Evaluation of Lutetium (177Lu) Vipivotide Tetraxetan in Oligo-metastatic Hormone-sensitive Prostate Cancer: A Randomized Controlled Trial

The primary objective of this study is to evaluate the effect of **177Lu-PSMA RLT** in patients with oligo-metastatic, hormone-sensitive metastatic **prostate cancer**. This will be assessed by comparing the fraction of patients experiencing disease progression, serving as a surrogate for progression-free survival, and meeting EOT 1 criteria within 6 months. The comparison will be made between a group treated with 177Lu-PSMA RLT and a group receiving the current standard of care, which is deferred androgen deprivation therapy. This objective is clinically relevant as it aims to determine the efficacy of 177Lu-PSMA RLT in delaying disease progression, potentially offering a more effective treatment option for patients with this condition.

Secondary objectives include estimating the ADT-free survival, assessing response and toxicity as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0), evaluating the radiological state of the disease through differences in the amount and size of suspicious nodes on 18F-PSMA PET and whole-body MRI between pre- and post-therapy, and conducting quality of life assessments. These objectives are important for understanding the broader impact of the treatment on patient health and well-being.

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 categorized as ages 18 to 64 and 65 and older. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on specific criteria, including a histologically proven adenocarcinoma of the prostate, biochemical recurrence, and a positive 18F-PSMA-PET-CT scan indicating metastases in bones and/or lymph nodes. The trial population is characterized by a good general health status, as indicated by laboratory values and an ECOG performance status of 0-1. Lifestyle considerations such as diet and physical activity are not specified. The trial excludes individuals with prior hormonal therapy or taxane-based chemotherapy, ensuring a focus on hormone-sensitive metastatic cases. Participants must have a life expectancy greater than six months, and no prior local treatment options for oligo-metastases are viable.

The clinical trial is designed to evaluate the efficacy of **Lutetium (177Lu) vipivotide tetraxetan** in patients with oligo-metastatic, hormone-sensitive **prostate cancer**. This is a Phase II, randomized, double-blind, controlled study comparing the investigational treatment with the current standard of care, which is deferred androgen deprivation therapy. The trial is expected to run from July 2020 to April 2025, with a total duration of approximately 57 months. Participants will be involved in the study for a maximum treatment period of 6 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven adenocarcinoma of the prostate, specific laboratory values, and a positive 18F-PSMA-PET-CT scan. Following the screening, eligible participants will be randomized into one of the two study arms. The investigational arm will receive **Lutetium (177Lu) vipivotide tetraxetan** via intravenous infusion, while the control arm will follow the standard care protocol. Study visits will include regular follow-up assessments to monitor disease progression, PSA response, and any adverse events, as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0).

The primary endpoint of the study is to assess the fraction of patients experiencing disease progression within a 6-month follow-up period. Secondary endpoints include ADT-free survival, radiological assessment of disease state, and quality of life evaluations. Participants will be required to attend an end-of-study visit to conclude their involvement in the trial. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial aims to provide valuable insights into the potential benefits of **Lutetium (177Lu) vipivotide tetraxetan** in managing prostate cancer, contributing to the advancement of therapeutic strategies for this condition.

The clinical trial involves the use of **18F-PSMA-1007**, a radiopharmaceutical agent formulated as a **solution for injection**. This experimental medication is administered via **intravenous injection**. The dosing regimen specifies a maximum daily dose of 4 MBq/kg, with a total dose not exceeding 450 MBq. The treatment period for this agent is limited to a maximum of 1 day. The active substance, **18F-PSMA-1007**, is of chemical origin and is utilized in the study to evaluate its efficacy in the context of oligo-metastatic hormone-sensitive prostate cancer.

Another key component of the trial is **Pluvicto 1 000 MBq/mL solution for injection/infusion**, which contains the active substance **Lutetium (177Lu) Vipivotide Tetraxetan**. This agent is administered through **intravenous infusion**. The dosing schedule allows for a maximum daily and total dose of 7400 MBq, with the treatment period extending up to 6 months. The active substance is derived from a protein of other origin and is employed in the study to assess its therapeutic impact on the progression of prostate cancer. This product is authorized for use in the European Union under the marketing authorization number EU/1/22/1703/001.

In addition to the experimental treatments, the study includes a comparator group receiving the current standard of care, which involves deferred androgen deprivation therapy. This non-experimental treatment serves as a control to evaluate the efficacy of the experimental agents. Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the outcomes of the treatments.

Efficacy in the clinical trial titled "Lutetium-177-PSMA in Oligo-metastatic Hormone Sensitive Prostate Cancer" will be assessed using several primary and secondary endpoints. The primary endpoints include the fraction of patients experiencing **disease progression** within a 6-month follow-up period, serving as a surrogate for progression-free survival, and the time to disease progression while meeting EOT 1 criteria in both treatment groups. These groups consist of patients treated with 177Lu-PSMA RLT and those receiving the current standard of care, which is deferred androgen deprivation therapy.

Secondary endpoints will evaluate additional parameters such as ADT-free survival, PSA response, and toxicity, which will be defined according to the NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0). Radiological assessments will be conducted to determine the state of the disease by comparing the amount and size of suspicious nodes using 18F-PSMA PET/CT and whole-body MRI before and after therapy. Quality of life assessments will also be performed in both arms of the study. These efficacy parameters will be measured and analyzed at specified timepoints throughout the trial to ensure comprehensive evaluation of the treatment's impact on patients with oligo-metastatic, hormone-sensitive prostate cancer.