Treating Prostate Cancer That Has Come Back After Surgery With Apalutamide and Targeted Radiation Based on PET Imaging

Prostate Adenocarcinoma Clinical Trial

Official title:

Phase III Study of Local or Systemic Therapy INtensification DIrected by PET in Prostate CAncer Patients With Post-ProstaTEctomy Biochemical Recurrence (INDICATE)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04423211
• Other study ID #: EA8191
• Secondary ID: NCI-2020-02686EA
• Status: Recruiting
• Phase: Phase 3
• Start date: October 8, 2020
• Est. completion date: December 31, 2032

Study information

• Verified date: May 2023
• Source: Eastern Cooperative Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase III trial tests two questions by two separate comparisons of therapies. The first question is whether enhanced therapy (apalutamide in combination with abiraterone + prednisone) added to standard of care (prostate radiation therapy and short term androgen deprivation) is more effective compared to standard of care alone in patients with prostate cancer who experience biochemical recurrence (a rise in the blood level of prostate specific antigen [PSA] after surgical removal of the prostate cancer).

A second question tests treatment in patients with biochemical recurrence who show prostate cancer spreading outside the pelvis (metastasis) by positron emission tomography (PET) imaging. In these patients, the benefit of adding metastasis-directed radiation to enhanced therapy (apalutamide in combination with abiraterone + prednisone) is tested.

Diagnostic procedures, such as PET, may help doctors look for cancer that has spread to the pelvis. Androgens are hormones that may cause the growth of prostate cancer cells. Apalutamide may help fight prostate cancer by blocking the use of androgens by the tumor cells. Metastasis-directed targeted radiation therapy uses high energy rays to kill tumor cells and shrink tumors that have spread. This trial may help doctors determine if using PET results to deliver more tailored treatment (i.e., adding apalutamide, with or without targeted radiation therapy, to standard of care treatment) works better than standard of care treatment alone in patients with biochemical recurrence of prostate cancer.

Description:

PRIMARY OBJECTIVES:

I. For patients without PET-evidence of extrapelvic metastases, to evaluate whether the addition of enhanced systemic therapy to standard of care (SOC) salvage radiation therapy (RT) could prolong progression-free survival (PFS).

II. For patients with PET-evidence of extrapelvic metastases, to evaluate whether the addition of metastasis-directed RT to enhanced systemic therapy and SOC salvage RT could prolong PFS.

III. To compare overall quality of life, measured by Functional Assessment of Cancer Therapy

• Prostate (FACT-P) total score, at 6 months between the two sets of treatment arms (A with B and C with D). (QUALITY OF LIFE [QOL] OBJECTIVE)

SECONDARY OBJECTIVES:

I. To evaluate overall survival in each arm. II. To evaluate event-free survival in each arm. III. To evaluate time to prostate-specific antigen (PSA) progression in each arm.

IV. To assess the incidence of adverse events with the addition of enhanced systemic therapy in patients without PET-evidence of extrapelvic metastases.

V. To assess the incidence of adverse events with local ablative metastasis-directed RT for PET-positive metastatic disease in patients with PET-evidence of extrapelvic metastases.

VI. To estimate the detection rate of PET at the patient and regional level, and to evaluate its concordance with the follow-up Food and Drug Administration (FDA)-approved conventional imaging modalities (CIM) (as available) considered standard-of-care per institution, including computed tomography (CT), bone scintigraphy, magnetic resonance imaging (MRI) and PET imaging.

VII. To determine the distribution of PET-positive lesions among anatomic sites (prostate fossa, intrapelvic soft tissue/lymph node, extrapelvic soft tissue/lymph node, and bone metastases) in patients with post-radical prostatectomy (RP) biochemical recurrence (BCR), correlated with PSA (level, doubling time, velocity) and other relevant clinical parameters.

VIII. To compare the change in overall QOL, measured by FACT-P total score, from baseline to 6 months between the two sets of treatment arms (A with B and C with D). (QOL OBJECTIVE) IX. To compare patient-reported fatigue (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue scores) at 6 months between the two sets of treatment arms (A with B and C with D). (QOL OBJECTIVE) X. To compare patient-reported overall QOL (FACT-P scores), fatigue (FACIT-Fatigue scores) and pain interference (patient reported outcomes measurement information system [PROMIS] Pain Interference Short Form 4a) between the two sets of treatment arms (A with B and C with D) at the time of disease progression. (QOL OBJECTIVE)

EXPLORATORY OBJECTIVES:

I.To determine the value of repeat PET (PET2) at time of second PSA progression, clinical concern for progression, or 12 months after completion of enhanced systemic therapy, whichever comes first to assess response to therapy (enhanced systemic therapy +/- focal RT and/or androgen deprivation therapy [ADT]) compared to available standard response assessments (PSA and conventional imaging modalities [CIM]).

II. To compare cognitive function, measured by FACT - cognitive function (Cog) peritoneal cancer index (PCI) and total scores, between the three treatment arms receiving enhanced systemic treatment with ADT and apalutamide (Arms B, C, and D) and antiandrogen therapy (ADT) alone (Arm A) at 6 and 12 month. (QOL OBJECTIVE) III. To compare the change in cognitive function, measured by change in FACT-Cog PCI and total scores, from baseline to 6 and baseline to 12 months, between the three treatment arms receiving enhanced systemic treatment with ADT and apalutamide (Arms B, C, and D) and ADT alone (Arm A) at 6 and 12 months. (QOL OBJECTIVE) IV. To characterize longitudinal change in cognitive function between baseline and 24 months in patients with prostate cancer receiving treatment for biochemical recurrence (BCR) and define clinical and disease related characteristics associated with greater cognitive change by the FACT-Cog PCI and total scores. (QOL OBJECTIVE)

OUTLINE:

STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 intravenously (IV) undergo a repeat PET2 at time of PSA progression or clinical concerns for progression or 12 months after completion of enhanced systemic therapy, whichever occurs first. Patients in Arm C or D using another tracer for PET1 do not undergo PET2.

STEP 1: Patients are randomized to 1 of 4 arms based on results of fluciclovine F18 PET/CT or PET/MR in Step 0.

ARM A (PET NEGATIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC external beam radiation therapy (EBRT) for 6 months. Patients also receive goserelin acetate subcutaneously (SC), leuprolide acetate intramuscularly (IM), triptorelin IM, relugolix orally (PO), or degarelix SC for 6 months starting up to 3 months prior to EBRT but no later than 7 days after start of EBRT. All treatment continues for 6 months in the absence of disease progression or unacceptable toxicity.

ARM B (PET NEGATIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC EBRT and receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix PO, or degarelix SC as in Arm A. Patients also receive apalutamide PO once daily (QD) for 6 months in the absence of disease progression or unacceptable toxicity.

ARM C: (PET POSITIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC EBRT and receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix PO, or degarelix SC as in Arm A. Patients also receive apalutamide PO QD as in Arm B.

ARM D (PET POSITIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC EBRT and receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix PO, or degarelix SC as in Arm A and apalutamide PO QD as in Arm B. Patients also undergo stereotactic body radiation therapy (SBRT) or 3-dimensional (3D) conformal radiation therapy (CRT), intensity-modulated radiation therapy (IMRT) (including volume modulated arc therapy [VMAT]), and intensity-modulated proton therapy (IMPT) over 3-10 fractions in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for the first 2 years, every 6 months for years 3-5, and then annually for years 6-10.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 804
• Est. completion date: December 31, 2032
• Est. primary completion date: December 31, 2032
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• STEP 0: REGISTRATION ELIGIBILITY CRITERIA

• Patient must be male and >= 18 years of age.

• Patient must have had a radical prostatectomy (RP) as definitive therapy for histopathologically-proven prostatic adenocarcinoma

• Patient must have biochemical recurrence (BCR) after RP, defined as follows:

• If time to BCR, defined as time to first detectable PSA ( > lower limit of normal for assay used) after RP, is < 12 months, a minimum PSA level of >= 0.2 ng/mL and a confirmatory reading of >= 0.2 ng/mL is required, per the American Urological Association (AUA) definition (Note: patients with a persistent PSA reading of at least 0.2 ng/mL are eligible)

• If time to BCR, defined as time to first detectable PSA (> lower limit of normal for assay used) after RP, is >= 12 months, a minimum absolute PSA of 0.5 ng/mL is required

• If the patient has a detectable PSA (> lower limit of normal for assay used) at any time after RP AND has an eligible baseline SOC PET (PET1) with at least one positive lesion in any location, then there is no minimum PSA requirement

• Patients must have no definite evidence for extrapelvic metastatic disease by conventional imaging modalities (CIM) (CT abdomen/pelvis or MRI abdomen/pelvis AND bone scintigraphy, or equivalent), within 26 weeks prior to Step 0 registration. If a patient only has a study-eligible PET/CT or PET/MR (i.e., PET done without prior CIM): if the PET is negative for extrapelvic lesions, then baseline CIM is NOT required. If the PET positive for extrapelvic lesions, then patient should have a baseline CT/MRI for soft tissue lesions and/or a bone scan for osseous lesions

• Study eligible = PET using FDA-approved radiotracer and performed within 16 weeks prior to study registration

• Extra-pelvic metastases is defined as any osseous metastases and/or any extrapelvic soft tissue, lymph nodes and organ metastases; extra-pelvic is defined as superior to common iliac bifurcation, outside of standard prostate bed + whole pelvis nodal RT fields. Baseline PET/CT or PET/MR scan (PET1) is eligible for this study if the SOC PET scan is completed with an FDA approved radiotracer for prostate cancer after Step 0 registration and prior to Step 1 randomization OR up to 16 weeks prior to Step 0 registration

• Patient must be a candidate for SOC post-prostatectomy radiation therapy (RT) to the prostate bed and pelvic nodes with androgen deprivation therapy (ADT)

• Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible

• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Patient must not have started ADT for biochemical recurrence prior to baseline PET (PET1) imaging. A short course of low-dose anti-androgen such as bicalutamide, given after baseline study PET/CT but prior to study registration, is permitted as a brief temporizing measure in advance of starting protocol-approved SOC ADT.

• Patient must not be enrolled in another therapeutic clinical trial

• Patient must be able to lie flat and still for approximately 20-30 minutes or otherwise tolerate a PET scan and radiation treatment planning and delivery

• Patients undergoing a PET/MR must meet local institutional safety guidelines for MRI

• Patient must not have history of seizures or known condition that may cause predisposal to seizures (e.g., stroke or head trauma resulting in loss of consciousness) within 1 year prior to registration

• Patient must not have history of inflammatory bowel disease or any gastrointestinal disorder affecting absorption that is expected to increase risk of complication from radiotherapy

• Hemoglobin (Hgb) >= 9.0 g/dL (independent of transfusion and/or growth factors within 3 months prior to Step 0 registration) (obtained within 8 weeks prior to Step 0 registration)

• Leukocytes >= 3,000/mcL (obtained within 8 weeks prior to Step 0 registration)

• Absolute neutrophil count >= 1,500/mcL (obtained within 8 weeks prior to Step 0 registration)

• Platelets >= 100,000/mcL (obtained within 8 weeks prior to Step 0 registration)

• Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (patients with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, must have a direct bilirubin of < 1.5 x ULN to be eligible) (obtained within 8 weeks prior to Step 0 registration)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained within 8 weeks prior to Step 0 registration)

• Creatine < 1.5 x instituional ULN (or measured creatinine clearance > 30 mL/min)

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

• 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. To be eligible for this trial, patients should be class I or II (by patient symptoms) or A or B (by objective assessment)

• Patient must not have completed a course of prior pelvic radiation therapy for any reason

• Patient must agree not to father children while on study

• Patient must be English or Spanish speaking to be eligible for the QOL component of the study

• NOTE: Sites cannot translate the associated QOL forms

• STEP 1: RANDOMIZATION ELIGIBILITY CRITERIA

• Patient must have completed a baseline SOC PET/CT or PET/MR (PET1 scan) using FDA approved radiotracer with results of extra-pelvic metastases involvement known (positive or negative). The PET1 must have been completed after Step 0 registration and prior to Step 1 randomization OR up to 12 weeks prior to Step 0 registration

• For patients with negative extra-pelvic metastases, PET-imaging status of intra-pelvic nodes must be known (positive or negative)

• For patients with positive extra-pelvic metastases (defined as any PET positive lesions outside of standard salvage RT fields [prostate bed +/- typical whole pelvis]), the number of extra-pelvic lesions must be known (1 - 5 or > 5 extra-pelvic lesions)

Related Conditions & MeSH terms

• Biochemically Recurrent Prostate Carcinoma
• Carcinoma
• Metastatic Prostate Carcinoma
• Prostate Adenocarcinoma
• Prostatic Neoplasms
• Stage IVB Prostate Cancer AJCC v8

Intervention

Radiation:
• 3-Dimensional Conformal Radiation Therapy
Undergo 3D CRT

Drug:
• Apalutamide
Given PO

Procedure:
• Computed Tomography
Undergo PET/CT

Drug:
• Degarelix
Given SC

Radiation:
• External Beam Radiation Therapy
Undergo EBRT

Other:
• Fluciclovine F18
Given IV

Drug:
• Goserelin Acetate
Given SC

Procedure:
• Intensity-Modulated Proton Therapy
Undergo IMPT

Radiation:
• Intensity-Modulated Radiation Therapy
Undergo IMRT

Drug:
• Leuprolide Acetate
Given IM

Procedure:
• Magnetic Resonance Imaging
Undergo PET/MR
• Positron Emission Tomography
Undergo PET/CT or PET/MR

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Drug:
• Relugolix
Given PO

Radiation:
• Stereotactic Body Radiation Therapy
Undergo SBRT

Drug:
• Triptorelin
Given IM

Radiation:
• Volume Modulated Arc Therapy
Undergo VMAT

Locations

Country	Name	City	State
United States	Providence Regional Cancer System-Aberdeen	Aberdeen	Washington
United States	Alton Memorial Hospital	Alton	Illinois
United States	UPMC Altoona	Altoona	Pennsylvania
United States	Alaska Breast Care and Surgery LLC	Anchorage	Alaska
United States	Alaska Oncology and Hematology LLC	Anchorage	Alaska
United States	Alaska Women's Cancer Care	Anchorage	Alaska
United States	Anchorage Associates in Radiation Medicine	Anchorage	Alaska
United States	Anchorage Oncology Centre	Anchorage	Alaska
United States	Katmai Oncology Group	Anchorage	Alaska
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	Langlade Hospital and Cancer Center	Antigo	Wisconsin
United States	Mission Hope Medical Oncology - Arroyo Grande	Arroyo Grande	California
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	MaineHealth Coastal Cancer Treatment Center	Bath	Maine
United States	Northwell Health Imbert Cancer Center	Bay Shore	New York
United States	UPMC-Heritage Valley Health System Beaver	Beaver	Pennsylvania
United States	PeaceHealth Saint Joseph Medical Center	Bellingham	Washington
United States	Saint Charles Health System	Bend	Oregon
United States	Suburban Hospital	Bethesda	Maryland
United States	MaineHealth/SMHC Cancer Care and Blood Disorders-Biddeford	Biddeford	Maine
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Central Care Cancer Center - Bolivar	Bolivar	Missouri
United States	Bozeman Deaconess Hospital	Bozeman	Montana
United States	Harrison Medical Center	Bremerton	Washington
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Montefiore Medical Center-Einstein Campus	Bronx	New York
United States	Montefiore Medical Center-Weiler Hospital	Bronx	New York
United States	Crozer-Keystone Regional Cancer Center at Broomall	Broomall	Pennsylvania
United States	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California
United States	Minnesota Oncology - Burnsville	Burnsville	Minnesota
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Cooper Hospital University Medical Center	Camden	New Jersey
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Southeast Cancer Center	Cape Girardeau	Missouri
United States	Memorial Hospital of Carbondale	Carbondale	Illinois
United States	Carlisle Regional Cancer Center	Carlisle	Pennsylvania
United States	Mercy Cancer Center - Carmichael	Carmichael	California
United States	Mercy San Juan Medical Center	Carmichael	California
United States	SIH Cancer Institute	Carterville	Illinois
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Centralia Oncology Clinic	Centralia	Illinois
United States	Providence Regional Cancer System-Centralia	Centralia	Washington
United States	Saint Mary's Hospital	Centralia	Illinois
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern University	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Bethesda North Hospital	Cincinnati	Ohio
United States	Good Samaritan Hospital - Cincinnati	Cincinnati	Ohio
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	Clackamas Radiation Oncology Center	Clackamas	Oregon
United States	Providence Cancer Institute Clackamas Clinic	Clackamas	Oregon
United States	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Rocky Mountain Cancer Centers-Penrose	Colorado Springs	Colorado
United States	Saint Francis Cancer Center	Colorado Springs	Colorado
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Bay Area Hospital	Coos Bay	Oregon
United States	City of Hope Corona	Corona	California
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	UT Southwestern Simmons Cancer Center - RedBird	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Carle at The Riverfront	Danville	Illinois
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	Porter Adventist Hospital	Denver	Colorado
United States	Illinois CancerCare-Dixon	Dixon	Illinois
United States	Delaware County Memorial Hospital	Drexel Hill	Pennsylvania
United States	City of Hope Comprehensive Cancer Center	Duarte	California
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	Fairview Southdale Hospital	Edina	Minnesota
United States	Swedish Cancer Institute-Edmonds	Edmonds	Washington
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Mercy Cancer Center - Elk Grove	Elk Grove	California
United States	UPMC Hillman Cancer Center Erie	Erie	Pennsylvania
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Providence Regional Cancer Partnership	Everett	Washington
United States	Parkland Health Center - Farmington	Farmington	Missouri
United States	UPMC Cancer Center at UPMC Horizon	Farrell	Pennsylvania
United States	Mercy Hospital Fort Smith	Fort Smith	Arkansas
United States	UT Southwestern/Simmons Cancer Center-Fort Worth	Fort Worth	Texas
United States	Unity Hospital	Fridley	Minnesota
United States	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho
United States	Fox Chase Cancer Center Buckingham	Furlong	Pennsylvania
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Western Illinois Cancer Treatment Center	Galesburg	Illinois
United States	Central Care Cancer Center - Garden City	Garden City	Kansas
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	UM Baltimore Washington Medical Center/Tate Cancer Center	Glen Burnie	Maryland
United States	Crozer Regional Cancer Center at Brinton Lake	Glen Mills	Pennsylvania
United States	Central Care Cancer Center - Great Bend	Great Bend	Kansas
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	Great Falls Clinic	Great Falls	Montana
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	Baptist Cancer Center-Grenada	Grenada	Mississippi
United States	Legacy Mount Hood Medical Center	Gresham	Oregon
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	UPMC Pinnacle Cancer Center/Community Osteopathic Campus	Harrisburg	Pennsylvania
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Swedish Cancer Institute-Issaquah	Issaquah	Washington
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Capital Region Southwest Campus	Jefferson City	Missouri
United States	UW Cancer Center Johnson Creek	Johnson Creek	Wisconsin
United States	UPMC-Johnstown/John P. Murtha Regional Cancer Center	Johnstown	Pennsylvania
United States	Freeman Health System	Joplin	Missouri
United States	Mercy Hospital Joplin	Joplin	Missouri
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	CHI Health Good Samaritan	Kearney	Nebraska
United States	Vidant Oncology-Kenansville	Kenansville	North Carolina
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Vidant Oncology-Kinston	Kinston	North Carolina
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Providence Regional Cancer System-Lacey	Lacey	Washington
United States	Northwell Health/Center for Advanced Medicine	Lake Success	New York
United States	Saint Anthony Hospital	Lakewood	Colorado
United States	City of Hope Antelope Valley	Lancaster	California
United States	Saint Joseph Hospital	Lexington	Kentucky
United States	Saint Joseph Hospital East	Lexington	Kentucky
United States	Saint Joseph Radiation Oncology Resource Center	Lexington	Kentucky
United States	Littleton Adventist Hospital	Littleton	Colorado
United States	Longmont United Hospital	Longmont	Colorado
United States	PeaceHealth Saint John Medical Center	Longview	Washington
United States	Los Angeles General Medical Center	Los Angeles	California
United States	UCLA / Jonsson Comprehensive Cancer Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	Jewish Hospital	Louisville	Kentucky
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	William S Middleton VA Medical Center	Madison	Wisconsin
United States	Fairview Clinics and Surgery Center Maple Grove	Maple Grove	Minnesota
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Saint John's Hospital - Healtheast	Maplewood	Minnesota
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Loyola University Medical Center	Maywood	Illinois
United States	UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion	Mechanicsburg	Pennsylvania
United States	Mercy UC Davis Cancer Center	Merced	California
United States	Idaho Urologic Institute-Meridian	Meridian	Idaho
United States	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Health Partners Inc	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Community Medical Hospital	Missoula	Montana
United States	Saint Patrick Hospital - Community Hospital	Missoula	Montana
United States	UPMC Cancer Center - Monroeville	Monroeville	Pennsylvania
United States	Monticello Cancer Center	Monticello	Minnesota
United States	UPMC Hillman Cancer Center in Coraopolis	Moon	Pennsylvania
United States	Good Samaritan Regional Health Center	Mount Vernon	Illinois
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho
United States	UPMC Cancer Center-Natrona Heights	Natrona Heights	Pennsylvania
United States	Baptist Memorial Hospital and Cancer Center-Union County	New Albany	Mississippi
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	UPMC Hillman Cancer Center - New Castle	New Castle	Pennsylvania
United States	Cancer Center of Western Wisconsin	New Richmond	Wisconsin
United States	Lenox Hill Hospital	New York	New York
United States	Manhattan Eye Ear and Throat Hospital	New York	New York
United States	Mount Sinai Chelsea	New York	New York
United States	Mount Sinai Hospital	New York	New York
United States	Mount Sinai Union Square	New York	New York
United States	Mount Sinai West	New York	New York
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	HSHS Saint Elizabeth's Hospital	O'Fallon	Illinois
United States	Mercy Hospital Oklahoma City	Oklahoma City	Oklahoma
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska
United States	Alegent Health Immanuel Medical Center	Omaha	Nebraska
United States	Alegent Health Lakeside Hospital	Omaha	Nebraska
United States	Creighton University Medical Center	Omaha	Nebraska
United States	Providence Willamette Falls Medical Center	Oregon City	Oregon
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Baptist Memorial Hospital and Cancer Center-Oxford	Oxford	Mississippi
United States	Parker Adventist Hospital	Parker	Colorado
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Valley Radiation Oncology	Peru	Illinois
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Penn Presbyterian Medical Center	Philadelphia	Pennsylvania
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	University of Pennsylvania/Abramson 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 Clair Hospital Cancer Center	Pittsburgh	Pennsylvania
United States	UPMC-Saint Margaret	Pittsburgh	Pennsylvania
United States	UPMC-Shadyside Hospital	Pittsburgh	Pennsylvania
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Maine Medical Center-Bramhall Campus	Portland	Maine
United States	Oregon Health and Science University	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Saint Mary Corwin Medical Center	Pueblo	Colorado
United States	Ascension Saint Mary's Hospital	Rhinelander	Wisconsin
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	UT Southwestern Clinical Center at Richardson/Plano	Richardson	Texas
United States	Vidant Oncology-Richlands	Richlands	North Carolina
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	SwedishAmerican Regional Cancer Center/ACT	Rockford	Illinois
United States	Mercy Cancer Center - Rocklin	Rocklin	California
United States	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri
United States	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri
United States	Mercy Cancer Center - Sacramento	Sacramento	California
United States	Coborn Cancer Center at Saint Cloud Hospital	Saint Cloud	Minnesota
United States	Heartland Regional Medical Center	Saint Joseph	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Mercy Hospital South	Saint Louis	Missouri
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
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	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri
United States	Audie L Murphy VA Hospital	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Pacific Central Coast Health Center-San Luis Obispo	San Luis Obispo	California
United States	MaineHealth Cancer Care Center of York County	Sanford	Maine
United States	MaineHealth/SMHC Cancer Care and Blood Disorders-Sanford	Sanford	Maine
United States	Mission Hope Medical Oncology - Santa Maria	Santa Maria	California
United States	Maine Medical Center- Scarborough Campus	Scarborough	Maine
United States	FHCC at Northwest Hospital	Seattle	Washington
United States	FHCC South Lake Union	Seattle	Washington
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Swedish Medical Center-Ballard Campus	Seattle	Washington
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	University of Washington Medical Center - Montlake	Seattle	Washington
United States	PeaceHealth United General Medical Center	Sedro-Woolley	Washington
United States	UPMC Cancer Center at UPMC Northwest	Seneca	Pennsylvania
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
United States	Welch Cancer Center	Sheridan	Wyoming
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	Phelps Memorial Hospital Center	Sleepy Hollow	New York
United States	Robert Wood Johnson University Hospital Somerset	Somerville	New Jersey
United States	City of Hope South Pasadena	South Pasadena	California
United States	Maine Medical Partners - South Portland	South Portland	Maine
United States	CoxHealth South Hospital	Springfield	Missouri
United States	Memorial Medical Center	Springfield	Illinois
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	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	Lakeview Hospital	Stillwater	Minnesota
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Missouri Baptist Sullivan Hospital	Sullivan	Missouri
United States	BJC Outpatient Center at Sunset Hills	Sunset Hills	Missouri
United States	Community Medical Center	Toms River	New Jersey
United States	Legacy Meridian Park Hospital	Tualatin	Oregon
United States	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho
United States	UPMC Cancer Center-Uniontown	Uniontown	Pennsylvania
United States	UPMC Uniontown Hospital Radiation Oncology	Uniontown	Pennsylvania
United States	Carle Cancer Center	Urbana	Illinois
United States	The Carle Foundation Hospital	Urbana	Illinois
United States	Legacy Cancer Institute Medical Oncology and Day Treatment	Vancouver	Washington
United States	Legacy Salmon Creek Hospital	Vancouver	Washington
United States	PeaceHealth Southwest Medical Center	Vancouver	Washington
United States	MD Anderson Cancer Center at Cooper-Voorhees	Voorhees	New Jersey
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	Sibley Memorial Hospital	Washington	District of Columbia
United States	UPMC Washington Hospital Radiation Oncology	Washington	Pennsylvania
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	UPMC Susquehanna	Williamsport	Pennsylvania
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Aspirus Cancer Care - Wisconsin Rapids	Wisconsin Rapids	Wisconsin
United States	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota
United States	Woodland Memorial Hospital	Woodland	California
United States	UPMC Memorial	York	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
ECOG-ACRIN Cancer Research Group	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS)	The power of the PFS analysis is 85% using one-sided 0.025 level stratified logrank test. The overall type I error will be controlled using an O'Brien-Fleming boundary function	From randomization to radiographic progression by conventional imaging or positron emission tomography (PET), symptomatic disease or death, whichever occurs first, assessed up to 10 years
Primary	PFS prolongation in patients without PET-evidence of extrapelvic metastases	Will evaluate whether the addition of enhanced systemic therapy to standard of care salvage therapy could prolong PFS in this patient population. Will be an intention-to-treat analysis of all randomized patients and performed in parallel with patients with PET-evidence of extrapelvic metastases.	Up to 10 years
Primary	PFS prolongation in patients with PET-evidence of extrapelvic metastases	Will evaluate whether the addition of metastasis-directed radiation therapy to standard of care salvage therapy and enhanced systemic therapy could prolong PFS in this patient population. Will be an intention-to-treat analysis of all randomized patients and performed in parallel without patients with PET-evidence of extrapelvic metastases.	Up to 10 years
Primary	Quality of life (QOL)	Descriptive statistics will be used to characterize QOL over time in each arm.	Up to 24 months
Secondary	Overall survival (OS)	Will be characterized by the method of Kaplan and Meier and a logrank test will be used to compare OS between the two arms in each cohort.	From randomization to death or date last known alive, assessed up to 10 years
Secondary	Event-free survival	Will be characterized by the method of Kaplan and Meier and a logrank test will be used to compare EFS between the two arms in each cohort.	From randomization to radiographic progression by conventional imaging or PET, symptomatic disease, or initiation of new treatment for the disease or death, whichever occurs first, assessed up to 10 years
Secondary	Time to prostate-specific antigen (PSA) progression	Patients without any progression will be censored at the date of last disease assessment that shows free of PSA progression. Will be characterized by the method of Kaplan and Meier and a logrank test will be used to compare time to PSA progression between the two arms in each cohort.	From randomization to documented PSA progression or radiographic progression, whichever occurs first, assessed up to 10 years
Secondary	Incidence of adverse events	Toxicity will be defined using the Common Terminology Criteria for Adverse Events.	Up to 10 years
Secondary	Detection rate of fluciclovine F18 (18F-fluciclovine) PET	For the detection rate, the proportion of baseline standard of care 18F-fluciclovine PET (PET1) positive results at the patient and regional (prostate fossa, intrapelvic soft tissue/lymph node, extrapelvic soft tissue/lymph node, and bone metastases) level will be calculated and its 95% confidence interval will be estimated using the Exact method based on the binomial distribution.	At time of PSA recurrence, as clinically indicated or 12 months after completion of enhanced systemic therapy (whichever occurs first), assessed up to 10 years
Secondary	Concordance of detection rate with the follow-up conventional imaging modalities (CIM)	Will use Cohen's Kappa coefficient to measure the agreement between dichotomized PET results and the dichotomized CIM results. Baseline CIM comparison will not be performed because as per our study eligibility criteria, baseline CIM will be negative for metastases.	At time of PSA recurrence, as clinically indicated or 12 months after completion of enhanced systemic therapy (whichever occurs first), assessed up to 10 years
Secondary	Distribution of 18F-fluciclovine PET-positive lesions among anatomic sites	The rate of 18F-fluciclovine PET-positive lesions will be reported for each anatomic site, including prostate fossa, intrapelvic soft tissue/lymph node, extrapelvic soft tissue/lymph node, and bone metastases. Their confidence intervals will be estimated using the Exact method for the binomial distribution. To evaluate if PSA (level, doubling time, velocity) and other relevant clinical parameters affects the positivity distribution, will use the logistic regression to model with the binary outcome (positive vs. negative from PET) and covariates will include anatomic site, PSA, and other clinical parameters. Will test the interactions between anatomic site and PSA (plus other clinical parameters) to see if the positivity distribution across anatomic site may change according to the levels of the interacted terms. Will use the technique of generalized estimating equation to account for the outcome correlations within subjects.	Baseline
Secondary	Value of repeat PET to assess response to therapy compared to standard response assessments	Analyses will be conducted to evaluate qualitative visual evidence of 18F-fluciclovine PET positive metastatic lesions and quantitative PET standardized-uptake value (SUV) changes on a lesion-to-lesion basis from 18F-fluciclovine PET1 (baseline) to PET2 on visually determined sites of recurrence and metastatic disease. This will be compared to reference standard-of-care conventional imaging (Prostate Cancer Working Group 2 criteria) and PSA response at PET2 time point to determine PET2 response to therapy. PET2 visual and quantitative assessment will also be compared to PFS in the time-to-event analysis using a log-rank test (PET2 visual assessment) and a Cox proportional hazards regression (PET2 quantitative assessment). PET SUV parameters to be obtained at PET1 and PET2 will include SUVmax, SUVpeak. PET SUV change from PET1 to PET2 will include absolute SUVmax and SUVpeak change (PET2-PET1) and percent change of SUVmax and SUVpeak (% change = 100*[(PET2-PET1)/PET1]).)	At time of second PSA recurrence or 12 months after completion of enhanced systemic therapy (whichever occurs first), assessed up to 10 years
Secondary	Comparison - Functional Assessment of Cancer Therapy (FACT)- prostate (P)	For the PET-negative cohort, with 216 analyzable patients in each arm, the study will have about 84% power to detect a 6-point (0.29 standard deviation) difference between the two arms using a two-sample t test with two-sided type I error of 0.05. The power will be greater than 99% if the difference between the two arms is 10 points (0.48 standard deviation). For the PET-positive cohort, with 146 analyzable patients in each arm, the study will have 68% and 98% power to detect a 6-point (0.29 standard deviation) and a 10-point (0.48 standard deviation) differences between the two arms, respectively, using the same test.	At baseline and 3, 6, 9, 12 months
Secondary	Change in FACT-P and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue	A paired t test will be used to compare FACT-P scores at these two time points in each arm. A two-sample t test will be performed to compare the changes in FACT-P scores from baseline to 6 months between the two arms of each cohort. The FACIT-Fatigue scores at 6 months will be compared between the two arms of each cohort using a two-sample t test.	Baseline up to 6 months
Secondary	QOL Assessments at Progression	A paired t test will be used to compare FACT-P total scores, FACIT-Fatigue scores and pain scores at these two time points in each arm. The changes in these scores from baseline to progression will be evaluated in each arm.	Up to 10 years
Secondary	FACT- cognitive functioning (Cog)	Will be compared between two groups of patients on this study, patients receiving antiandrogen therapy (ADT) + apalutamide (Arms B, C and D) and patients receiving ADT alone (Arm A), at different time points. To ensure similarity of the three arms with systemic treatments (Arms B, C and D), a comparison in FACT-Cog total scores among these three arms will be performed using the Kruskal-Wallis test before combining them together to be compared with Arm A.	Up to 12 months