PEACE 6 Vulnerable : A double-blind randomised phase III trial evaluating the efficacy of ADT +/- darolutamide in de novo metastatic prostate cancer patients with vulnerable functional ability and not elected for docetaxel or androgen receptor targeted agents.

The primary objective of this study is to compare the **efficacy** of androgen deprivation therapy (ADT) combined with darolutamide versus ADT combined with placebo in terms of radiographic progression-free survival in patients with castration-naïve de novo metastatic prostate cancer who have vulnerable functional ability and are not selected for treatment with docetaxel or other androgen receptor pathway inhibitors. This objective is clinically relevant as it aims to determine the potential benefits of adding darolutamide to standard ADT in improving disease control in a specific patient population that may not tolerate more aggressive treatments.

Secondary objectives include:

• Assessing the efficacy of ADT + darolutamide versus ADT + placebo in terms of castration-resistant prostate cancer-free survival, clinical progression-free survival, and overall survival.
• Evaluating the safety profile of the ADT + darolutamide combination.
• Determining the time to worsening in prostate cancer-related urinary symptoms.
• Measuring the time to the next symptomatic skeletal event.
• Assessing the prostate-specific antigen (PSA) response.
• Evaluating prostate cancer-specific survival.
• Assessing the effect of ADT + darolutamide on subsequent lines of therapy.
• Evaluating the evolution of quality of life and geriatric status during the treatment period.
• Evaluating the impact of sarcopenia on survival and treatment response.

The clinical trial involves a total of **20 participants** diagnosed with **adenocarcinoma of the prostate**. The study population consists exclusively of male subjects, aged 18 years and older, who have been diagnosed with castration-naïve de novo metastatic prostate cancer. Participants were selected based on their inability to undergo treatment with docetaxel or other androgen receptor pathway inhibitors, and they must meet at least one frailty criterion. The trial does not include a vulnerable population. Participants are required to have adequate bone marrow, liver, and renal function, as well as measurable disease or bone lesions evaluable according to PCWG3 criteria. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to use adequate contraception if sexually active. The selection process ensures that all participants have signed a written informed consent form and are willing and able to comply with the trial protocol, including treatment, scheduled visits, and follow-up examinations.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of androgen deprivation therapy (ADT) with or without **darolutamide** in patients with castration-naïve de novo metastatic **prostate cancer**. The primary objective is to assess radiographic progression-free survival, while secondary endpoints include castration-resistant prostate cancer-free survival, clinical progression-free survival, overall survival, and toxicity evaluation. The trial is expected to run until May 2037, with recruitment having commenced in April 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed adenocarcinoma of the prostate, adequate organ function, and ineligibility for certain treatments. Following randomization, participants will attend regular follow-up visits to monitor treatment effects and progression, with assessments conducted according to PCWG3 criteria. The end-of-study visit will conclude the participant's involvement, unless early termination is warranted due to adverse events, withdrawal of consent, or other protocol-specified conditions.

The expected duration of participant involvement is contingent upon individual progression and response to treatment, with the maximum treatment period set at one year. Participants are required to comply with protocol stipulations, including the use of adequate contraception and adherence to scheduled visits and examinations. The trial's design ensures rigorous monitoring and data collection to achieve its objectives, contributing valuable insights into the management of metastatic prostate cancer in this patient population.

The clinical trial involves the administration of **darolutamide**, a nonsteroidal androgen receptor (AR) antagonist, as the experimental medication. The pharmaceutical form of darolutamide is a film-coated tablet, identified by the product code BAY 1841788, and is manufactured by Bayer AG. Each tablet contains 300 mg of the active substance. The medication is administered orally, with a maximum daily dose of 1200 mg, which equates to four tablets per day. The treatment period is set for a maximum of one year. Compliance with the dosing schedule is monitored through regular assessments to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, the study includes a comparator treatment consisting of androgen deprivation therapy (ADT) combined with a placebo. The placebo is designed to match the film-coated tablet form of darolutamide, ensuring blinding in the double-blind randomized phase III trial. The placebo is administered orally with the same frequency and dosage schedule as the experimental medication, maintaining consistency across treatment arms. Participant compliance with the placebo regimen is similarly monitored to ensure the integrity of the trial data.

Efficacy in this clinical trial will be assessed primarily through **radiographic progression-free survival**. This endpoint is defined as the time from randomization to radiographic progression, as evaluated by the investigator according to the PCWG3 criteria, or death, whichever occurs first. Secondary endpoints include **castration-resistant prostate cancer (CRPC)-free survival**, which measures the time from randomization to the onset of CRPC or death, and **overall survival**, defined as the time from randomization to death from any cause. For subjects alive at the time of analysis, data will be censored on the last date the subject was known to be alive, lost to follow-up, or withdrew consent. Additionally, **clinical progression-free survival** will be evaluated, defined as the time from randomization to the first occurrence of clinical progression. Toxicity will be assessed according to version 5 of the National Cancer Institute's Common Terminology Criteria for Adverse Events. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the comparative effectiveness of ADT plus darolutamide versus ADT plus placebo in patients with castration-naïve de novo metastatic prostate cancer.