Phase III Evaluation of Acetylsalicylic Acid and Atorvastatin on Overall Survival in Castration-Resistant Prostate Cancer Patients

The primary objective of this Phase III trial is to evaluate the benefit of **acetylsalicylic acid** and **atorvastatin** on overall survival (OS) in patients with castration-resistant prostate cancer. This is clinically relevant as improving OS is a critical endpoint in the management of this advanced stage of prostate cancer, where treatment options are limited and the disease is typically aggressive.

Secondary objectives include:

• Assessing prostate cancer-specific survival, focusing on deaths due to prostate cancer.
• Evaluating progression-free survival, including PSA progression by PCWG3 criteria or investigator assessment.
• Assessing radiographic progression-free survival as defined by PCWG3 criteria.
• Determining the time to next anticancer treatment.
• Describing safety using NCI-CTCAE Version 5.0, focusing on adverse events related to acetylsalicylic acid and/or statin.
• Describing cardiovascular morbidity, including hospitalization and mortality, or any Grade 3/4 cardiovascular adverse events.
• Determining changes from baseline in BMI, body weight, and waist measurement under treatment and their correlation with OS.
• Correlating metabolic parameters, including lipid levels, with OS.
• Correlating low levels of vitamin D with OS.
• Correlating Lymphocyte to Neutrophil Ratio (LNR) and C-reactive protein (CRP) with OS.
• Validating a prognostic 3-lipid signature.
• Assessing whether atorvastatin treatment during standard-of-care therapy for metastatic castration-resistant prostate cancer can reverse a poor prognostic circulating lipid signature and improve OS.

The clinical trial focuses on **castration-resistant prostate cancer** and involves a study population exclusively composed of male subjects. The age range of participants is 18 years and older, with a life expectancy of at least six months. The trial does not include a vulnerable population. Participants were selected based on specific inclusion criteria, such as having a histologically confirmed adenocarcinoma of the prostate, no possibility of curative local therapy, and ongoing androgen deprivation therapy. The trial population is required to have a performance status of 0, 1, or 2, and adequate renal and liver function. Participants must not have previously used life-prolonging treatments for castration-resistant prostate cancer, although up to six weeks of such treatments before trial inclusion is permissible. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase III** study designed to evaluate the efficacy of **acetylsalicylic acid** and **atorvastatin** in patients with **castration-resistant prostate cancer**. The primary objective is to assess the impact of these medications on overall survival. 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 June 26, 2019, to June 26, 2038, with a maximum treatment period of 180 days for each participant.

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, age of at least 18 years, and adequate renal and liver function. Following successful screening, participants will be randomized to receive either the investigational products or a control. The study includes regular follow-up visits to monitor safety and efficacy, assess progression-free survival, and collect data on secondary endpoints such as prostate cancer-specific survival and cardiovascular morbidity. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.

The expected length of participant involvement is up to 180 days, with conditions for early termination including significant adverse events or withdrawal of consent. Participants are required to continue androgen deprivation therapy if not surgically castrated and must not have previously used life-prolonging treatments for castration-resistant prostate cancer, except for a limited duration prior to trial inclusion. The trial allows participation in other clinical studies, provided they do not share the same primary endpoint of overall survival.

The clinical trial involves the administration of two experimental medications: **acetylsalicylic acid** and **atorvastatin**. The first experimental medication, **acetylsalicylic acid**, is provided under the product name "RESITUNE 100 mg, comprimé gastro-résistant." This medication is formulated as a **gastro-resistant tablet** and is administered orally. The dosage is set at 100 mg per day, with a maximum treatment period of 180 days. The active substance, **acetylsalicylic acid**, is of chemical origin and is classified under the ATC code B01AC06. The product is manufactured by Pfizer Holding France and is authorized for use in France.

The second experimental medication, **atorvastatin**, is provided under the product name "TAHOR 80 mg, comprimé pelliculé." This medication is formulated as a **film-coated tablet** and is also administered orally. The dosage is set at 80 mg per day, with a maximum treatment period of 180 days. The active substance, **atorvastatin**, is of chemical origin and is classified under the ATC code C10AA05. The product is manufactured by Viatris UP and is authorized for use in France.

Both medications are administered as part of the trial to evaluate their combined effect on overall survival in patients with castrate-resistant prostate cancer. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **overall survival (OS)**. This primary endpoint will be calculated from the date of randomization to the date of death or the last follow-up date in the case of censored data. Secondary endpoints include prostate cancer-specific survival, progression-free survival, radiographic progression-free survival, time to next anticancer treatment, and safety assessments based on NCI-CTC V5.0 criteria. Additional secondary endpoints involve cardiovascular morbidity, changes in body mass index (BMI), body weight, waist measurements, and various translational research parameters such as metabolic parameters, lipid profiles, vitamin D levels, lymphocyte to neutrophil ratio (LNR), C-reactive protein (CRP), and lipid signature.

The trial will utilize validated criteria and scales, such as the PCWG3 criteria for progression-free survival and NCI-CTC V5.0 for safety assessments. The schedule for measuring and collecting these efficacy parameters will be aligned with the trial's protocol, ensuring systematic data collection at predefined timepoints. The analysis of these parameters will be conducted using appropriate statistical methods to determine the efficacy of acetylsalicylic acid and atorvastatin in patients with castrate-resistant prostate cancer.