Evaluation of Metastasis-Directed Radiotherapy with or without Leuprorelin Acetate in Biochemically Recurrent Oligo-Metastatic Prostate Cancer

The primary objective of this study is to evaluate the hypothesis that the addition of **androgen deprivation therapy (ADT)** to metastasis-directed radiotherapy (MDRT) in patients with oligo-metastatic prostate cancer prolongs metastases progression-free survival (MPFS) compared to MDRT alone. This is clinically relevant as it may offer a more effective treatment strategy for patients with biochemical recurrence after primary treatment of prostate cancer, presenting with up to four metastases.

The secondary objective is to gain further insight into the sensitivity of the **PSMA-PET scan** for detecting (oligo)metastases at low PSA levels. Understanding this sensitivity is crucial for improving diagnostic accuracy and treatment planning in prostate cancer management.

The clinical trial involves **male** participants diagnosed with biochemical recurrence following primary treatment for **prostate cancer**, specifically those presenting with four or fewer metastases. The study population is composed of adult males aged 18 years and older, with a **WHO performance status** ranging from 0 to 2, indicating a general good health status. Participants were selected based on specific criteria, including a histologically confirmed initial diagnosis of adenocarcinoma of the prostate and a biochemical recurrence as defined by the European Association of Urology guidelines. The trial excludes individuals with visceral metastases and includes those with a maximum of four lesions in bone and lymph nodes, as identified by PSMA-PET scans. The **PSA** levels must be below 10 ng/ml, or below 5 ng/ml for those on chronic finasteride use. The sponsor has not provided information regarding the total number of participants. The trial does not include female or vulnerable populations, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of adding **androgen deprivation therapy (ADT)** to metastasis-directed radiotherapy (MDRT) in patients with oligo-recurrent prostate cancer. This is a Phase III randomized, double-blind, controlled trial. The primary objective is to assess whether the combination of ADT and MDRT prolongs metastases progression-free survival compared to MDRT alone. The trial is expected to run from January 2020 to December 2025, with a primary endpoint of 2-year metastases progression-free survival. Secondary endpoints include 3-year PSA progression, clinical progression-free survival, and quality of life, among others.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically proven diagnosis of adenocarcinoma of the prostate, biochemical recurrence, and a maximum of four metastases. Following randomization, participants will receive either the combination treatment or MDRT alone. Follow-up visits will be scheduled to monitor treatment response, adverse events, and disease progression. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected length of participant involvement is up to six months of treatment, with additional follow-up for up to three years to assess long-term outcomes. Conditions that may lead to early termination from the study include significant adverse events, disease progression beyond the defined criteria, or withdrawal of consent. The trial will utilize **leuprorelin acetate** as the active substance in the ADT regimen, administered as a solution for injection. The study aims to provide valuable insights into the potential benefits of combining ADT with MDRT in this patient population.

The clinical trial involves the administration of **Eligard 22.5 mg**, a pharmaceutical product formulated as a **solution for injection**. The active substance in this medication is **leuprorelin acetate**, also known as leuprolide acetate. This compound is classified under the ATC code L02AE02, indicating its role as a **gonadotropin-releasing hormone agonist**. Eligard is provided as a powder and solvent for solution for injection, manufactured by Recordati Industria Chimica e Farmaceutica S.P.A. The medication is administered via injection, with a maximum daily dose of 45 mg and a total treatment period not exceeding six months. The dosing schedule is designed to ensure optimal therapeutic levels of the active substance, and participant compliance is monitored throughout the study to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, the study protocol includes the use of standard-of-care therapy, which may involve metastasis-directed radiotherapy (MDRT) as a comparator treatment. This approach is intended to evaluate the efficacy of androgen deprivation therapy (ADT) in combination with MDRT in patients with oligo-recurrent prostate cancer. The trial aims to determine whether the addition of ADT prolongs metastases progression-free survival compared to MDRT alone. Compliance with the administration of both experimental and non-experimental treatments is closely monitored to ensure the integrity of the study results.

Efficacy in the clinical trial titled "ADOPT; Androgen Deprivation therapy for Oligo-recurrent Prostate cancer in addition to radioTherapy" will be assessed using several parameters. The primary endpoint is the 2-year **metastases progression-free survival** (MPFS), which will be measured to evaluate the effectiveness of adding androgen deprivation therapy (ADT) to metastasis-directed radiotherapy (MDRT) in patients with oligo-metastatic prostate cancer. Secondary endpoints include 3-year PSA progression, the start of second-line treatment, initiation of second MDRT treatment for new or progressive oligometastases, acute and late toxicity (up to 3 years), clinical progression-free survival, quality of life, progression pattern, time to start of palliative ADT, time to castration-resistance, disease-specific and overall survival, sensitivity of the imaging modality (PSMA-PET/CT or PSMA-PET/MRI) for patients receiving MDRT, and predictive biomarkers.