A Study to Compare Darolutamide Given With Androgen Deprivation Therapy (ADT) With ADT in Men With Hormone Sensitive Prostate Cancer and Raise of Prostate Specific Antigen (PSA) Levels After Local Therapies

Study Overview
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Brief Summary
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Researchers are looking for a better way to treat men at high-risk of biochemical recurrence (BCR) of prostate cancer. BCR means that in men who had prostate cancer and were treated by either surgery and/ or radiation therapy, the blood level of a specific protein called PSA rises. PSA is a marker of prostate cancer cells activity. The PSA increase means that the cancer has come back even though conventional imaging such as computed tomography (CT) scans, magnetic resonance imaging (MRI) and bone scans does not show any lesion of prostate cancer. Recently a more sensitive imaging method called prostate-specific membrane antigen [PSMA] positron emission tomography [PET]) /computed tomography [CT]) scan may identify prostate cancer lesions not detectable by conventional imaging. Men with BCR have a higher risk of their cancer spreading to other parts of the body, particularly when PSA levels raised to a certain limit within a short period of time after local therapies. Once the cancer spreads to other parts of the body, it can become even harder to treat. In men with prostate cancer, male sex hormones (also called androgens) like testosterone can help the cancer grow and spread. To reduce androgens levels in these patients, there are treatments that block androgens production in the body called androgen deprivation therapy (ADT). ADT is often used to stop prostate cancer. Another way to stop prostate cancer growth and spread is to block the action of androgen receptors on prostate cancer cells called androgen receptor inhibitors (ARIs). The new generation ARIs including darolutamide can block the action of androgens receptors and are available for the treatment of prostate cancer in addition to ADT. It is already known that men with prostate cancer benefit from these treatments. The main objective of this study is to learn if the combination of darolutamide and ADT prolongs the time that the participants live without their cancer getting worse, or to death due to any cause, compared to placebo (which is a treatment that looks like a medicine but does not have any medicine in it) and ADT given for a pre-specified duration of 24 months. To do this, the study team will measure the time from the date of treatment allocation to the finding of new cancer spread in the participants by using PSMA PET/CT, or death due to any cause. The PSMA PET/CT scans is performed using a radioactive substance called a tracer that specifically binds to the prostate-specific membrane antigen (PSMA) which is a protein often found in large amounts on prostate cancer cells. To avoid bias in treatment, the study participants will be randomly (by chance) allocated to one of two treatment groups. Based on the allocated treatment group, the participants will either take darolutamide plus ADT or placebo plus ADT twice daily as tablets by mouth. The study will consist of a test (screening) phase, a treatment phase and a follow-up phase. The treatment duration is pre-specified to be 24 months unless the cancer gets worse, the participants have medical problems, or they leave the study for any reason. In addition, image guided radiotherapy (IGRT) or surgery is allowed and your doctor will explain the benefits and risks of this type of therapy. During the study, the study team will: take blood and urine samples. measure PSA and testosterone levels in the blood samples do physical examinations check the participants' overall health examine heart health using electrocardiogram (ECG) check vital signs check cancer status using PSMA PET/CT scans, CT, MRI and bone scans take tumor samples (if required) ask the participants if they have medical problems About 30 days after the participants have taken their last treatment, the study doctors and their team will check the participants' health and if their cancer worsened. The study team will continue to check this and regularly ask the participants questions about medical problems and subsequent therapies until they leave the study for any reason or until they leave the study for any reason or until the end of the study, whatever comes first.

Official Title
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A Randomized, Double-blind, Placebo-controlled Phase 3 Study of Darolutamide Plus Androgen Deprivation Therapy (ADT) Compared With Placebo Plus ADT in Patients With High-risk Biochemical Recurrence (BCR) of Prostate Cancer

Conditions
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Biochemically Recurrent Prostate Cancer

Intervention / Treatment
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* Drug: Darolutamide (BAY1841788, Nubeqa)
* Other: Placebo matching darolutamide
* Other: ADT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving signed informed consent as described which includes compliance with the requirements, restrictions listed in the informed consent form (ICF), and in this protocol. Male ≥18 years of age at the time of signing the informed consent. Histologically or cytologically confirmed adenocarcinoma of prostate. Prostate cancer initially treated by: radical prostatectomy (RP) followed by adjuvant radiotherapy (ART), or salvage radiotherapy (SRT), or RP in participants who are unfit (or refused) for ART or SRT, or primary radiotherapy (RT). High-risk biochemical recurrence (BCR), defined as Prostate-specific antigen doubling time (PSADT) <12 months calculated using the formula provided by the Sponsor, and PSA ≥0.2 ng/mL after ART or SRT post RP or after RP in participants who are unfit for ART or SRT (local or central values accepted), or PSA ≥2 ng/mL above the nadir after primary RT only (local or central values accepted). Participants must undergo prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) within the 42-day Screening period using either 18F-DCFPyL (piflufolastat F 18) or 68Ga-PSMA-11 which will be assessed by blinded independent central review (BICR) to identify at least one PSMA PET/CT lesion of prostate cancer. Serum testosterone ≥150 ng/dL (5.2 nmol/L) (local or central values accepted). Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Blood counts at screening: Hemoglobin ≥9.0 g/dL (participant must not have received blood transfusion within 7 days prior to sample being taken); Absolute neutrophil count (ANC) ≥1.5x10^9/L (participant must not have received any growth factor within 4 weeks prior to sample being taken); Platelet count ≥100x10^9/L. Screening values of: Alanine aminotransferase (ALT) ≤1.5 x upper limit of normal (ULN); Aspartate aminotransferase (AST) ≤1.5 x ULN; Total bilirubin (TBL) ≤1.5 ULN, (except participants with a diagnosis of Gilbert's disease); Estimated glomerular filtration rate (eGFR) >40 ml/min/1.73 m^2 calculated by the CKD-EPI formula. Sexually active male participants must agree to use contraception as detailed in the protocol during the Treatment period and for at least 1 week after the last dose of study treatment, and refrain from donating sperm during this period. Exclusion Criteria: Pathological finding consistent with small cell, ductal or ≥50 % component of neuroendocrine carcinoma of the prostate. History of bilateral orchiectomy. Metastases or recurrent /new malignant lesions in prostate gland/bed seminal vesicles, lymph nodes below the CIA bifurcation on conventional imaging (CI) as assessed by BICR during screening. Brain metastasis on PSMA PET /CT by BICR at screening. High-risk BCR after primary radiotherapy with new loco-regional lesions on screening PSMA PET/CT who are eligible for curative salvage prostatectomy. Note: Participants treated with curative salvage prostatectomy after primary RT who meet the PSA criteria (inclusion criteria 5) may be considered for the study. Prior treatment with second generation (e.g. enzalutamide, apalutamide) androgen receptor inhibitors (ARIs) and CYP 17 inhibitors (e.g., abiraterone) within 18 months prior to signing of the ICF. Prior treatments with PSMA-radiotherapeutics within 12 months prior to randomization. Prior radiotherapy (including image-guided radiotherapy) as primary, adjuvant or salvage treatment completed within 8 weeks prior to signing of the ICF. Any prior malignancy (other than adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) within 5 years. History of pelvic radiotherapy for other malignancy.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Darolutamide+ADT<br>Participants will receive darolutamide plus ADT twice daily with food for a pre-specified duration of 24 months. | Drug: Darolutamide (BAY1841788, Nubeqa)<br>* Coated tablet, 300 mg / tablet, oral.<br>Other: ADT<br>* Luteinizing hormone-releasing hormone [LHRH] agonist/antagonists<br>|
| Placebo Comparator: Placebo+ADT<br>Participants will receive Placebo plus ADT twice daily with food for a pre-specified duration of 24 months. | Other: Placebo matching darolutamide<br>* Coated tablet, oral<br>Other: ADT<br>* Luteinizing hormone-releasing hormone [LHRH] agonist/antagonists<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological progression-free survival (rPFS) by Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) assessed by Blinded independent central review (BICR) |  | After randomization to after last treatment, approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metastasis-free survival (MFS) by Conventional imaging (CI) assessed by BICR |  | After randomization to after last treatment, approximately 46 months | 
| Time to Castration-resistant prostate cancer (CRPC) assessed by investigator |  | After randomization to after last treatment, approximately 46 months | 
| Time to initiation of first subsequent systemic antineoplastic therapy |  | After randomization to after last treatment, approximately 46 months | 
| Time to loco-regional progression by PSMA PET/CT |  | After randomization to after last treatment, approximately 46 months | 
| Time to first Symptomatic skeletal event (SSE) |  | After randomization to after last treatment, approximately 46 months | 
| Overall survival (OS) |  | After randomization to after last treatment, approximately 46 months | 
| Prostate-specific antigen (PSA) undetectable rates (<0.2 ng/mL) |  | After randomization to after last treatment, approximately 46 months | 
| Time to deterioration in the Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score | 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). | After randomization to after last treatment, approximately 24 months | 
| Time to symptomatic progression |  | After randomization to after last treatment, approximately 46 months | 
| Number of participants with Treatment-emergent adverse events (TEAEs) and Treatment-emergent serious adverse events (TESAEs) categorized by severity |  | After the first treatment until 30 days (+7 days) after the last treatment, up to 25 months | 
| Number of participants who discontinue study treatment due to a TEAE |  | After the first treatment until 30 days (+7 days) after the last treatment, up to 25 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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darolutamide, high risk BCR, PSMA PET imaging