Treatment of High-Risk Prostate Cancer Guided by Novel Diagnostic Radio- and Molecular Tracers (THUNDER): A Two-part Phase 2/3 Trial

The primary objective of the study is to evaluate the improvements in **PSMA PET/CT metastasis-free survival** (ppMFS) in patients with high-risk prostate cancer. This is defined as the time from randomization to the occurrence of at least one new PSMA-PET-positive distant lesion or death from any cause. The clinical relevance of this objective lies in its potential to enhance the management and treatment strategies for prostate cancer by utilizing novel diagnostic tracers, thereby potentially improving patient outcomes.

The secondary objectives include:

• Overall survival (OS)
• Prostate cancer-specific survival
• Biochemical progression-free survival
• Time to next therapy
• Frequency and severity of adverse events (AEs)
• Determining differential treatment effects by comparing health-related quality of life (HRQL) scores between the randomly allocated groups

The clinical trial focuses on **prostate cancer** and involves a study population exclusively composed of male participants. The age range of the participants spans from adults to the elderly, specifically those aged 18 years and older. The trial does not include any vulnerable populations. Participants were selected based on specific criteria, including a histopathology-proven diagnosis of prostate cancer and high-risk disease characterized by factors such as a PSA level greater than 20 ng/mL, T-stage 3 or 4, or a Gleason score between 8 and 10. Additionally, participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status grade of 0 or 1. The trial does not provide information on the total number of participants, as the sponsor has not disclosed this data. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The trial population was selected to ensure participants' willingness to undergo specific procedures, including PSMA PET/CT scans and primary tumor sequencing, as well as adherence to standard of care radiotherapy and long-term androgen deprivation therapy.

The clinical trial is designed to evaluate the efficacy and safety of **darolutamide** in combination with standard of care (SOC) radiotherapy (RT) for the treatment of high-risk **prostate cancer**. This trial is structured as a two-part Phase 2/3 study, incorporating both intensification and de-intensification strategies. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from September 2023 to September 2030, with participant involvement expected to last up to 96 weeks, depending on the treatment arm.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histopathology-proven prostate cancer, high-risk disease factors, and an ECOG Performance Status grade of 0 or 1. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. The primary endpoint for the Phase 3 intensification study is the incidence of PSMA PET/CT metastasis-free survival (ppMFS), while the Phase 2 de-intensification study focuses on health-related quality of life (HRQL) as measured by the EPIC questionnaire. Secondary endpoints include overall survival, prostate cancer-specific mortality, and biochemical progression-free survival.

The end-of-study visit will occur at the conclusion of the treatment period or upon early termination, which may be necessitated by factors such as significant adverse events or disease progression. Participants will be closely monitored throughout the trial to ensure safety and adherence to the protocol. The trial aims to provide valuable insights into the potential benefits of darolutamide in improving outcomes for patients with high-risk prostate cancer.

The clinical trial involves the administration of several treatments, including experimental and non-experimental medications. The experimental medication **BAY 1841788**, also known as **darolutamide**, is provided in the form of a film-coated tablet. Each tablet contains 300 mg of darolutamide, and the maximum daily dose is 1200 mg. The medication is administered orally, with a treatment period extending up to 96 weeks. Darolutamide functions as an androgen receptor inhibitor, and participant compliance is monitored throughout the trial.

**TAXOTERE**, containing the active substance **docetaxel**, is used as a comparator treatment. It is available as a concentrate for solution for infusion, with a concentration of 160 mg/8 ml. The maximum daily dose is 75 mg/m², administered via intravenous infusion. The treatment period for docetaxel is up to 18 weeks. Docetaxel acts as a microtubule inhibitor, and its administration is closely monitored to ensure adherence to the dosing schedule.

**Orgovyx**, with the active ingredient **relugolix**, is another comparator treatment provided in the form of 120 mg film-coated tablets. The medication is administered orally, with a maximum daily dose of 120 mg and a treatment period of up to 96 weeks. Relugolix serves as an androgen deprivation therapy, and participant compliance is assessed regularly.

**ZOLADEX**, containing **goserelin acetate**, is administered as an implant. The available dosages are 3.6 mg and 10.8 mg, with subcutaneous use as the route of administration. The treatment period can extend up to 96 weeks. Goserelin acetate is a gonadotropin-releasing hormone analogue, and its administration is monitored to ensure proper dosing intervals.

**FIRMAGON**, with the active substance **degarelix**, is provided as a powder and solvent for solution for injection. The available dosages are 80 mg and 120 mg, administered via subcutaneous use. The treatment period is up to 96 weeks. Degarelix functions as a gonadotropin-releasing hormone analogue, and compliance with the dosing schedule is monitored.

**Decapeptyl Sustained Release**, containing **triptorelin**, is available in dosages of 3.75 mg, 11.25 mg, and 22.5 mg. It is administered as a suspension for injection, with intramuscular injection as the route of administration. The treatment period can extend up to 96 weeks. Triptorelin is a gonadotropin-releasing hormone analogue, and participant adherence to the dosing schedule is assessed.

**DEPO-ELIGARD**, with the active ingredient **leuprorelin acetate**, is provided as a powder and solvent for solution for injection. The available dosages are 7.5 mg, 22.5 mg, and 45 mg, administered via subcutaneous use. The treatment period is up to 96 weeks. Leuprorelin acetate acts as a gonadotropin-releasing hormone analogue, and compliance with the administration schedule is monitored.

A **placebo** of BAY 1841788 is also utilized in the trial. The placebo is administered in a manner consistent with the experimental medication to maintain blinding and ensure the integrity of the study results.

The clinical trial aims to assess the efficacy of treatments for high-risk prostate cancer using novel diagnostic radio- and molecular tracers. Efficacy will be evaluated through primary and secondary endpoints. The primary endpoints include the incidence of PSMA PET metastasis-free survival (ppMFS) in the Phase 3 Intensification study, defined as the time from randomization to the appearance of at least one new PSMA-PET-positive distant lesion or death from any cause. In the Phase 2 De-intensification study, health-related quality of life (HRQL) will be assessed using the Expanded Prostate Cancer Index Composite (EPIC) questionnaire, with specific point reductions in sexual and hormonal subdomains considered clinically significant at 12 months. EPIC scores will be measured annually to monitor late effects.

Secondary endpoints include overall survival (OS), prostate cancer-specific mortality (PCSM), biochemical progression-free survival, and time to next systemic therapy (NEST). OS will be measured from randomization to death or last known follow-up, with living patients censored at the last follow-up. PCSM will be measured from randomization to prostate cancer death. Biochemical progression-free survival will be assessed from randomization to PSA failure, castrate resistance, salvage therapy, or death, with censoring at the last follow-up. NEST will be measured from randomization to death or local/systemic therapy for prostate cancer, with censoring at the last follow-up. Additionally, adverse events (AEs) will be graded and counted by study phase and treatment arm, and EPIC mean changes in subdomain scores will be compared over time for both change from baseline and absolute HRQL scores.