SUrGery with or without dARolutamide in high-risk and/or locally advanced prostate cancer

Trial ID: 2022-501518-67-00
Protocol: 22GENH03
Sponsor: Oncopole Claudius Regaud

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Diseases & Conditions

Prostate cancer

Objectives

The primary objective of this study is to determine if treatment with peri-operative **darolutamide** before and after surgery results in an improvement in non-curable progression-free survival, as compared to surgery alone, in patients with high-risk and/or locally advanced prostate cancer. This is clinically relevant as it may offer a therapeutic advantage in managing disease progression in this patient population.

Secondary objectives include:

To determine if treatment with peri-operative darolutamide before and after surgery results in an improvement in other efficacy endpoints, such as metastasis-free survival, prostate-specific antigen recurrence-free survival, and overall survival, compared to surgery alone.
To evaluate the pathological complete response rate in the experimental arm.
To characterize the safety profile of treatment with peri-operative darolutamide before and after surgery.
To evaluate the patient's quality of life.

Participants

The clinical trial focuses on **high-risk and/or locally advanced prostate cancer** and involves a study population exclusively composed of male participants. The age range of the participants is 18 years and older, with no upper age limit specified. The trial does not include a vulnerable population. Participants are required to have a histologically confirmed diagnosis of adenocarcinoma of the prostate, with specific criteria defining high-risk and/or locally advanced disease. The trial population was selected based on their eligibility for radical prostatectomy and adequate organ function, as determined by specific laboratory values. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Lifestyle considerations include the ability to swallow whole study drug tablets and adherence to effective contraception if engaged in sexual activity with a woman of childbearing potential. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **darolutamide** in combination with surgery compared to surgery alone in patients with high-risk and/or locally advanced prostate cancer. This is a randomized, double-blind, controlled trial with an estimated duration from March 2023 to March 2030. Participants will be randomly assigned to receive either the investigational product, **darolutamide**, or a placebo, in addition to undergoing surgery. The primary objective is to assess the improvement in non-curable progression-free survival (NC-PFS) with the addition of **darolutamide**.

The trial will include several study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis, and organ function. Participants must be at least 18 years old, have a histologically confirmed adenocarcinoma of the prostate, and meet specific high-risk criteria. The screening visit will also ensure that participants have no distant metastasis and are eligible for radical prostatectomy. Following the screening, participants will undergo randomization and commence treatment, which may last up to 9 months.

Throughout the trial, participants will attend regular follow-up visits to monitor their health status, treatment adherence, and any adverse events. These visits will include assessments of organ function, disease progression, and quality of life using standardized questionnaires. The end-of-study visit will occur after the completion of the treatment period or upon early termination from the study. Early termination may occur if a participant experiences significant adverse effects, withdraws consent, or fails to comply with the study protocol.

Participant involvement is expected to last for the duration of the treatment period, with additional follow-up visits as required. The trial will also evaluate secondary endpoints such as metastasis-free survival, PSA-recurrence-free survival, overall survival, and safety. The trial's findings will contribute to understanding the potential benefits of **darolutamide** in managing high-risk and/or locally advanced prostate cancer.

Treatment

The clinical trial involves the administration of the experimental medication **darolutamide**, marketed under the product name BAY 1841788. This medication is provided in the form of a **film-coated tablet** and is intended for oral administration. Each tablet contains 300 mg of darolutamide, and the maximum daily dose is set at 1200 mg. The treatment period for participants is up to 9 months. Darolutamide is a chemical-origin active substance developed by Bayer AG, and it is not formulated for pediatric use. The primary objective of the trial is to assess the efficacy of peri-operative darolutamide in improving non-curable progression-free survival in patients with high-risk and/or locally advanced prostate cancer.

In addition to the experimental treatment, the study includes a comparator group receiving standard surgical intervention without darolutamide. This allows for a direct comparison of outcomes between the experimental group and the standard-of-care group. The trial does not utilize a placebo, as the comparator is the surgical procedure alone. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol. Participants are required to take the medication as prescribed, and any deviations from the dosing regimen are documented and analyzed as part of the study's compliance assessment.

Efficacy

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **non-curable progression-free survival (NC-PFS)**, defined as the time from randomization to a non-curable event. Patients who are alive without a non-curable event at the time of analysis will be censored at the last disease assessment. Secondary endpoints include **metastasis-free survival (MFS)**, **PSA-recurrence-free survival (RFS)**, **overall survival**, and **pathological complete response rate**. MFS is defined as the time from randomization to the appearance of distant metastasis or death from any cause, with patients censored at the last disease assessment if alive without distant metastasis. PSA-RFS is defined as the time from randomization to PSA recurrence or death, with patients censored at the last PSA assessment if alive without PSA recurrence. Overall survival is defined as the time from randomization to death from any cause, with patients censored at the last known alive date. The pathological complete response rate is calculated as the number of patients with a complete response divided by the number of patients in the experimental arm.

Quality of life will be evaluated using validated questionnaires, including the Functional Assessment of Cancer Therapy-Prostate (FACT-P), EQ5D-5L, International Prostate Symptom Score (IPSS), and International Index of Erectile Function (IIEF-15). Safety will be assessed using the NCI-CTCAE Version 5.0. These assessments will be conducted at specified timepoints throughout the trial to ensure comprehensive data collection and analysis. The trial aims to determine if peri-operative darolutamide improves outcomes compared to surgery alone in patients with high-risk and/or locally advanced prostate cancer.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥18 years
Histologically confirmed adenocarcinoma of the prostate
High-risk and/or locally advanced prostate cancer diagnosis defined by: One of the following criteria is sufficient to define a high-risk and/or locally advanced prostate cancer: - ISUP grade 4 or 5 on biopsies - cN1 disease in MRI or PET-Scan - T3b disease in MRI If these criteria are not being identified, two of the following criteria are necessary to define high-risk and/or locally advanced prostate cancer: - PSA value >20 ng/ml - ≥ 50% of the core of biopsies need to be positive for adenocarcinoma ISUP grade 3 - T3a disease in MRI
No distant metastasis confirmed by imaging (i.e., MRI/CT-Scan and Bone Scintigraphy or PET-Scan)
Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0-1
Patient eligible for radical prostatectomy as per the investigator
Adequate organ function within 28 days prior to start of treatment determined by the following central laboratory values: - Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin less than the upper limit of normal (ULN; note that in subjects with Gilbert’s syndrome, if total bilirubin is >1.5 X ULN, measure direct and indirect bilirubin. If direct bilirubin is ≤1.5 X ULN, the subject may be eligible); - Serum creatinine <1.5 mg/dL; - Platelets ≥75,000/uL, without transfusion and/or growth factors within 1 month prior to randomization; - Hemoglobin >12.0 g/dL (7.4 mmol), without transfusion and/or growth factors within 1 month prior to randomization; - Adequate renal function: creatinine clearance/eGFR within normal limits to baseline assessed as per local standard method; - Normal cardiac function according to local standard by 12-lead Electrocardiogram (ECG) (complete, standardized 12-lead recording).
Patient able to receive darolutamide for up to 9 months, as per the investigator
Patient able to swallow whole study drug tablets
Life expectancy more than 5 years
Men engaged in sexual activity with a woman of childbearing potential should accept (or female partners of men enrolled in the study who are of childbearing potential or are pregnant) to use an highly effective contraception during darolutamide treatment and at least one week after the end of the investigational product
Signed informed consent
Patient able to participate and willing to give informed consent prior performance of any study-related procedures and to comply with the study protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations including follow up
Patient affiliated to a Social Health Insurance in France.

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Exclusion Criteria

Distant metastasis (clinical stage M1). Nodal disease below the iliac bifurcation (clinical stage N1) is not an exclusion.
Gastrointestinal conditions affecting absorption
Known or suspected contraindications or hypersensitivity to darolutamide
Treatment with strong CYP3A4 inducers and/or P-gp inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug
Major surgery within 28 days before first dose of study treatment
Any psychological, familial, geographic or social situation, according to the judgment of investigator, potentially preventing the provision of informed consent or compliance to study procedure
Patient who has forfeited his/her freedom by administrative or legal award or who is under legal protection (curatorship and guardianship, protection of justice)
Concurrent enrolment in another interventional therapeutic clinical study
Pathological finding consistent with small cell, ductal or neuroendocrine carcinoma of the prostate
Prior treatment for prostate cancer
Castrated men (Bilateral orchiectomy or other)
History of any pelvic radiation
Any of the following concurrent illness within 6 months prior to first dose of study drug: severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias or New York Heart Association Class II to IV heart disease; uncomplicated deep vein thrombosis is not considered exclusionary
Uncontrolled hypertension as indicated by a systolic blood pressure (BP) ≥ 160 mmHg or diastolic BP ≥ 100 mmHg at screening despite medical management. Participants with hypertension can enroll provided BP is stable and controlled by anti-hypertensive treatment
HIV-positive patient with one or more of the following: Not receiving highly active antiretroviral therapy; Had a change in antiretroviral therapy within 6 months of the start of screening; Receiving antiretroviral therapy that may interfere with study drug; CD4 count <350 at screening; AIDS-defining opportunistic infection within 6 months of start of screening
Active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction
Patients with a history of another malignancy at high risk of recurrence within 5 years and with a concurrent malignancy requiring active treatment or having required anticancer treatment within 6 months prior to inclusion