36 and 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hormone-naive prostate cancer