Testing the Addition of the Drug Relugolix to the Usual Radiation Therapy for Advanced-Stage Prostate Cancer

Prostate Adenocarcinoma Clinical Trial

— NRG PROMETHEAN  

Official title:

A Phase II Double-Blinded, Placebo-Controlled Trial of PROstate OligoMETastatic RadiotHErapy With or Without ANdrogen Deprivation Therapy in Oligometastatic Prostate Cancer (NRG Promethean)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05053152
• Other study ID #: NRG-GU011
• Secondary ID: NCI-2021-09164NR
• Status: Recruiting
• Phase: Phase 2
• Start date: December 8, 2021
• Est. completion date: October 10, 2029

Study information

• Verified date: February 2024
• Source: NRG Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial tests whether relugolix and radiation therapy works to shrink tumors in patients with prostate cancer that has spread in a limited way to 1 to 5 other parts of the body (oligometastatic). Testosterone can cause the growth of prostate cancer cells. Relugolix lowers the amount of testosterone made by the body. This may help stop the growth of tumor cells that need testosterone to grow. Giving relugolix with radiation therapy may help lower the chance of prostate cancer growing or spreading.

Description:

PRIMARY OBJECTIVE:

I. Compare conventional radiological progression-free survival (rPFS) for positron emission tomography (PET)-detected, biochemically recurrent, oligometastatic, castration-sensitive prostate cancer patients treated with stereotactic ablative body radiation therapy (SABR) plus placebo versus (vs.) SABR plus relugolix.

SECONDARY OBJECTIVES:

I. Compare conventional or PET-based radiological progression-free survival (prPFS) between treatment arms.

II. Compare patient-reported sexual and hormonal quality of life as assessed by corresponding Expanded Prostate Cancer Index Composite Short Form (EPIC-26) domains between treatment arms.

III. Compare other measures of quality of life obtained from the European Quality of Life Five Dimension Five Level Scale Questionnaire (EQ5D-5L), European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-30), and Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue instruments between the two treatment arms.

IV. Compare time to salvage therapy and time to castration-resistance between treatment arms.

V. Compare local progression (SABR-targeted lesion), biochemical progression, distant metastases, prostate cancer-specific mortality, metastasis-free survival, and overall survival between treatment arms.

VI. Determine adverse events rates and compare rates between the two treatment arms.

EXPLORATORY OBJECTIVE:

I. Evaluate genomic and peripheral tissue and blood markers of treatment response.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive placebo orally (PO) once daily (QD) on days 1-180 (three tablets on Day 1, one tablet daily on Days 2-180) and undergo SABR for 1-3 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive relugolix PO QD on days 1-180 (three tablets on Day 1, one tablet daily on Days 2-180) and undergo SABR for 1-3 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3 and 6 months, every 6 months for 4 years, and then annually thereafter.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 260
• Est. completion date: October 10, 2029
• Est. primary completion date: October 10, 2024
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of prostate adenocarcinoma at any anatomical location (for example, prostate, metastatic site), including intraductal or ductal carcinoma, at any time before registration

• Age = 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 within 120 days prior to registration

• Prior curative-intent treatment to the prostate, by either:

• External beam and/or brachytherapy to: Prostate alone, prostate and seminal vesicles, prostate and pelvic nodes, or radiation to all three sites

• Radical prostatectomy alone, radical prostatectomy plus postoperative radiotherapy to the prostate bed, or radical prostatectomy plus postoperative radiotherapy to the pelvic nodes

• Must meet study entry criteria based on the following diagnostic workup within 120 days prior to registration:

• History and physical examination;

• Technetium TC-99m (99mTc) bone scan (Must be negative);

• Either computed tomography (CT) or magnetic resonance imaging (MRI) of pelvis +/- abdomen (Must be negative);

• Fluciclovine or prostate-specific membrane antigen (PSMA) PET scan (Must be positive with exception of local disease);

• Note: All 3 scans are mandatory (bone scan; CT/magnetic resonance [MR]; PET)

• 1 - 5 oligometastatic lesions in bone and/or nodal/soft tissue sites on fluciclovine or PSMA PET within 120 days prior to registration and includes at least ONE of the following:

• Bone - each metastasis is counted (for example, 2 distinct lesions in the right ilium count as 2 oligometastatic lesions)

• Extrapelvic Nodal/ soft tissue - requires at least one extrapelvic inguinal or a nodal/soft tissue lesion superior to the iliac bifurcation (that is, American Joint Committee on Cancer [AJCC] M1a version 8)

• Note: Although a patient must have bone and/or extrapelvic disease to be eligible, when counting the number of oligometastatic lesions, each lymph node lesion, whether pelvic or extrapelvic, is counted (for example, 2 distinct lymph nodes in the right external iliac basin count as 2 oligometastatic lesions; one extrapelvic and one pelvic node count as 2 oligometastic lesions, etc)

• Serum total prostate-specific antigen (PSA) =10.0 ng/mL obtained within 120 days prior to registration that also meets ONE of the following PSA recurrence definitions:

• PSA = post-radiation therapy (RT) nadir PSA + 2 ng/mL, if patient received-radiation therapy to intact prostate, or

• Current PSA = 0.2 ng/mL, with a second confirmatory PSA = 0.2 ng/mL if patient received a radical prostatectomy with or without post-op RT

• Must have =3 PSA values within the last two years since end of primary treatment or within the last 2 years prior to registration, whichever is less

• Note: PSA doubling time must be calculated by entering all PSA values since end of primary treatment or within the last 2 years prior to registration (whichever is less) into the PSA Doubling Time Calculator found at MDCalc.com

• Serum total testosterone = 100 ng/dL within 120 days prior to registration

• Note: Prior androgen deprivation therapy (other than bilateral orchiectomy) is allowed if discontinued prior to registration and serum total testosterone is = 100 ng/dL

• Total bilirubin: = 1.5 x institutional upper limit of normal (ULN) (Note: In subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, subject is eligible if direct bilirubin is = 1.5 x ULN) (within 120 days prior to registration)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]): = 2.5 x institutional ULN (within 120 days prior to registration)

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

• Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B)

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Note: Known positive test for hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• The patient must agree to use a highly effective contraception (even men with vasectomies) if he is having sex with a woman of childbearing potential or with a woman who is pregnant while on study drug and for 2 weeks following the last dose of study drug

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information.

Exclusion Criteria:

• Clinical, biopsy-proven, or radiologic (conventional or PET imaging) evidence of local tumor recurrence in the prostate and/or periprostatic/seminal vesicle region after radiotherapy, or in the prostate bed after prostatectomy

• Note: if a patient had a prior local recurrence and received local salvage therapy, the patient is eligible if there is no current evidence of disease in the prostate/prostate bed. Patients with positive findings on examination or imaging remain eligible if biopsy of the site is negative for cancer.

• Currently on androgen deprivation or anti-androgen therapy

• Definitive radiologic evidence of metastatic disease on conventional imaging, defined by one of the following:

• Osseous metastasis on 99mTc radionuclide bone scan, or

• Extra pelvic nodal/soft tissue disease (> 1.5 cm in short axis) on CT or MRI pelvis +/- abdomen

• Spinal cord compression, or spinal intramedullary, brain, and/or visceral (for example liver, lung, etc.) metastasis

• Note: Spinal metastases (PET-detected) with epidural extension are eligible if there is > 0.3 cm spatial separation between the gross tumor volume and spinal cord.

• Biopsy-proven prostatic carcinoma with signet-ring, sarcomatoid, or neuroendocrine features (for example, small cell)

• Prior metastatic or non-metastatic, invasive malignancy (except non metastatic, non-melanomatous skin cancer) unless continuously disease free for = 3 years

• Prior chemotherapy for prostate cancer or bilateral orchiectomy

• Note: Prior chemotherapy for a different cancer is allowed if continuously disease-free for = 3 years

• Prior radiotherapy to a lesion (i.e. oligometastatic recurrence by PET)

• Note: Lesions outside of a previously irradiated planning treatment volume (PTV) are eligible as long as the prescription isovolume dose of any prior radiotherapy course is > 2.0 cm distant from new lesion

• Inability to treat all oligometastatic sites with radiotherapy in the judgement of the investigator

• Intrapelvic lymph nodes as only site of prostate cancer recurrence

• Inability to swallow whole, undivided, unchewed, and uncrushed pills

• Known gastrointestinal disorder affecting oral medication absorption

• Co-morbidity defined as follows:

• Patients with any comorbidities that would prohibit completion of protocol specified therapy

• Inflammatory bowel disease in patients in whom abdominopelvic radiotherapy is planned

• History of congenital long QT syndrome

• Current severe or unstable angina

• New York Heart Association functional classification III/IV heart failure (Note:

Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification)

Related Conditions & MeSH terms

• Oligometastatic Prostate Carcinoma
• Prostate Adenocarcinoma
• Prostatic Neoplasms
• Stage IVB Prostate Cancer AJCC v8

Intervention

Drug:
• Placebo Administration
Given PO

Other:
• Quality-of-Life Assessment
Ancillary studies

Drug:
• Relugolix
Given PO

Radiation:
• Stereotactic Body Radiation Therapy
Undergo SABR

Locations

Country	Name	City	State
Canada	University Health Network-Princess Margaret Hospital	Toronto	Ontario
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	UPMC Altoona	Altoona	Pennsylvania
United States	Mary Greeley Medical Center	Ames	Iowa
United States	McFarland Clinic - Ames	Ames	Iowa
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Langlade Hospital and Cancer Center	Antigo	Wisconsin
United States	Emory Saint Joseph's Hospital	Atlanta	Georgia
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Grady Health System	Atlanta	Georgia
United States	Piedmont Hospital	Atlanta	Georgia
United States	UCHealth University of Colorado Hospital	Aurora	Colorado
United States	UH Seidman Cancer Center at UH Avon Health Center	Avon	Ohio
United States	Advocate Good Shepherd Hospital	Barrington	Illinois
United States	UHHS-Chagrin Highlands Medical Center	Beachwood	Ohio
United States	UPMC-Heritage Valley Health System Beaver	Beaver	Pennsylvania
United States	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California
United States	Tower Cancer Research Foundation	Beverly Hills	California
United States	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado
United States	Saint Joseph Mercy Brighton	Brighton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Saint Joseph Mercy Canton	Canton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Carlisle Regional Cancer Center	Carlisle	Pennsylvania
United States	Miami Valley Hospital South	Centerville	Ohio
United States	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania
United States	Chambersburg Hospital	Chambersburg	Pennsylvania
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Advocate Illinois Masonic Medical Center	Chicago	Illinois
United States	Michigan Healthcare Professionals Clarkston	Clarkston	Michigan
United States	Case Western Reserve University	Cleveland	Ohio
United States	Memorial Hospital North	Colorado Springs	Colorado
United States	UCHealth Memorial Hospital Central	Colorado Springs	Colorado
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	AMG Crystal Lake - Oncology	Crystal Lake	Illinois
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Blood and Cancer Center	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Miami Valley Hospital North	Dayton	Ohio
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa
United States	Fox Chase Cancer Center - East Norriton Hospital Outpatient Center	East Norriton	Pennsylvania
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Advocate Sherman Hospital	Elgin	Illinois
United States	UPMC Hillman Cancer Center Erie	Erie	Pennsylvania
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Michigan Healthcare Professionals Farmington	Farmington Hills	Michigan
United States	UPMC Cancer Center at UPMC Horizon	Farrell	Pennsylvania
United States	Piedmont Fayette Hospital	Fayetteville	Georgia
United States	Cancer Care and Hematology-Fort Collins	Fort Collins	Colorado
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	Parkview Regional Medical Center	Fort Wayne	Indiana
United States	Beebe South Coastal Health Campus	Frankford	Delaware
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Fox Chase Cancer Center Buckingham	Furlong	Pennsylvania
United States	Aurora Cancer Care-Grafton	Grafton	Wisconsin
United States	UCHealth Greeley Hospital	Greeley	Colorado
United States	Aurora BayCare Medical Center	Green Bay	Wisconsin
United States	East Carolina University	Greenville	North Carolina
United States	UPMC Pinnacle Cancer Center/Community Osteopathic Campus	Harrisburg	Pennsylvania
United States	Advocate South Suburban Hospital	Hazel Crest	Illinois
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	UCHealth Highlands Ranch Hospital	Highlands Ranch	Colorado
United States	Edwards Comprehensive Cancer Center	Huntington	West Virginia
United States	IRMC Cancer Center	Indiana	Pennsylvania
United States	Jupiter Medical Center	Jupiter	Florida
United States	GenesisCare USA - Lakewood Ranch	Lakewood Ranch	Florida
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania
United States	AMG Libertyville - Oncology	Libertyville	Illinois
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Los Angeles General Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	Medical Center of the Rockies	Loveland	Colorado
United States	Covenant Medical Center-Lakeside	Lubbock	Texas
United States	Michigan Healthcare Professionals Macomb	Macomb	Michigan
United States	Michigan Healthcare Professionals Madison Heights	Madison Heights	Michigan
United States	Aurora Bay Area Medical Group-Marinette	Marinette	Wisconsin
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion	Mechanicsburg	Pennsylvania
United States	Riddle Memorial Hospital	Media	Pennsylvania
United States	Froedtert Menomonee Falls Hospital	Menomonee Falls	Wisconsin
United States	UH Seidman Cancer Center at Lake Health Mentor Campus	Mentor	Ohio
United States	East Jefferson General Hospital	Metairie	Louisiana
United States	LSU Healthcare Network / Metairie Multi-Specialty Clinic	Metairie	Louisiana
United States	Aurora Saint Luke's Medical Center	Milwaukee	Wisconsin
United States	Aurora Sinai Medical Center	Milwaukee	Wisconsin
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Memorial Medical Center	Modesto	California
United States	UPMC Hillman Cancer Center in Coraopolis	Moon	Pennsylvania
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	Carolina Regional Cancer Center	Myrtle Beach	South Carolina
United States	Cancer Center of Western Wisconsin	New Richmond	Wisconsin
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Drexel Town Square Health Center	Oak Creek	Wisconsin
United States	Advocate Christ Medical Center	Oak Lawn	Illinois
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin
United States	Paoli Memorial Hospital	Paoli	Pennsylvania
United States	The Valley Hospital-Luckow Pavilion	Paramus	New Jersey
United States	Advocate Lutheran General Hospital	Park Ridge	Illinois
United States	University Hospitals Parma Medical Center	Parma	Ohio
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Cancer Center at Saint Joseph's	Phoenix	Arizona
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	UPMC-Magee Womens Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Saint Margaret	Pittsburgh	Pennsylvania
United States	UPMC-Shadyside Hospital	Pittsburgh	Pennsylvania
United States	GenesisCare USA - Plantation	Plantation	Florida
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Oregon Health and Science University	Portland	Oregon
United States	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania
United States	University Hospitals Portage Medical Center	Ravenna	Ohio
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	Ascension Saint Mary's Hospital	Rhinelander	Wisconsin
United States	Highland Hospital	Rochester	New York
United States	University of Rochester	Rochester	New York
United States	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	Norris Cotton Cancer Center-North	Saint Johnsbury	Vermont
United States	Siteman Cancer Center at Christian Hospital	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 at Saint Peters Hospital	Saint Peters	Missouri
United States	UPMC Cancer Center at UPMC Northwest	Seneca	Pennsylvania
United States	Vince Lombardi Cancer Clinic-Sheboygan	Sheboygan	Wisconsin
United States	Memorial Hospital East	Shiloh	Illinois
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Memorial Medical Center	Springfield	Illinois
United States	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Aurora Medical Center in Summit	Summit	Wisconsin
United States	ProMedica Flower Hospital	Sylvania	Ohio
United States	GenesisCare USA - Troy	Troy	Michigan
United States	Upper Valley Medical Center	Troy	Ohio
United States	William Beaumont Hospital - Troy	Troy	Michigan
United States	UPMC Washington Hospital Radiation Oncology	Washington	Pennsylvania
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	Aurora Cancer Care-Milwaukee West	Wauwatosa	Wisconsin
United States	Wilmot Cancer Institute at Webster	Webster	New York
United States	Aurora West Allis Medical Center	West Allis	Wisconsin
United States	Froedtert West Bend Hospital/Kraemer Cancer Center	West Bend	Wisconsin
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Divine Providence Hospital	Williamsport	Pennsylvania
United States	Aspirus Cancer Care - Wisconsin Rapids	Wisconsin Rapids	Wisconsin
United States	Lankenau Medical Center	Wynnewood	Pennsylvania
United States	UPMC Memorial	York	Pennsylvania
United States	WellSpan Health-York Cancer Center	York	Pennsylvania
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
NRG Oncology	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Radiological progression-free survival (rPFS)	The rPFS curves will be estimated by the Kaplan-Meier method and compared between the two treatment arms using a one-sided, logrank test stratified by the three randomization factors.	Time from randomization to the occurrence of radiological progression detected by conventional imaging or death from any cause, assessed up to 5 years
Secondary	Positron emission tomography (PET)-based radiological progression-free survival	Will be estimated by the Kaplan-Meier method and compared between treatments arms by stratified logrank test. Cox regression models will also be fit, adjusted for the stratification factors and other prognostic baseline factors, to estimate hazard ratios, together with 95% confidence intervals.	Time from randomization to the occurrence of conventional or PET-based radiological progression or death from any cause, assessed up to 5 years
Secondary	Metastasis-free Survival	Will be estimated by the Kaplan-Meier method and compared between treatments arms by stratified logrank test. Cox regression models will also be fit, adjusted for the stratification factors and other prognostic baseline factors, to estimate hazard ratios, together with 95% confidence intervals.	From randomization to distant metastases or death from any cause, assessed up to 5 years
Secondary	Overall Survival	Will be estimated by the Kaplan-Meier method and compared between treatments arms by stratified logrank test. Cox regression models will also be fit, adjusted for the stratification factors and other prognostic baseline factors, to estimate hazard ratios, together with 95% confidence intervals.	From randomization to death from any cause, assessed up to 5 years
Secondary	Sexual Function	Assessed by Expanded Prostate Cancer Index Composite Short Form (EPIC-26).	Up to 5 years
Secondary	Fatigue	Assessed by Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue short form. Longitudinal profiles will be compared using mixed effects regression.	Up to 5 years