Hormone Therapy, Radiation Therapy, and Steroid 17alpha-monooxygenase TAK-700 in Treating Patients With High-Risk Prostate Cancer

Prostate Cancer Clinical Trial

Official title:

Phase III Trial of Dose Escalated Radiation Therapy and Standard Androgen Deprivation Therapy (ADT) With a GNRH Agonist vs. Dose Escalated Radiation Therapy and Enhanced ADT With a GNRH Agonist and TAK-700 For Men With High Risk Prostate Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01546987
• Other study ID #: RTOG 1115
• Secondary ID: CDR0000727326NCI
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: May 2012
• Est. completion date: June 2029

Study information

• Verified date: January 2023
• Source: Radiation Therapy Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Androgens can cause the growth of prostate cancer cells. Drugs, such as steroid 17alpha-monooxygenase TAK-700, when used with other hormone therapy, may lessen the amount of androgens made by the body. Radiation therapy uses high energy x rays to kill tumor cells. This may be an effective treatment for prostate cancer when combined with hormone therapy. Studying quality-of-life in patients having cancer treatment may help identify the intermediate- and long-term effects of treatment on patients with prostate cancer.

PURPOSE: This randomized phase III trial is studying the use of hormone therapy, including TAK-700, together with radiation therapy in treating patients with prostate cancer.

Description:

OBJECTIVES:

Primary

• To evaluate the difference in overall survival of patients with clinically localized prostate cancer with unfavorable prognostic features between a) standard treatment (androgen-deprivation therapy [ADT] + radiotherapy) and b) standard treatment with the addition of 24 months of steroid 17alpha-monooxygenase TAK-700 (TAK-700).

Secondary

• To characterize differences between the treatment groups with respect to incidence of unexpected grade ≥ 3 adverse events and/or clinically significant decrement in patient-reported quality of life (QOL) among subjects treated with TAK-700.

• To compare rates and cumulative incidence of biochemical control (freedom from PSA failure), local/regional progression, and distant metastases.

• To compare rate and cumulative incidence of clinical failure, defined as prostate-specific antigen (PSA) > 25 ng/mL, documented local disease progression, regional or distant metastasis, or initiation of ADT.

• To compare prostate cancer-specific survival and other-cause mortality.

• To compare the change in severity of fatigue as measured by the Patient-Reported Outcome Measurement Information System (PROMIS) fatigue short form.

• To compare changes in patient-reported QOL as measured by Expanded Prostate Cancer Index Composite (EPIC).

• To assess quality-adjusted survival using the EQ-5D.

• To compare nadir and average serum testosterone at 12 and 24 months during treatment.

• To compare changes in hemoglobin A1C, fasting glucose, and fasting insulin during 24 months of systemic treatment and during the first three years of follow-up.

• To compare changes in fasting lipid levels during 24 months of treatment and during the first three years of follow-up.

• To compare changes in body mass index (BMI) during 24 months of treatment and during the first three years of follow-up.

• To compare the incidence of adverse events ascertained via CTCAE version 4.

• To compare the rate of recovery of testosterone to > 230 ng/dL (accepted threshold for supplementation) after 12 and 24 months of follow-up.

• To compare the median time to recovery of testosterone to > 230 ng/dL during the first five years of follow-up.

• To assess cumulative incidence of relevant clinical survivorship endpoints including new diagnosis of type 2 diabetes, coronary artery disease, myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, or osteoporotic fracture.

OUTLINE: This is a multicenter, randomized study. Patients are stratified according to risk group (see Disease Characteristics) and type of radiation therapy (RT) boost (intensity-modulated RT (IMRT) vs brachytherapy). Patients are randomized to 1 of 2 treatment arms.

After completion of study therapy, patients are followed every 3 months for 2 years, every 6 months for 1 year, and then annually thereafter.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 239
• Est. completion date: June 2029
• Est. primary completion date: November 1, 2021
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Histologically confirmed diagnosis of adenocarcinoma of the prostate within 180 days prior to registration at high risk for recurrence as determined by one of the following combinations:

• Gleason Score (GS) = 9, PSA = 150 ng/mL, any T stage

• GS = 8, PSA < 20 ng/mL, T stage = T2

• GS = 8, PSA = 20-150 ng/mL, any T stage

• GS = 7, PSA = 20-150 ng/mL, any T stage

2. History/physical examination within 60 days prior to registration.

3. Clinically negative lymph nodes as established by imaging [abdominal and/or pelvic computerized tomography (CT) or abdominal and/or pelvic magnetic resonance imaging (MRI)], nodal sampling, or dissection within 90 days prior to registration.

•Patients with lymph nodes equivocal or questionable by imaging are eligible if the nodes are < 2.0 cm.

4. No distant metastases (M0) on bone scan within 90 days prior to registration (18F-Na bone scan is an acceptable substitute).

•Equivocal bone scan findings are allowed if plain films are negative for metastasis.

5. Baseline serum prostate-specific antigen (PSA) value performed with an FDA-approved assay (e.g., Abbott, Hybritech), obtained prior to any luteinizing hormone-releasing hormone (LHRH) or anti-androgen therapy, within 180 days of randomization.

6. Androgen deprivation therapy (ADT), such as LHRH agonists (e.g., goserelin, leuprolide), anti-androgens (e.g., flutamide, bicalutamide), estrogens (e.g., DES), or surgical castration (orchiectomy), may have been started prior to registration, provided that registration is within 50 days of beginning ADT. Please note: If the patient has started ADT he will not be eligible to participate in the quality of life component of this study.

7. Prior testosterone administration is allowed if last administered at least 90 days prior to registration.

8. Zubrod Performance Status 0-1 within 21 days prior to registration

9. Age = 18

10. Complete blood count (CBC)/differential obtained within 14 days prior to registration on study, with adequate bone marrow function defined as follows:

• Absolute neutrophil count (ANC) = 1,800 cells/mm3

• Platelets = 100,000 cells/mm3

• Hemoglobin = 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb = 8.0 g/dl is acceptable.)

11. Serum creatinine < 2.0 mg/dl and creatinine clearance (can be calculated) > 40 mL/minute within 21 days prior to registration

12. Bilirubin < 1.5x upper limit of normal (ULN) and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 2.5x ULN within 21 days prior to registration

13. Serum testosterone within 21 days prior to registration

14. Chemistry (including sodium, potassium, chloride, bicarbonate (carbon dioxide), blood urea nitrogen (BUN), glucose, calcium, magnesium and phosphorous) and liver panels (including albumin and alkaline phosphatase) obtained within 21 days prior to registration

15. Fasting glucose, fasting insulin, lipid panel [cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL)], and Hemoglobin A1C within 21 days prior to registration

16. Screening calculated ejection fraction of = to institutional lower limit of normal by multiple gated acquisition (MUGA) scan or by echocardiogram (ECHO).

17. Baseline electrocardiogram (ECG) within 180 days prior to registration

18. Patients, even if surgically sterilized (ie, status post vasectomy), who:

1. Agree to practice effective barrier contraception during the entire study treatment period and for 4 months (120 days) after the last dose of study drug, or

2. Agree to completely abstain from intercourse.

19. Patient must be able to provide study-specific informed consent prior to study entry.

Exclusion Criteria:

1. PSA > 150

2. Definite evidence of metastatic disease.

3. Pathologically positive lymph nodes or nodes > 2.0 cm on imaging.

4. Prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral orchiectomy for any reason.

5. Prior invasive malignancy (except non-melanoma skin cancer) unless disease-free or not requiring systemic therapy for a minimum of 3 years.

6. Prior systemic chemotherapy for prostate cancer (Note that prior chemotherapy for a different cancer is allowed).

7. Prior radiotherapy, including brachytherapy, to the region of the prostate that would result in overlap of radiation therapy fields.

•Any patient undergoing brachytherapy must have transrectal ultrasound confirmation of prostate volume <60 cc, American Urological Association (AUA) score =15 within 60 days of registration, and no history of prior transurethral resection of the prostate (TURP); prior TURP is permitted for patients who receive external beam radiation therapy [EBRT] only).

8. Previous hormonal therapy for > 50 days.

9. Known hypersensitivity to TAK-700 or related compounds

10. A history of adrenal insufficiency

11. History of myocardial infarction, unstable symptomatic ischemic heart disease, ongoing arrhythmias of Grade > 2 [NCI CTCAE, version 4.02] (U.S. Department of Health and Human Services, National Institutes of Health National Cancer Institute, 2009), thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (e.g., pericardial effusion restrictive cardiomyopathy) within 6 months prior to registration. Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed.

12. New York Heart Association Class III or IV heart failure.

13. ECG abnormalities of:

1. Q-wave infarction, unless identified 6 or more months prior to screening

2. QTc interval > 460 msec

14. Patients who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

15. Prior allergic reaction to the drugs involved in this protocol.

16. Study entry PSA obtained during the following time frames:

1. 10-day period following prostate biopsy;

2. following initiation of hormonal therapy.

17. Cushing's syndrome

18. Severe chronic renal disease (serum creatinine > 2.0 mg/dl and confirmed by creatinine clearance < 40 mL/minute)

19. Chronic liver disease (bilirubin > 1.5x ULN, ALT or AST > 2.5x ULN)

20. Chronic treatment with glucocorticoids within one year

21. Uncontrolled hypertension despite appropriate medical therapy within 21 days prior to registration (blood pressure of greater than 150 mm Hg systolic and 90 mm Hg diastolic at 2 separate measurements no more than 60 minutes apart during Screening visit)

22. Unwilling or unable to comply with the protocol or cooperate fully with the investigator and site personnel.

23. Major surgery within 14 days prior to registration

24. Serious infection within 14 days prior to registration

25. Uncontrolled nausea, vomiting, or diarrhea [Common Terminology Criteria for Adverse Events (CTCAE) grade = 3] despite appropriate medical therapy at the time of registration

26. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-700, including difficulty swallowing tablets

Related Conditions & MeSH terms

• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• GnRH agonist
LHRH agonists are administered with a variety of techniques. The manufacturer's instructions should be followed. Begins within 6 weeks after registration (if not started prior) at same time as anti-androgen and TAK-700 (if applicable).
• Anti-androgen
Starts at same time as GnRH agonist, ends at end of radiation therapy. Either flutamide (orally 250 mg three times a day) or bicalutamide (orally 50 mg once a day).
• TAK-700
300 mg twice daily (BID) (600 mg per day) orally, continuously for 2 years starting with ADT.

Radiation:
• Radiation therapy
Starts 8-10 weeks after initiation of ADT. Initially 45 Gy (1.8 Gy / fraction) to prostate and pelvic lymph nodes delivered with 3DCRT/IMRT, then a boost using intensity-modulated radiation therapy (IMRT), low dose rate (LDR) brachytherapy, or high dose rate (HDR) brachytherapy.

Locations

Country	Name	City	State
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	BCCA-Cancer Centre for the Southern Interior	Kelowna	British Columbia
Canada	London Regional Cancer Program	London	Ontario
Canada	CHUM - Hopital Notre-Dame	Montreal	Quebec
Canada	Ottawa Health Research Institute-General Division	Ottawa	Ontario
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
United States	Bixby Medical Center	Adrian	Michigan
United States	Akron General Medical Center	Akron	Ohio
United States	Summa Akron City Hospital/Cooper Cancer Center	Akron	Ohio
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	University of Michigan	Ann Arbor	Michigan
United States	Appleton Medical Center	Appleton	Wisconsin
United States	Emory University/Winship Cancer Institute	Atlanta	Georgia
United States	Grady Health System	Atlanta	Georgia
United States	Piedmont Hospital	Atlanta	Georgia
United States	Sutter Cancer Centers Radiation Oncology Services-Auburn	Auburn	California
United States	University of Colorado Cancer Center - Anschutz Cancer Pavilion	Aurora	Colorado
United States	Saint Agnes Hospital	Baltimore	Maryland
United States	Summa Barberton Hospital	Barberton	Ohio
United States	Mary Bird Perkins Cancer Center	Baton Rouge	Louisiana
United States	Texas Oncology PA - Bedford	Bedford	Texas
United States	Sanford Clinic North-Bemidgi	Bemidji	Minnesota
United States	The Kirklin Clinic at Acton Road	Birmingham	Alabama
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Saint Alphonsus Regional Medical Center	Boise	Idaho
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Cooper Hospital University Medical Center	Camden	New Jersey
United States	Sutter Cancer Centers Radiation Oncology Services-Cameron Park	Cameron Park	California
United States	Southeast Cancer Center	Cape Girardeau	Missouri
United States	Mercy San Juan Medical Center	Carmichael	California
United States	Geaugra Hospital	Chardon	Ohio
United States	Weiss Memorial Hospital	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Ohio State University Medical Center	Columbus	Ohio
United States	Concord Hospital	Concord	New Hampshire
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Atlanta VA Medical Center	Decatur	Georgia
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	University of Miami Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Delaware County Memorial Hospital	Drexel Hill	Pennsylvania
United States	Saint Luke's Hospital of Duluth	Duluth	Minnesota
United States	Mercy Cancer Center-Elyria	Elyria	Ohio
United States	The Regional Cancer Center	Erie	Pennsylvania
United States	Exeter Hospital	Exeter	New Hampshire
United States	Saint Anne's Hospital	Fall River	Massachusetts
United States	Sanford Medical Center-Fargo	Fargo	North Dakota
United States	Saint Francis Hospital	Federal Way	Washington
United States	McLaren-Flint	Flint	Michigan
United States	Poudre Valley Radiation Oncology	Fort Collins	Colorado
United States	Parkview Hospital Randallia	Fort Wayne	Indiana
United States	Radiation Oncology Associates PC	Fort Wayne	Indiana
United States	The Klabzuba Cancer Center	Fort Worth	Texas
United States	University of Texas Medical Branch at Galveston	Galveston	Texas
United States	Adams Cancer Center	Gettysburg	Pennsylvania
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	Saint Mary's Hospital	Green Bay	Wisconsin
United States	Saint Vincent Hospital	Green Bay	Wisconsin
United States	Gibbs Cancer Center-Pelham	Greer	South Carolina
United States	Sentara Cancer Institute at Sentara CarePlex Hospital	Hampton	Virginia
United States	Cherry Tree Cancer Center	Hanover	Pennsylvania
United States	Hartford Hospital	Hartford	Connecticut
United States	Hines Veterans Administration Hospital	Hines	Illinois
United States	Queen's Medical Center	Honolulu	Hawaii
United States	M D Anderson Cancer Center	Houston	Texas
United States	Memorial Hermann Memorial City Medical Center	Houston	Texas
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Kansas City Cancer Center - South	Kansas City	Missouri
United States	Kansas City Cancer Centers - North	Kansas City	Missouri
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Gundersen Lutheran	La Crosse	Wisconsin
United States	Great Lakes Cancer Institute-Lapeer Campus	Lapeer	Michigan
United States	UTMB Cancer Center at Victory Lakes	League City	Texas
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	Kansas City Cancer Center-Lee's Summit	Lee's Summit	Missouri
United States	University of Kentucky	Lexington	Kentucky
United States	Veterans Administration Long Beach Medical Center	Long Beach	California
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Los Angeles County-USC Medical Center	Los Angeles	California
United States	University of Southern California/Norris Cancer Center	Los Angeles	California
United States	Elliot Hospital	Manchester	New Hampshire
United States	Bay Area Medical Center	Marinette	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	Rogue Valley Medical Center	Medford	Oregon
United States	Summa Health Center at Lake Medina	Medina	Ohio
United States	Lake University Ireland Cancer Center	Mentor	Ohio
United States	Columbia Saint Mary's Hospital - Ozaukee	Mequon	Wisconsin
United States	Idaho Urologic Institute PA	Meridian	Idaho
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Southwest General Health Center Ireland Cancer Center	Middleburg Heights	Ohio
United States	Dana-Farber/Brigham and Women's Cancer Center at Milford Regional	Milford	Massachusetts
United States	Clement J. Zablocki VA Medical Center	Milwaukee	Wisconsin
United States	Columbia Saint Mary's Water Tower Medical Commons	Milwaukee	Wisconsin
United States	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Intermountain Medical Center	Murray	Utah
United States	The Hospital of Central Connecticut	New Britain	Connecticut
United States	Saint Peter's University Hospital	New Brunswick	New Jersey
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Touro Infirmary	New Orleans	Louisiana
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Sentara Hospitals	Norfolk	Virginia
United States	William Backus Hospital	Norwich	Connecticut
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	The Nebraska Medical Center	Omaha	Nebraska
United States	UHHS-Chagrin Highlands Medical Center	Orange Village	Ohio
United States	Florida Hospital	Orlando	Florida
United States	Kansas City Cancer Centers-Southwest	Overland Park	Kansas
United States	McLaren Cancer Institute-Owosso	Owosso	Michigan
United States	Paoli Memorial Hospital	Paoli	Pennsylvania
United States	North Shore Medical Center Cancer Center	Peabody	Massachusetts
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	Northern Michigan Regional Hospital	Petoskey	Michigan
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Arizona Oncology-Deer Valley Center	Phoenix	Arizona
United States	Pomona Valley Hospital Medical Center	Pomona	California
United States	Wheaton Franciscan Cancer Care - All Saints	Racine	Wisconsin
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Robinson Radiation Oncology	Ravenna	Ohio
United States	Oncology and Hematology Associates of Southwest Virginia	Roanoke	Virginia
United States	Rohnert Park Cancer Center	Rohnert Park	California
United States	Sutter Cancer Centers Radiation Oncology Services-Roseville	Roseville	California
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	Sutter General Hospital	Sacramento	California
United States	Dixie Medical Center Regional Cancer Center	Saint George	Utah
United States	Barnes-Jewish West County Hospital	Saint Louis	Missouri
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Saint John's Mercy Medical Center	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Regions Hospital	Saint Paul	Minnesota
United States	Siteman Cancer Center - Saint Peters	Saint Peters	Missouri
United States	Peninsula Regional Medical Center	Salisbury	Maryland
United States	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah
United States	University of California At San Diego	San Diego	California
United States	UCSF-Mount Zion	San Francisco	California
United States	Ireland Cancer Center at Firelands Regional Medical Center	Sandusky	Ohio
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	Saint Joseph's-Candler Health System	Savannah	Georgia
United States	Maine Medical Center- Scarborough Campus	Scarborough	Maine
United States	Arizona Oncology Services Foundation	Scottsdale	Arizona
United States	Virginia Mason CCOP	Seattle	Washington
United States	Texas Cancer Center-Sherman	Sherman	Texas
United States	Kaiser Permanente Cancer Treatment Center	South San Francisco	California
United States	Dana-Farber/Brigham and Women's Cancer Center at South Shore	South Weymouth	Massachusetts
United States	Spartanburg Regional Medical Center	Spartanburg	South Carolina
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Stanford University Hospitals and Clinics	Stanford	California
United States	Door County Cancer Center	Sturgeon Bay	Wisconsin
United States	Texas Oncology Cancer Center Sugar Land	Sugar Land	Texas
United States	Flower Hospital	Sylvania	Ohio
United States	William Beaumont Hospital - Troy	Troy	Michigan
United States	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma
United States	Sutter Cancer Centers Radiation Oncology Services-Vacaville	Vacaville	California
United States	Sutter Solano Medical Center	Vallejo	California
United States	Sentara Virginia Beach General Hospital	Virginia Beach	Virginia
United States	MD Anderson Cancer Center at Cooper-Voorhees	Voorhees	New Jersey
United States	Lexington Medical Center	West Columbia	South Carolina
United States	Reading Hospital	West Reading	Pennsylvania
United States	UHHS-Westlake Medical Center	Westlake	Ohio
United States	Lankenau Hospital	Wynnewood	Pennsylvania
United States	WellSpan Health-York Hospital	York	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
Radiation Therapy Oncology Group	National Cancer Institute (NCI), NRG Oncology

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Biochemical Failure (Primary Endpoint of Revised Protocol)	Note, the revised protocol (see Limitations and Caveats) changed this outcome measure from secondary (original protocol) to primary. Biochemical failure will be defined by the Phoenix definition (PSA = 2 ng/ml over the nadir PSA, the presence of local, regional, or distant recurrence, or the initiation of salvage androgen deprivation therapy. Time to failure is defined as time from randomization to the date of first failure, last known follow-up (censored), or death without failure (competing risk). Failure rates are estimated using the cumulative incidence method, while treatment effect comparisons are based on cause-specific hazards (deaths censored). Five-year rates are provided here.	From randomization to last follow-up. Follow-up schedule: every 3 months from start of treatment for 2 years, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 9.1 years. Five-year rates are reported here.
Secondary	Percentage of Patients Alive [Overall Survival] (Primary Endpoint of Original Protocol)	Note, the revised protocol (see Limitations and Caveats) changed this outcome measure from primary (original protocol) to secondary. Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. 5-year rates are provided.	From randomization to last follow-up. Follow-up schedule: every 3 months from start of treatment for 2 years, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 9.1 years. Five-year rates are reported here.
Secondary	Percentage of Participants With Grade 3 or Higher Adverse Events	Time to grade 3 or higher adverse event (event) is defined as time from randomization to the date of first event, last known follow-up (censored), or death without failure (competing risk). Event rates are estimated using the cumulative incidence method, while treatment effect comparisons are based on cause-specific hazards (deaths censored). Five-year rates are provided here.	From randomization to last follow-up. Follow-up schedule: every 3 months from start of treatment for 2 years, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 9.1 years. Five-year rates are reported here.
Secondary	Percentage of Participants With Local Progression	Local recurrence (failure) is defined as biopsy proven recurrence within the prostate gland. Time to failure is defined as time from randomization to the date of failure, last known follow-up (censored), or death without failure (competing risk). Failure rates are estimated using the cumulative incidence method, while treatment effect comparisons are based on cause-specific hazards (deaths censored). Five-year rates are provided here.	From randomization to last follow-up. Follow-up schedule: every 3 months from start of treatment for 2 years, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 9.1 years. Five-year rates reported.
Secondary	Percentage of Participants With Distant Metastases	Distant metastases (failure) is defined as imaging or biopsy demonstrated evidence for systemic recurrence. Biopsy was not required, however it was encouraged in absence of a rising PSA. Time to failure is defined as time from randomization to the date of first failure, last known follow-up (censored), or death without failure (competing risk). Failure rates are estimated using the cumulative incidence method, while treatment effect comparisons are based on cause-specific hazards (deaths censored). Five-year rates are provided here. Note, the protocol lists this endpoint as regional or distant metastasis, but regional progression data was not collected.	From randomization to last follow-up. Follow-up schedule: every 3 months from start of treatment for 2 years, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 9.1 years. Five-year rates are reported here.
Secondary	Percentage of Participants With General Clinical Treatment Failure	General clinical treatment failure (GCTF) is defined as: PSA > 25 ng/ml, documented local disease progression, regional or distant metastasis, or initiation of salvage androgen deprivation therapy. Failure time is defined as time from registration to the date of failure, last known follow-up (censored), or death without failure (competing risk). Failure rates are estimated using the cumulative incidence method, while treatment effect comparisons are based on cause-specific hazards (deaths censored). Five-year rates are provided here.	From randomization to last follow-up. Follow-up schedule: every 3 months from start of treatment for 2 years, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 9.1 years. Five-year rates are reported here.
Secondary	Percentage of Participants With Death Due to Prostate Cancer	Time to prostate cancer death is defined as time from randomization to the date of death due to prostate cancer, last known follow-up (censored), or death due to other causes (competing risk). Failure rates were to be estimated using the cumulative incidence method. If too few events occur for meaningful estimates, then only counts of events will be reported.	From randomization to last follow-up. Follow-up schedule: every 3 months from start of treatment for 2 years, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 9.1 years. Five-year rates are reported here.
Secondary	Change in Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form at One Year	The PROMIS Fatigue short form 8a contains 8 questions, each with 5 responses ranging from 1 to 5, evaluating self-reported fatigue symptoms over the past 7 days. The total score is the sum of all questions which is then converted into a pro-rated T-score with a mean of 50 and standard deviation of 10, with a possible range of 33.1 to 77.8. Higher scores indicate more fatigue. Change is defined as value at one year - value at baseline. Positive change from baseline indicates increased fatigue at one year.	Baseline, one year
Secondary	Change in Patient-reported Quality of Life as Measured by Expanded Prostate Cancer Index Composite (EPIC) Short Form at One Year	The EPIC-Short Form is a 26-item, validated self-administered tool to assess disease-specific aspects of prostate cancer and its therapies consisting of five summary domains (bowel, urinary incontinence, urinary irritation/obstruction, sexual, and hormonal function). Responses for each item form a Likert scale which are transformed to a 0-100 scale. A domain score is the average of the transformed domain item scores, ranging from 0-100 with higher scores representing better health-related quality of life (HRQOL). Change at one year is defined as one-year value - baseline value. Positive change at one year indicates improved quality of life.	Baseline, one year
Secondary	Serum Testosterone		Baseline,12 months, 24 months
Secondary	Fasting Total Cholesterol		Baseline, 12 months, 24 months
Secondary	Serum High-density Lipoprotein (HDL)		Baseline, 12 months, 24 months
Secondary	Serum High-density Lipoprotein (LDL)		Baseline, 12 months, 24 months
Secondary	Hemoglobin A1c		Baseline, 12 months, 24 months
Secondary	Fasting Plasma Glucose		Baseline, 12 months, 24 months
Secondary	Fasting Plasma Insulin		Baseline, 12 months, 24 months
Secondary	Change From Baseline in Body Mass Index (BMI)	Body Mass Index (BMI) is a person's weight in kilograms (or pounds) divided by the square of height in meters (or feet). Change from baseline = time point value - baseline value.	Baseline and yearly to five years.
Secondary	Number of Participants by Highest Grade Adverse Event	Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data	From registration to last follow-up. Follow-up schedule: every 3 months from start of treatment for 2 years, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 9.1 years. Five-year rates are reported here.
Secondary	Testosterone Recovery at 12 and 24 Months	Testosterone recovery is defined as testosterone level after treatment greater than 230 ng/dL. Time to testosterone recovery is defined as time from randomization to the date of testosterone recovery, biochemical, local, or distant failure (competing risk), salvage therapy (competing risk), death (competing risk), or last known follow-up (censored). Testosterone recovery rates are estimated using the cumulative incidence method.	From registration to last follow-up. Follow-up schedule: every 3 months from start of treatment for 2 years, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 9.1 years.
Secondary	Median Testosterone Recovery Time	Testosterone recovery is defined as testosterone level after treatment greater than 230 ng/dL. Testosterone recovery rates are estimated using the Kaplan-Meier method, censoring for biochemical, local, or distant failure, salvage therapy, death, and otherwise alive without event. Testosterone recovery time is defined as time from randomization to testosterone recovery or censoring.	From randomization to last follow-up. Follow-up schedule: every 3 months from start of treatment for 2 years, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 9.1 years. Five-year rates are reported here.
Secondary	Number of Patients With Clinical Survivorship Events	Clinical survivorship events are defined as the following newly diagnosed non-fatal cardiovascular events or other clinical endpoints relevant to prostate cancer survivorship: type 2 diabetes, coronary artery disease, myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, and osteoporotic fracture.	From randomization to last follow-up. Follow-up schedule: every 3 months from start of treatment for 2 years, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 9.1 years. Five-year rates are reported here.