Evaluation of Transdermal Estradiol and Exercise in Reducing Adverse Effects of Androgen Deprivation Therapy in Prostate Cancer Patients Undergoing Radiation Therapy

The primary objective of the study is to estimate the efficacy of **estradiol** (E2) in improving sexual dysfunction during androgen deprivation therapy (ADT) for prostate cancer. This is clinically relevant as sexual dysfunction is a common and distressing side effect of ADT, impacting the quality of life of patients undergoing treatment for prostate cancer.

Secondary objectives include:

• Investigating the occurrence of ADT-induced adverse effects during ADT.
• Estimating the safety and tolerability of transdermal E2 during ADT treatment of prostate cancer.
• Estimating the impact of E2 with or without resistance training in mitigating the adverse effects of ADT on physical performance, body composition, and systematic biomarkers.
• Estimating the safety and tolerability of resistance training with or without transdermal E2 during ADT.
• Investigating the impact of transdermal E2 with or without resistance training on quality of life and perceived fatigue during ADT.

The clinical trial focuses on **prostate cancer** and involves a study population exclusively composed of male participants. The age range of the participants is adults over 18 years, with a body mass index between 18.5 and 30.0. Participants are required to have a sufficient performance status, classified as ECOG 0-1, and must be starting radiotherapy with adjuvant androgen deprivation therapy (ADT) for at least one year. The trial does not include a vulnerable population, and all participants have provided informed consent. 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 designed to evaluate the efficacy of **transdermal estradiol** in improving sexual dysfunction during androgen deprivation therapy (ADT) for patients with localized **prostate cancer** undergoing radiotherapy. This study is a randomized, double-blind, controlled trial, categorized as a Phase 4 trial. The trial is expected to commence recruitment on September 1, 2023, and conclude by December 31, 2028. Participants will be involved in the study for a maximum treatment period of 12 months, during which they will receive a daily dose of 0.75 mg of estradiol via transdermal gel application. The trial will also assess the impact of a 6-month resistance exercise program on various health parameters.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening visit, will confirm eligibility based on criteria such as age, performance status, and body mass index. Follow-up visits will occur at regular intervals to monitor the occurrence of ADT-induced adverse effects, assess the tolerability and safety of the treatment, and evaluate changes in muscle strength, functional capacity, body composition, and quality of life. The end-of-study visit will finalize data collection and assess the primary endpoint, which is the efficacy of transdermal estradiol in mitigating sexual symptoms associated with ADT.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include significant adverse reactions to the treatment, withdrawal of consent, or any medical condition that contraindicates continued participation. The trial's methodology ensures rigorous data collection and analysis to achieve its primary and secondary endpoints, contributing valuable insights into the management of adverse effects associated with ADT in prostate cancer treatment.

The clinical trial involves the administration of **Estrogel**, a transdermal gel containing **estradiol** as the active substance. The pharmaceutical form is a gel, and it is applied transdermally. The maximum daily dose is 0.75 mg, with a total treatment period of up to 12 months. The gel is manufactured by Besins Healthcare Ireland Limited and is not a pediatric formulation. The administration of the gel is intended to mitigate adverse effects associated with androgen deprivation therapy in prostate cancer treatment.

Another treatment used in the trial is **Enanton Depot Dual**, which contains **leuprorelin acetate**. This product is a suspension for injection in a pre-filled syringe, with a maximum dose of 11.25 mg administered via injection. The treatment period can extend up to 16 months. The product is manufactured by Orion Corporation and is classified as a protein-based substance. It serves as a comparator treatment in the study.

Additionally, the trial includes the use of **Orgovyx**, which contains **relugolix** as the active ingredient. This medication is provided in the form of film-coated tablets, with a maximum daily dose of 120 mg administered orally. The treatment duration is up to 12 months. Manufactured by Accord Healthcare S.L.U., this chemical-based product is used as a standard-of-care therapy in the study.

Lastly, **Leuprorelin Sandoz** is utilized, containing **leuprorelin** as the active substance. It is provided as an implant in a pre-filled syringe, with a maximum dose of 5 mg administered via injection. The treatment period can last up to 16 months. This protein-based product is manufactured by Sandoz A/S and is used as an auxiliary treatment in the trial.

The clinical trial aims to assess the efficacy of transdermal **estradiol** in improving sexual dysfunction during androgen deprivation therapy (ADT) for prostate cancer. The primary endpoint is the efficacy of transdermal **estradiol** in mitigating the sexual symptoms associated with ADT. Secondary endpoints include the occurrence of ADT-induced adverse effects, tolerability and safety of transdermal **estradiol** during the one-year ADT adjuvant treatment period, and the impact of transdermal **estradiol** with or without 6-month resistance exercise on muscle strength, functional capacity, body composition, lean-body muscle mass, and systematic biomarkers. Additionally, the trial will evaluate the safety and tolerability of 6-month physical exercise combined with or without transdermal **estradiol** during ADT, as well as quality of life and perceived fatigue in different study groups.

Data collection will involve validated scales and laboratory tests to measure the specified endpoints. The trial is designed to include men with localized prostate cancer starting radiotherapy with adjuvant ADT for at least one year, who meet specific inclusion criteria such as age over 18 years, sufficient performance status (ECOG 0-1), and a body mass index between 18.5 and 30.0. The trial is set to begin recruitment on September 1, 2023, and is estimated to conclude by December 31, 2028. The study is categorized as a phase II trial, focusing on the efficacy and safety of the intervention.