Evaluation of Darolutamide in Combination with Androgen Deprivation Therapy and Radiation for High-Risk Localized Prostate Cancer: A Phase 3 Randomized Trial

Trial ID: 2024-514565-18-00
Sponsor: Cancer Trials Ireland

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Diseases & Conditions

Prostate cancer

Objectives

The primary objective of this study is to evaluate **metastasis-free survival** (MFS) in patients with localized very high-risk cancer of the prostate. This is clinically relevant as MFS is a critical endpoint that reflects the time until the development of distant metastasis or death from any cause, providing insight into the efficacy of the treatment in delaying disease progression.

Secondary objectives include:

Overall survival (OS), assessing death from any cause.
Prostate cancer-specific survival, focusing on mortality directly attributable to prostate cancer.
PSA-progression free survival, measuring the time until prostate-specific antigen levels indicate disease progression.
Time to subsequent hormonal therapy, evaluating the duration before the need to restart or change hormonal treatment due to recurrence or progression.
Time to castration-resistance, based on PCWG3 criteria, indicating the time until the disease becomes resistant to castration-level testosterone.
Frequency and severity of adverse events, using CTCAE v5.0 and RTOG/EORTC criteria to assess treatment safety.
Health-related quality of life, measured by EORTC QLQ-C30, QLQ-PR25, and EQ-5D-5L questionnaires.
Fear of cancer recurrence, evaluated using the Fear of Cancer Recurrence Inventory (FCRI).
Incremental cost-effectiveness, analyzing the economic impact of the treatment.
Identification of biomarkers that are prognostic and/or predictive of response to treatment, safety, and resistance, examining associations with clinical outcomes.

Participants

The clinical trial involves a total of **1071 participants** diagnosed with **Localised Very High-Risk Cancer of the Prostate**. The study population consists exclusively of **male subjects** aged 18 years and older, with a pathological diagnosis of adenocarcinoma of the prostate. Participants were selected based on specific inclusion criteria, including adequate bone marrow, liver, and renal function, as well as an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. The trial does not include a vulnerable population. Participants are required to have a planned study treatment that can commence within seven days post-randomization and must be willing to complete health-related quality of life questionnaires unless hindered by literacy or vision limitations. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the selection process or lifestyle factors.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of **darolutamide** in combination with androgen deprivation therapy and radiation therapy in patients with localized very high-risk prostate cancer. The trial aims to assess the primary endpoint of metastasis-free survival (MFS), with secondary endpoints including overall survival, prostate cancer-specific survival, and PSA progression-free survival, among others. The study is expected to run until June 2029, with recruitment having commenced in May 2021.

Participants will be involved in the study for a maximum treatment period of 96 weeks, with the possibility of early termination if specific conditions arise, such as adverse events or non-compliance with study protocols. The trial includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, diagnosis, and organ function; regular follow-up visits to monitor treatment response and safety; and an end-of-study visit to assess final outcomes and gather data on long-term effects.

Inclusion criteria require participants to be men aged 18 years or older with a pathological diagnosis of adenocarcinoma of the prostate, among other health and treatment-related conditions. The study is structured to ensure that treatment can commence within seven days post-randomization, and participants must be willing to comply with all study requirements, including completing health-related quality of life questionnaires unless unable due to literacy or vision limitations. The trial's design and methodology are structured to provide robust data on the effectiveness and safety of the treatment regimen in this patient population.

Treatment

The clinical trial involves the administration of **darolutamide**, an experimental medication identified by the product code 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, a chemical compound developed by Bayer AG. The maximum daily dose for participants is set at 1200 mg, which equates to four tablets per day. The total maximum dose over the course of the trial is 806,400 mg, with a treatment period extending up to 96 weeks. Participants are required to adhere to the dosing schedule, and compliance will be monitored throughout the study to ensure accurate data collection and participant safety.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled trial. The placebo is designed to mimic the appearance of the BAY 1841788 film-coated tablet, also in a 300 mg form, but contains no active pharmaceutical ingredients. The placebo is administered orally, following the same dosing schedule as the experimental medication, to maintain the integrity of the study's blinding process. The use of a placebo allows for the assessment of darolutamide's efficacy and safety in comparison to a non-active treatment, providing a robust framework for evaluating the trial's primary objective of metastasis-free survival in patients with very high-risk, clinically localized prostate cancer.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the endpoint of **Metastasis-free Survival (MFS)**, which includes the occurrence of metastasis or death from any cause. Secondary endpoints will further evaluate efficacy and include Overall Survival (OS), Prostate cancer-specific Survival, PSA Progression-free Survival, Time to Subsequent Hormonal Therapy, Time to Castration Resistance (PCWG3 criteria), and Health Related Quality of Life (HRQL). Additionally, the trial will assess the frequency and severity of adverse events, Fear of Cancer Recurrence, Incremental cost-effectiveness, and prognostic/predictive biomarkers.

The trial is designed as a randomized, phase 3, double-blind, placebo-controlled study. The efficacy parameters will be measured and collected at specified timepoints throughout the trial duration, which is estimated to conclude by June 2029. The assessments will be conducted using validated scales and laboratory tests, ensuring the reliability and accuracy of the data collected. The trial will involve the administration of the investigational product, **darolutamide**, in the form of film-coated tablets, with a maximum daily dose of 1200 mg, over a treatment period of up to 96 weeks. The trial will also include a placebo group for comparative analysis.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Men aged 18 years and older, with pathological diagnosis of adenocarcinoma of the prostate
EITHER planned for primary RT and judged to be at very high risk for recurrence based on any of the following: • Grade Group 5, OR • Grade Group 4 AND one or more of the following: clinical T2b-4 OR MRI with seminal vesicle invasion OR extracapsular extension OR PSA* > 20ng/mL, OR • Pelvic nodal involvement (involvement of lymph nodes (LNs) at or below the bifurcation of the aorta into the common iliac arteries) defined radiologically as greater than 10mm on short axis using standard CT or MRI, or pathologically confirmed (PSMA PET alone is not considered enough if ≤ 10mm) OR Post-radical prostatectomy ≤ 365 days prior to randomisation and planned for RT with PSA* ≥ 0.1 ng/mL that has risen or remained stable (within ≤ 0.05 ng/mL) since a previous level at least 1 week earlier, judged to be at very high risk for recurrence based on any of the following: • Grade Group 5, OR • Grade Group 4 AND pT3a or higher, OR • Pelvic nodal involvement (involvement of LNs at or below the bifurcation of the aorta into the common iliac arteries) defined radiologically as greater than 10mm on short axis using standard CT or MRI, or pathologically confirmed (PSMA PET alone is not considered enough if ≤ 10mm) * Screening PSA levels are those measured within 240 days prior to randomisation.
Adequate bone marrow function: Haemoglobin ≥ 100g/L, white cell count (WCC) ≥ 4.0x109/L, absolute neutrophil count (ANC) ≥ 1.5x109/L and platelets > 100 x 109/L
Adequate liver function: alanine aminotransferase (ALT) < 2 x upper limit of normal (ULN) and total bilirubin < 1.5 x ULN, (or if total bilirubin is between 1.5 - 2 x ULN, they must have a normal conjugated bilirubin)
Adequate renal function: calculated creatinine clearance > 30 mL/min (Cockroft-Gault)
Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1
Study treatment both planned and able to start within 7 days after randomisation
Willing to complete health-related quality of life (HRQL) questionnaires UNLESS is unable to complete because of literacy or limited vision
Willing and able to comply with all study requirements, including standard of care treatment such as EBRT, timing and/or nature of required assessments
Signed, written informed consent

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Exclusion Criteria

Prostate cancer with predominant non-adenocarcinoma features (sarcomatoid or spindle cell or neuroendocrine small cell or squamous cell components or other non-adenocarcinoma)
Involvement of LNs by conventional CT imaging superior to the common iliac artery bifurcation, and/or outside the pelvis (distant LNs). LN involvement is defined by histopathological confirmation, or by a short axis measurement > 10mm on standard imaging (CT or MRI, but not PET).
Evidence of metastatic disease. Minimum imaging requirements to exclude metastatic disease are diagnostic quality imaging of both the pelvis and the abdomen (CT or MRI), chest (CXR or CT), and a whole-body radioisotope bone scan (WBBS). • If endocrine therapy (ET) had not started, imaging must be within 60 days prior to randomisation. • If ET has been started, radiographic imaging (CT/MRI/CXR) must have been performed no more than 60 days prior to starting ET and no more than 30 days after starting ET and prior to randomisation. If a WBBS was not performed within this timeframe, but a PSMA PET performed within this timeframe showed no bone metastases, then a WBBS must be performed before randomisation.
PSA > 100 ng/mL at any time
Any prior use of new generation potent AR inhibition (abiraterone, enzalutamide, apalutamide, darolutamide or similar agents).
Prior endocrine therapy for prostate cancer except for the following which are allowed: • (i) LHRHA and/or (ii) a first-generation nonsteroidal antiandrogen (NSAA) are allowed if commenced no more than 90 days before randomisation. If an NSAA has been used, it must be stopped before starting study treatment with darolutamide/placebo; and • Prior use of 5-alpha reductase inhibitor is allowed and if used, it must be stopped before starting study treatment with darolutamide/placebo.
Bilateral orchidectomy
Prior pelvic brachytherapy or other radiotherapy that would result in an overlap of radiotherapy fields that would preclude the required RT
History of • Loss of consciousness or transient ischemic attack or stroke within 6 months prior to randomisation, or • Significant cardiovascular disease within 6 months prior to randomisation: including myocardial infarction, unstable angina, congestive heart failure (NYHA grade II or greater), ongoing arrhythmias of Grade > 2 (CTCAE v5.0), thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism), coronary artery bypass graft. Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed.
Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of darolutamide, including difficulty swallowing tablets
History of another malignancy within 5 years prior to randomisation except for those malignancies treated with curative intent with a predicted risk of relapse of less than 10% including but not limited to non-melanoma carcinoma of the skin; or adequately treated, non-muscle-invasive urothelial carcinoma of the bladder (i.e., Tis, Ta and low grade T1 tumours). All such cases with a history of malignancy within the last 5 years are to be discussed with study team before randomisation. Melanoma in-situ and other adequately treated in-situ neoplasms are not considered malignancies for the purposes of eligibility assessment.
Concurrent illness, including severe infection, which might jeopardise the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety (HIV infection is not an exclusion criterion if it is controlled with anti-retroviral drugs that are unaffected by concomitant darolutamide)
Presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse
Patients who are sexually active with women of child-bearing potential and not willing/able to use medically acceptable and highly effective forms of contraception during study treatment and for at least 4 weeks after completion of study treatment. Contraception must include: - Condom use (also required if sexual partner is pregnant), and - Additional birth control with low failure rate (less than 1% per year) when used consistently and correctly. E.g., combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner, true sexual abstinence. True sexual abstinence will only be an acceptable form of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to study treatment, and withdrawal are not acceptable methods of contraception.
Participation in other clinical trials of investigational agents for the treatment of prostate cancer or other diseases
Major surgery within 21 days prior to randomisation
Patients with history of hypersensitivity to the study treatment