Evaluation of 177Lu-PSMA as Systemic Adjuvant Therapy in High-Risk Prostate Cancer Post-Radical Locoregional Radiotherapy and Hormone Therapy

The primary objective of this study is the **assessment of treatment failure** in patients with high and very high risk **prostate cancer** following radical treatment with locoregional teleradiotherapy and hormone therapy. This is evaluated by measuring the biochemical progression ratio, defined according to the Phoenix criteria, as a rise in prostate-specific antigen (PSA) by 2 ng/mL or more above the nadir, confirmed by a subsequent examination at least four weeks later. This objective is clinically relevant as it helps determine the efficacy of the systemic adjuvant treatment with 177Lu-PSMA in preventing disease progression.

Secondary objectives include: - **Biochemical Progression Free Survival (bPFS)** assessment, defined as a rise in PSA by 2 ng/mL or more above the nadir, confirmed by a consecutive examination performed at least four weeks later. - **Radiological Progression Free Survival (rPFS)**, defined in accordance with the PCWG3 criteria. - Assessment of the time to inclusion of the next therapeutic intervention. - **Safety and Tolerability** assessment according to the Common Terminology Criteria for Adverse Events (CTCAE v. 5.0). - **Quality of life** assessment.

The clinical trial focuses on **prostate cancer** and involves a study population exclusively composed of male participants, as female subjects are not included. The age range of participants is over 18 years, with no upper age limit specified. The trial does not involve a vulnerable population. Participants are required to have a histopathologically proven high-risk or very-high-risk prostate cancer, as defined by the NCCN v1.2023 criteria. The general health status of participants includes an ECOG performance status of 0 to 2, indicating they are fully active or capable of self-care. Participants must have completed radical locoregional treatment, specifically teleradiotherapy, within three months prior to inclusion in the study. They must also exhibit no signs of tumor cell dissemination within 28 days before trial inclusion, confirmed by radiological examinations and 68Ga-PSMA PET/CT examination. Additionally, participants are required to have a castrate testosterone level and adequate function of main organs, including bone marrow, liver, and kidneys. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of **lutetium (177Lu) vipivotide tetraxetan** as a systemic adjuvant treatment in patients with high and very high-risk **prostate cancer** following radical locoregional treatment with teleradiotherapy and hormone therapy. This is a randomized, double-blind, controlled trial, categorized as a non-commercial phase 2 study. The trial is expected to run from July 2023 to November 2030, with the primary objective being the assessment of treatment failure, specifically the biochemical progression ratio as defined by the Phoenix criteria.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histopathologically proven high-risk or very-high-risk prostate cancer, completion of locoregional treatment within three months prior to inclusion, and adequate organ function. The trial will include follow-up visits to monitor the primary and secondary endpoints, which include biochemical progression-free survival, radiological progression-free survival, and the frequency of adverse events. The end-of-study visit will conclude the participant's involvement, assessing the overall outcomes and any long-term effects of the treatment.

The expected length of participant involvement is approximately seven years, from the start of recruitment to the estimated end date of the trial. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, withdrawal of consent, or any medical condition that contraindicates continued participation. The trial will utilize **Pluvicto 1 000 MBq/mL solution for injection/infusion** administered via IV infusion, with a maximum daily dose of 7.4 GBq. The study aims to provide valuable insights into the treatment's impact on survival and quality of life in this patient population.

The clinical trial involves the administration of **Pluvicto**, a **solution for injection/infusion** containing the active substance **lutetium (177Lu) vipivotide tetraxetan**. This experimental medication is provided in a concentration of 1,000 MBq/mL and is intended for intravenous infusion. The maximum daily dose is set at 7.4 GBq, with the same amount being the maximum total dose permissible during the treatment period. The treatment is designed to be administered over a maximum period of one day. The pharmaceutical form of the medication is a solution, and it is not formulated for pediatric use. The active substance, lutetium (177Lu) vipivotide tetraxetan, is classified under the ATC code V10XX, which pertains to various therapeutic radiopharmaceuticals. The origin of the active substance is categorized as "Protein - Other".

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial focuses solely on the administration of the experimental medication, Pluvicto. Participant compliance with the dosing schedule will be monitored to ensure adherence to the protocol. The trial aims to assess treatment failure by evaluating the biochemical progression ratio, specifically the rise of PSA levels according to the Phoenix criteria. The study is conducted under the authorization of Novartis Europharm Limited, with the marketing authorization number EU/1/22/1703/001.

Efficacy in this clinical trial will be assessed through the primary endpoint of the **biochemical failure ratio**. This involves evaluating the biochemical progression ratio, defined according to the Phoenix criteria as a rise in prostate-specific antigen (PSA) by 2 ng/mL or more above the nadir, which is the lowest PSA level achieved after treatment. This progression must be confirmed by a consecutive examination performed at least four weeks later. Secondary endpoints include Biochemical Progression Free Survival, which measures the time from the end of **177Lu-PSMA** treatment to biochemical progression or death, and Radiological Progression Free Survival, which assesses the time from the end of treatment to radiological progression as defined by the PCWG3 criteria or death. Additional secondary endpoints include the time from the end of treatment to the inclusion of other therapeutic interventions, the frequency and count of patients experiencing adverse events, and the comparison of quality of life ratios using the EORTC QLQ-PR25 between study groups. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the treatment's impact on patients with high and very high-risk prostate cancer following radical locoregional treatment.