Transdermal Estradiol and Exercise in Mitigating Adverse Effects of Androgen Deprivation Therapy for Prostate Cancer Radiation Therapy

The current study is an open-label study examining a drug with known tolerability and safety profile (phase IIA trial). The study will recruit 310 prostate cancer patients with high-risk disease and scheduled for external beam radiation with adjuvant subcutaneous androgen deprivation therapy, leuprorelin (LHRH agonist).

Stratified randomization (n=310) will be done in a 1:1 fashion to the transdermal estradiol + androgen deprivation therapy arm or control arm (androgen deprivation therapy only). Stratified randomization will be based on two covariates, which are sexual dysfunction score and BMI. The use of the stratified randomization method will guarantee even distribution of covariates, which could likely affect the study outcomes. Additionally, a total of 120 participants who are willing to participate in the supervised resistance training program and have sufficient performance status (ECOG 0-1) will be randomized to the resistance training group or the non-training control group. A total of 30 men from each arm will be recruited to supervised training and 30 men from each arm the non-training control group. Participants of the ESTRACISE who do not participate in the exercise substudy will form a non-training group (n=95 per arm). The stratified randomization of the substudy participants in the training group or the non-training control group will be done in a 1:1 fashion before the start of the training period. Stratified randomization will be based on two main covariates, which are age and the self-reported physical activity level of the participant.

ESTRACISE participants allocated to the transdermal estradiol arm will use transdermal estradiol gel (E2) as a dose of 750 ug (EstroGel 0.6 mg/ml) in addition to androgen deprivation therapy for 12 months. Additionally, substudy participants allocated to the resistance training groups will be attending supervised group resistance training sessions twice a week for six months. The resistance training will start after six months of androgen deprivation therapy. Participants in the non-training groups are advised to stay physically active but they will do it at their own discretion.

According to the standard treatment protocol, all participants will receive androgen deprivation therapy as leuprorelin, subcutaneous injections at three months intervals for a minimum of one year, and standard external beam radiation for prostate cancer with standard clinical dosing and fractionation at the discretion of the radiation oncologist.

The research methodologies include questionnaires (expanded prostate cancer index composition 26, world health organization quality of life brief version, and patient health questionnaire), adverse event screening, medication compliance screening, computerized tomography (CT) of the thigh muscle, bioimpedance analysis (BIA), 3D-imaging of the body composition, body composition and bone mineral assessment by dual-energy x-ray absorptiometry (DXA), strength, functional capacity, physical activity measurements, and serum and plasma blood samples. In addition, muscle biopsies are collected from a subset of participants allocated in the resistance training (n=60) and non-training control groups (n=60). The primary measurement timepoints are baseline (0 months), after six months of androgen deprivation therapy, and after twelve months of androgen deprivation therapy.

Based on prior sample size estimation of primary outcome the n=310 should be more than adequate to detect statistically significant differences in the mean sexual domain score between the two study arms. The true difference in the mean is expected to be 10, with a probability (power) of 0.8, a Type 1 error probability of 0.05, and with dropout rate of 10%.

• The occurrence of androgen deprivation therapy induced adverse effects. [Time frame: Twelve and six months.]
• Number of participants with transdermal estradiol-related adverse events as assessed by CTCAE (Common Terminology Criteria for Adverse Events). [Time frame: Twelve and six months.]
• Impact of transdermal estradiol with or without 6-month supervised resistance training on one repetition maximum tests of both the leg press and barbell biceps curl, and maximal hand grip strength assessed with a dynamometer. [Time frame: Twelve and six months.]
• Impact of transdermal estradiol with or without 6-month supervised resistance training on explosive strength of the leg extensors assessed with a countermovement jump (CMJ). [Time frame: Twelve and six months.]
• Impact of transdermal estradiol with or without 6-month supervised resistance training on 6-minute walk (functional capacity). [Time frame: Twelve and six months.]
• Impact of transdermal estradiol with or without 6-month supervised resistance training on loaded 10-stair climb test (functional capacity). [Time frame: Twelve and six months.]
• Impact of transdermal estradiol with or without 6-month supervised resistance training on body composition. [Time frame: Twelve and six months.]
• Impact of transdermal estradiol with or without 6-month supervised resistance training on bone mineral density. [Time frame: Twelve and six months.]
• Impact of transdermal estradiol with or without 6-month supervised resistance training on mid-thigh muscle mass. [Time frame: Twelve and six months.]
• Impact of transdermal estradiol with or without 6-month supervised resistance training on mid-thigh fat mass. [Time frame: Twelve and six months.]
• Impact of transdermal estradiol with or without 6-month supervised resistance training on hormone (testosterone and estradiol) levels, and cancer (PSA) status. [Time frame: Twelve and six months.]
• Impact of transdermal estradiol with or without 6-month supervised resistance training on concentration of PVK, IL-6, TNF-α, AFOS, Alat, Krea, Cholesterol, LDL-C, HDL-C, and triglycerides). [Time frame: Twelve and six months.]