Estrogen to Improve Quality of Life for Men With Newly Diagnosed or Recurrent Metastatic Hormone Sensitive Prostate Cancer, EQUIP Trial

Inclusion Criteria:

* Must be willing to provide informed consent prior to any study specific procedures
* Age ≥ 18 years
* Documented histologically confirmed adenocarcinoma of the prostate
* Patients must have evidence of newly diagnosed or relapsed metastatic hormone sensitive prostate cancer on CT, positron emission tomography (PET), MRI or bone scan
* No prior chemotherapy for the treatment of hormone sensitive prostate cancer
* No prior therapy with an LHRH analogue or next-generation androgen receptor-signaling inhibitor (e.g. abiraterone, enzalutamide, etc.). Participants may have initiated on a first-generation androgen receptor (AR) antagonist (e.g. bicalutamide) prior to enrollment
* Hemoglobin ≥ 9 g/dL with no blood transfusion in the past 28 days (measured within 30 days prior to administration of study treatment)
* Platelet count ≥ 100 x 10\^9/L (measured within 30 days prior to administration of study treatment)
* Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L (measured within 30 days prior to administration of study treatment)
* Aspartate aminotransferase (AST) or serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) or serum glutamic pyruvate transaminase (SGPT) ≤ 2.5 x institutional upper limit of normal (measured within 30 days prior to administration of study treatment)
* Patient must have creatinine clearance estimated using the Cockcroft-Gault equation (measured within 30 days prior to administration of study treatment)
* Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) with exception for Gilbert's syndrome (measured within 30 days prior to administration of study treatment)
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
* Patients must have a life expectancy ≥ 16 weeks
* Patients must be willing and able to comply with protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
* At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by CT, MRI and/or bone scan and is suitable for repeated assessment. Subjects without bone metastases must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
* Male patients and their partners, who are sexually active and of childbearing potential, must agree to the use of two highly effective forms of contraception in combination, throughout the period of taking study treatment and for 6 months after last dose of study drug(s) to prevent pregnancy in a partner

Exclusion Criteria:

* Involvement in the planning and/or conduct of the study
* Other malignancy unless curatively treated with no evidence of disease for ≥ 2 years. Exceptions include adequately treated non-melanoma skin cancer or non-muscle invasive bladder cancer
* Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. Patient with spinal cord compression unless considered to have received definitive therapy for this and evidence of clinically stable disease for 28 days
* Patients considered inappropriate to receive docetaxel chemotherapy by their treating provider
* Use of corticosteroids at a dose equivalent to \> 10 mg of prednisone daily
* Planning to receive concurrent treatment with another systemic cancer therapy, aside from an LHRH analogue
* Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
* Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, uncontrolled major seizure disorder, uncontrolled hypertension (blood pressure \[BP\] ≥ 165/100), unstable spinal cord compression, superior vena cava syndrome or extensive interstitial lung disease
* Patients with a known hypersensitivity to transdermal estradiol, LHRH analogue, ARSIs or any of the excipients of these products
* Patients with known active hepatitis (i.e., hepatitis B or C) due to risk of transmitting the infection through body or other body fluids
* Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition (including laboratory abnormalities) that could interfere with patient safety or provision of informed consent to participate in this study
* Any psychological, familial, sociological or geographical condition that could potentially interfere with compliance with the study protocol and follow-up schedule
* Evidence of a pre-existing condition that, in the opinion of the investigator, would put the patient at risk from estradiol therapy.

  * Some examples include: history of blood clotting disorder, migraines with aura or other focal neurological symptom, angina (New York Heart Association grade III or higher)
* Prior history of deep venous thrombosis or pulmonary embolism within 5 years prior to enrollment in the study and not currently on systemic anticoagulation

  * Excluded due to risk of venous thromboembolism from hormone supplementation
* Patients with New York Heart Association (NYHA) class III or IV heart failure or history of a prior myocardial infarction (MI) or cerebrovascular accident (stroke or transient ischemic attack) within 5 years of enrollment to the study

  * Excluded due to increased risk of cardiovascular events with estradiol supplementation