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

Phase 3

Recruiting

• Conditions: Biochemically Recurrent Prostate Carcinoma; Stage IVB Prostate Cancer AJCC v8; Metastatic Prostate Carcinoma; Prostate Adenocarcinoma
• Interventions: Procedure: Computed Tomography; Radiation: 3-Dimensional Conformal Radiation Therapy; Drug: Apalutamide; Drug: Degarelix; Radiation: External Beam Radiation Therapy; Other: Fluciclovine F18; Drug: Goserelin Acetate; Drug: Leuprolide Acetate; Procedure: Magnetic Resonance Imaging; Procedure: Positron Emission Tomography; Procedure: Intensity-Modulated Proton Therapy; Other: Quality-of-Life Assessment; Radiation: Intensity-Modulated Radiation Therapy; Other: Questionnaire Administration; Drug: Relugolix; Drug: Triptorelin; Radiation: Stereotactic Body Radiation Therapy; Radiation: Volume Modulated Arc Therapy

• Registration Number: NCT04423211
• Lead Sponsor: ECOG-ACRIN Cancer Research Group

Brief 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.

Detailed 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.

Study Timeline

• Study First Submitted: 2020-06-05
• Study First Submitted QC: 2020-06-05
• Study First Posted: 2020-06-09
• Study Start: 2020-10-08
• Status Verified: 2024-06
• Last Update Submitted: 2024-11-04
• Last Update Posted: 2024-11-05
• Primary Completion: 2032-12-31
• Study Completion: 2032-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Male
• Target Recruitment: 804

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)

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A (EBRT, short-term androgen deprivation therapy [STAD])	Goserelin Acetate	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extera pelvic metastases undergo SOC EBRT for 6 months. Patients also receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix 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 C (EBRT, STAD, apalutamide)	Leuprolide Acetate	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 (EBRT, STAD, apalutamide, RT)	Leuprolide Acetate	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm A (EBRT, short-term androgen deprivation therapy [STAD])	Computed Tomography	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extera pelvic metastases undergo SOC EBRT for 6 months. Patients also receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix 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 (EBRT, STAD, apalutamide)	Computed Tomography	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extra pelvic metastases 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 for 6 months in the absence of disease progression or unacceptable toxicity.
Arm A (EBRT, short-term androgen deprivation therapy [STAD])	Fluciclovine F18	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extera pelvic metastases undergo SOC EBRT for 6 months. Patients also receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix 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 A (EBRT, short-term androgen deprivation therapy [STAD])	Magnetic Resonance Imaging	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extera pelvic metastases undergo SOC EBRT for 6 months. Patients also receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix 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 A (EBRT, short-term androgen deprivation therapy [STAD])	External Beam Radiation Therapy	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extera pelvic metastases undergo SOC EBRT for 6 months. Patients also receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix 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 A (EBRT, short-term androgen deprivation therapy [STAD])	Questionnaire Administration	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extera pelvic metastases undergo SOC EBRT for 6 months. Patients also receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix 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 A (EBRT, short-term androgen deprivation therapy [STAD])	Leuprolide Acetate	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extera pelvic metastases undergo SOC EBRT for 6 months. Patients also receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix 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 A (EBRT, short-term androgen deprivation therapy [STAD])	Positron Emission Tomography	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extera pelvic metastases undergo SOC EBRT for 6 months. Patients also receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix 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 A (EBRT, short-term androgen deprivation therapy [STAD])	Quality-of-Life Assessment	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extera pelvic metastases undergo SOC EBRT for 6 months. Patients also receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix 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 (EBRT, STAD, apalutamide)	External Beam Radiation Therapy	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extra pelvic metastases 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 for 6 months in the absence of disease progression or unacceptable toxicity.
Arm B (EBRT, STAD, apalutamide)	Goserelin Acetate	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extra pelvic metastases 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 for 6 months in the absence of disease progression or unacceptable toxicity.
Arm B (EBRT, STAD, apalutamide)	Quality-of-Life Assessment	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extra pelvic metastases 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 for 6 months in the absence of disease progression or unacceptable toxicity.
Arm C (EBRT, STAD, apalutamide)	Computed Tomography	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 B (EBRT, STAD, apalutamide)	Questionnaire Administration	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extra pelvic metastases 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 for 6 months in the absence of disease progression or unacceptable toxicity.
Arm C (EBRT, STAD, apalutamide)	Magnetic Resonance Imaging	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 B (EBRT, STAD, apalutamide)	Fluciclovine F18	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extra pelvic metastases 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 for 6 months in the absence of disease progression or unacceptable toxicity.
Arm B (EBRT, STAD, apalutamide)	Magnetic Resonance Imaging	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extra pelvic metastases 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 for 6 months in the absence of disease progression or unacceptable toxicity.
Arm B (EBRT, STAD, apalutamide)	Positron Emission Tomography	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extra pelvic metastases 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 for 6 months in the absence of disease progression or unacceptable toxicity.
Arm B (EBRT, STAD, apalutamide)	Leuprolide Acetate	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extra pelvic metastases 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 for 6 months in the absence of disease progression or unacceptable toxicity.
Arm C (EBRT, STAD, apalutamide)	Fluciclovine F18	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 C (EBRT, STAD, apalutamide)	Questionnaire Administration	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 C (EBRT, STAD, apalutamide)	External Beam Radiation Therapy	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 C (EBRT, STAD, apalutamide)	Positron Emission Tomography	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 (EBRT, STAD, apalutamide, RT)	3-Dimensional Conformal Radiation Therapy	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm C (EBRT, STAD, apalutamide)	Goserelin Acetate	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 (EBRT, STAD, apalutamide, RT)	Computed Tomography	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm D (EBRT, STAD, apalutamide, RT)	Fluciclovine F18	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm D (EBRT, STAD, apalutamide, RT)	Quality-of-Life Assessment	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm C (EBRT, STAD, apalutamide)	Quality-of-Life Assessment	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 (EBRT, STAD, apalutamide, RT)	External Beam Radiation Therapy	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm D (EBRT, STAD, apalutamide, RT)	Intensity-Modulated Radiation Therapy	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm D (EBRT, STAD, apalutamide, RT)	Goserelin Acetate	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm D (EBRT, STAD, apalutamide, RT)	Intensity-Modulated Proton Therapy	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm D (EBRT, STAD, apalutamide, RT)	Volume Modulated Arc Therapy	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm D (EBRT, STAD, apalutamide, RT)	Magnetic Resonance Imaging	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm D (EBRT, STAD, apalutamide, RT)	Questionnaire Administration	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm D (EBRT, STAD, apalutamide, RT)	Positron Emission Tomography	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm D (EBRT, STAD, apalutamide, RT)	Stereotactic Body Radiation Therapy	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm B (EBRT, STAD, apalutamide)	Apalutamide	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extra pelvic metastases 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 for 6 months in the absence of disease progression or unacceptable toxicity.
Arm A (EBRT, short-term androgen deprivation therapy [STAD])	Degarelix	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extera pelvic metastases undergo SOC EBRT for 6 months. Patients also receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix 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 A (EBRT, short-term androgen deprivation therapy [STAD])	Relugolix	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extera pelvic metastases undergo SOC EBRT for 6 months. Patients also receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix 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 A (EBRT, short-term androgen deprivation therapy [STAD])	Triptorelin	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extera pelvic metastases undergo SOC EBRT for 6 months. Patients also receive goserelin acetate SC, leuprolide acetate IM, triptorelin IM, relugolix 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 (EBRT, STAD, apalutamide)	Degarelix	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extra pelvic metastases 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 for 6 months in the absence of disease progression or unacceptable toxicity.
Arm B (EBRT, STAD, apalutamide)	Relugolix	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extra pelvic metastases 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 for 6 months in the absence of disease progression or unacceptable toxicity.
Arm B (EBRT, STAD, apalutamide)	Triptorelin	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET negative for extra pelvic metastases 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 for 6 months in the absence of disease progression or unacceptable toxicity.
Arm C (EBRT, STAD, apalutamide)	Apalutamide	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 C (EBRT, STAD, apalutamide)	Degarelix	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 C (EBRT, STAD, apalutamide)	Relugolix	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 C (EBRT, STAD, apalutamide)	Triptorelin	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 (EBRT, STAD, apalutamide, RT)	Apalutamide	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm D (EBRT, STAD, apalutamide, RT)	Degarelix	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm D (EBRT, STAD, apalutamide, RT)	Relugolix	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.
Arm D (EBRT, STAD, apalutamide, RT)	Triptorelin	STEP 0: Patients undergo SOC PET/CT or PET/MR scan at baseline. Patients randomized to Arms C or D and receiving fluciclovine F18 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 who are PET positive for extra pelvic metastases 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 SBRT or 3D CRT, IMRT (including VMAT), and IMPT over 3-10 fractions in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Progression-free survival (PFS)	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	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
PFS prolongation in patients without PET-evidence of extrapelvic metastases	Up to 10 years	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.
PFS prolongation in patients with PET-evidence of extrapelvic metastases	Up to 10 years	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.
Quality of life (QOL)	Up to 24 months	Descriptive statistics will be used to characterize QOL over time in each arm.

Secondary Outcome Measures

Name	Time	Method
Incidence of adverse events	Up to 10 years	Toxicity will be defined using the Common Terminology Criteria for Adverse Events.
Time to prostate-specific antigen (PSA) progression	From randomization to documented PSA progression or radiographic progression, whichever occurs first, assessed up to 10 years	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.
Detection rate of fluciclovine F18 (18F-fluciclovine) PET	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	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.
QOL Assessments at Progression	Up to 10 years	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.
Concordance of detection rate with the follow-up conventional imaging modalities (CIM)	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	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.
Overall survival (OS)	From randomization to death or date last known alive, assessed up to 10 years	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.
Event-free survival	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	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.
Distribution of 18F-fluciclovine PET-positive lesions among anatomic sites	Baseline	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.
Value of repeat PET to assess response to therapy compared to standard response assessments	At time of second PSA recurrence or 12 months after completion of enhanced systemic therapy (whichever occurs first), assessed up to 10 years	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\*\[(PET2-PET1)/PET1\]).)
Comparison - Functional Assessment of Cancer Therapy (FACT)- prostate (P)	At baseline and 3, 6, 9, 12 months	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.
Change in FACT-P and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue	Baseline up to 6 months	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.
FACT- cognitive functioning (Cog)	Up to 12 months	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.

Trial Locations

Locations (302)

Rush University Medical Center; 🇺🇸 Chicago, Illinois, United States

Anchorage Associates in Radiation Medicine; 🇺🇸 Anchorage, Alaska, 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 Oncology Centre; 🇺🇸 Anchorage, Alaska, United States

Katmai Oncology Group; 🇺🇸 Anchorage, Alaska, United States

Providence Alaska Medical Center; 🇺🇸 Anchorage, Alaska, United States

Cancer Center at Saint Joseph's; 🇺🇸 Phoenix, Arizona, United States

Mercy Hospital Fort Smith; 🇺🇸 Fort Smith, Arkansas, United States

Mission Hope Medical Oncology - Arroyo Grande; 🇺🇸 Arroyo Grande, California, United States

Providence Saint Joseph Medical Center/Disney Family Cancer Center; 🇺🇸 Burbank, California, United States

Mercy Cancer Center - Carmichael; 🇺🇸 Carmichael, California, United States

Mercy San Juan Medical Center; 🇺🇸 Carmichael, California, United States

City of Hope Corona; 🇺🇸 Corona, California, United States

City of Hope Comprehensive Cancer Center; 🇺🇸 Duarte, California, United States

Mercy Cancer Center - Elk Grove; 🇺🇸 Elk Grove, California, United States

UC San Diego Moores Cancer Center; 🇺🇸 La Jolla, California, United States

City of Hope Antelope Valley; 🇺🇸 Lancaster, California, United States

Los Angeles General Medical Center; 🇺🇸 Los Angeles, California, United States

USC / Norris Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

UCLA / Jonsson Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

Mercy Cancer Center; 🇺🇸 Merced, California, United States

Mercy Cancer Center - Rocklin; 🇺🇸 Rocklin, California, United States

Mercy Cancer Center - Sacramento; 🇺🇸 Sacramento, California, United States

Pacific Central Coast Health Center-San Luis Obispo; 🇺🇸 San Luis Obispo, California, United States

Mission Hope Medical Oncology - Santa Maria; 🇺🇸 Santa Maria, California, United States

City of Hope South Pasadena; 🇺🇸 South Pasadena, California, United States

City of Hope Upland; 🇺🇸 Upland, California, United States

Woodland Memorial Hospital; 🇺🇸 Woodland, California, 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

Porter Adventist Hospital; 🇺🇸 Denver, Colorado, United States

Saint Anthony Hospital; 🇺🇸 Lakewood, Colorado, United States

Littleton Adventist Hospital; 🇺🇸 Littleton, Colorado, United States

Longmont United Hospital; 🇺🇸 Longmont, Colorado, United States

Parker Adventist Hospital; 🇺🇸 Parker, Colorado, United States

Saint Mary Corwin Medical Center; 🇺🇸 Pueblo, Colorado, United States

Sibley Memorial Hospital; 🇺🇸 Washington, District of Columbia, United States

Moffitt Cancer Center-International Plaza; 🇺🇸 Tampa, Florida, United States

Moffitt Cancer Center - McKinley Campus; 🇺🇸 Tampa, Florida, United States

Moffitt Cancer Center; 🇺🇸 Tampa, Florida, United States

Saint Alphonsus Cancer Care Center-Boise; 🇺🇸 Boise, Idaho, United States

Saint Luke's Cancer Institute - Boise; 🇺🇸 Boise, Idaho, United States

Saint Alphonsus Cancer Care Center-Caldwell; 🇺🇸 Caldwell, Idaho, United States

Kootenai Health - Coeur d'Alene; 🇺🇸 Coeur d'Alene, Idaho, United States

Saint Luke's Cancer Institute - Fruitland; 🇺🇸 Fruitland, Idaho, United States

Idaho Urologic Institute-Meridian; 🇺🇸 Meridian, Idaho, United States

Saint Luke's Cancer Institute - Meridian; 🇺🇸 Meridian, Idaho, United States

Saint Luke's Cancer Institute - Nampa; 🇺🇸 Nampa, Idaho, United States

Saint Alphonsus Cancer Care Center-Nampa; 🇺🇸 Nampa, Idaho, United States

Kootenai Clinic Cancer Services - Post Falls; 🇺🇸 Post Falls, Idaho, United States

Saint Luke's Cancer Institute - Twin Falls; 🇺🇸 Twin Falls, Idaho, United States

Alton Memorial Hospital; 🇺🇸 Alton, Illinois, United States

Rush - Copley Medical Center; 🇺🇸 Aurora, Illinois, United States

Illinois CancerCare-Bloomington; 🇺🇸 Bloomington, Illinois, United States

Illinois CancerCare-Canton; 🇺🇸 Canton, Illinois, United States

Memorial Hospital of Carbondale; 🇺🇸 Carbondale, Illinois, United States

SIH Cancer Institute; 🇺🇸 Carterville, Illinois, United States

Illinois CancerCare-Carthage; 🇺🇸 Carthage, Illinois, United States

Centralia Oncology Clinic; 🇺🇸 Centralia, Illinois, United States

Saint Mary's Hospital; 🇺🇸 Centralia, Illinois, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

Carle at The Riverfront; 🇺🇸 Danville, Illinois, United States

University of Illinois; 🇺🇸 Chicago, 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

Illinois CancerCare-Dixon; 🇺🇸 Dixon, Illinois, United States

Carle Physician Group-Effingham; 🇺🇸 Effingham, Illinois, United States

Crossroads Cancer Center; 🇺🇸 Effingham, Illinois, United States

Illinois CancerCare-Eureka; 🇺🇸 Eureka, Illinois, United States

Illinois CancerCare-Galesburg; 🇺🇸 Galesburg, Illinois, United States

Western Illinois Cancer Treatment Center; 🇺🇸 Galesburg, Illinois, United States

Northwestern Medicine Cancer Center Delnor; 🇺🇸 Geneva, Illinois, United States

Illinois CancerCare-Kewanee Clinic; 🇺🇸 Kewanee, Illinois, United States

Illinois CancerCare-Macomb; 🇺🇸 Macomb, Illinois, United States

Carle Physician Group-Mattoon/Charleston; 🇺🇸 Mattoon, Illinois, United States

Loyola University Medical Center; 🇺🇸 Maywood, Illinois, United States

Good Samaritan Regional Health Center; 🇺🇸 Mount Vernon, Illinois, United States

Cancer Care Center of O'Fallon; 🇺🇸 O'Fallon, Illinois, United States

HSHS Saint Elizabeth's Hospital; 🇺🇸 O'Fallon, Illinois, United States

Illinois CancerCare-Ottawa Clinic; 🇺🇸 Ottawa, Illinois, 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

Illinois CancerCare-Princeton; 🇺🇸 Princeton, Illinois, United States

UW Health Carbone Cancer Center Rockford; 🇺🇸 Rockford, Illinois, United States

Southern Illinois University School of Medicine; 🇺🇸 Springfield, Illinois, United States

Springfield Clinic; 🇺🇸 Springfield, Illinois, United States

Memorial Medical Center; 🇺🇸 Springfield, Illinois, United States

Carle Cancer Center; 🇺🇸 Urbana, Illinois, United States

The Carle Foundation Hospital; 🇺🇸 Urbana, Illinois, United States

Northwestern Medicine Cancer Center Warrenville; 🇺🇸 Warrenville, Illinois, United States

Illinois CancerCare - Washington; 🇺🇸 Washington, Illinois, United States

Central Care Cancer Center - Great Bend; 🇺🇸 Great Bend, Kansas, United States

Central Care Cancer Center - Garden City; 🇺🇸 Garden City, Kansas, United States

Saint Joseph Hospital; 🇺🇸 Lexington, Kentucky, United States

Saint Joseph Radiation Oncology Resource Center; 🇺🇸 Lexington, Kentucky, United States

Saint Joseph Hospital East; 🇺🇸 Lexington, Kentucky, United States

Jewish Hospital; 🇺🇸 Louisville, Kentucky, United States

MaineHealth Coastal Cancer Treatment Center; 🇺🇸 Bath, Maine, United States

MaineHealth/SMHC Cancer Care and Blood Disorders-Biddeford; 🇺🇸 Biddeford, Maine, United States

Maine Medical Center-Bramhall Campus; 🇺🇸 Portland, Maine, 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

Maine Medical Center- Scarborough Campus; 🇺🇸 Scarborough, Maine, United States

Maine Medical Partners - South Portland; 🇺🇸 South Portland, Maine, United States

University of Maryland/Greenebaum Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Johns Hopkins University/Sidney Kimmel Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Suburban Hospital; 🇺🇸 Bethesda, Maryland, United States

UM Baltimore Washington Medical Center/Tate Cancer Center; 🇺🇸 Glen Burnie, Maryland, United States

Minnesota Oncology - Burnsville; 🇺🇸 Burnsville, Minnesota, United States

Mercy Hospital; 🇺🇸 Coon Rapids, Minnesota, United States

Fairview Southdale Hospital; 🇺🇸 Edina, Minnesota, United States

Unity Hospital; 🇺🇸 Fridley, Minnesota, 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

Abbott-Northwestern Hospital; 🇺🇸 Minneapolis, Minnesota, United States

Hennepin County Medical Center; 🇺🇸 Minneapolis, Minnesota, United States

Health Partners Inc; 🇺🇸 Minneapolis, Minnesota, United States

Monticello Cancer Center; 🇺🇸 Monticello, Minnesota, United States

North Memorial Medical Health Center; 🇺🇸 Robbinsdale, Minnesota, United States

Coborn Cancer Center at Saint Cloud Hospital; 🇺🇸 Saint Cloud, Minnesota, 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

Saint Francis Regional Medical Center; 🇺🇸 Shakopee, Minnesota, United States

Lakeview Hospital; 🇺🇸 Stillwater, Minnesota, United States

Ridgeview Medical Center; 🇺🇸 Waconia, Minnesota, United States

Rice Memorial Hospital; 🇺🇸 Willmar, Minnesota, United States

Minnesota Oncology Hematology PA-Woodbury; 🇺🇸 Woodbury, Minnesota, United States

Baptist Cancer Center-Grenada; 🇺🇸 Grenada, Mississippi, United States

University of Mississippi Medical Center; 🇺🇸 Jackson, Mississippi, United States

Baptist Memorial Hospital and Cancer Center-Union County; 🇺🇸 New Albany, Mississippi, United States

Baptist Memorial Hospital and Cancer Center-Oxford; 🇺🇸 Oxford, Mississippi, United States

Central Care Cancer Center - Bolivar; 🇺🇸 Bolivar, Missouri, United States

Saint Francis Medical Center; 🇺🇸 Cape Girardeau, Missouri, United States

Southeast Cancer Center; 🇺🇸 Cape Girardeau, Missouri, United States

Siteman Cancer Center at West County Hospital; 🇺🇸 Creve Coeur, Missouri, United States

Parkland Health Center - Farmington; 🇺🇸 Farmington, Missouri, United States

MU Health Care Goldschmidt Cancer Center; 🇺🇸 Jefferson City, Missouri, United States

Freeman Health System; 🇺🇸 Joplin, Missouri, United States

Mercy Hospital Joplin; 🇺🇸 Joplin, Missouri, United States

Delbert Day Cancer Institute at PCRMC; 🇺🇸 Rolla, Missouri, United States

Mercy Clinic-Rolla-Cancer and Hematology; 🇺🇸 Rolla, Missouri, United States

Heartland Regional Medical Center; 🇺🇸 Saint Joseph, Missouri, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Mercy Hospital South; 🇺🇸 Saint Louis, Missouri, United States

Siteman Cancer Center-South County; 🇺🇸 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

Mercy Hospital Saint Louis; 🇺🇸 Saint Louis, Missouri, United States

Siteman Cancer Center at Saint Peters Hospital; 🇺🇸 Saint Peters, Missouri, United States

Sainte Genevieve County Memorial Hospital; 🇺🇸 Sainte Genevieve, Missouri, United States

Mercy Hospital Springfield; 🇺🇸 Springfield, Missouri, United States

CoxHealth South Hospital; 🇺🇸 Springfield, Missouri, United States

Missouri Baptist Sullivan Hospital; 🇺🇸 Sullivan, Missouri, United States

BJC Outpatient Center at Sunset Hills; 🇺🇸 Sunset Hills, Missouri, United States

Billings Clinic Cancer Center; 🇺🇸 Billings, Montana, United States

Bozeman Health Deaconess Hospital; 🇺🇸 Bozeman, Montana, United States

Benefis Sletten Cancer Institute; 🇺🇸 Great Falls, Montana, United States

Great Falls Clinic; 🇺🇸 Great Falls, Montana, United States

Kalispell Regional Medical Center; 🇺🇸 Kalispell, Montana, United States

Saint Patrick Hospital - Community Hospital; 🇺🇸 Missoula, Montana, United States

Community Medical Center; 🇺🇸 Toms River, New Jersey, United States

CHI Health Good Samaritan; 🇺🇸 Kearney, Nebraska, United States

Alegent Health Immanuel Medical Center; 🇺🇸 Omaha, Nebraska, United States

Alegent Health Bergan Mercy Medical Center; 🇺🇸 Omaha, Nebraska, United States

Alegent Health Lakeside Hospital; 🇺🇸 Omaha, Nebraska, United States

Creighton University Medical Center; 🇺🇸 Omaha, Nebraska, United States

Cooper Hospital University Medical Center; 🇺🇸 Camden, New Jersey, United States

Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States

Rutgers Cancer Institute of New Jersey; 🇺🇸 New Brunswick, New Jersey, United States

Robert Wood Johnson University Hospital Somerset; 🇺🇸 Somerville, New Jersey, United States

MD Anderson Cancer Center at Cooper-Voorhees; 🇺🇸 Voorhees, New Jersey, United States

Northwell Health Imbert Cancer Center; 🇺🇸 Bay Shore, New York, United States

Montefiore Medical Center-Einstein Campus; 🇺🇸 Bronx, New York, United States

Montefiore Medical Center-Weiler Hospital; 🇺🇸 Bronx, New York, United States

Montefiore Medical Center - Moses Campus; 🇺🇸 Bronx, New York, United States

Northwell Health/Center for Advanced Medicine; 🇺🇸 Lake Success, New York, United States

Mount Sinai Union Square; 🇺🇸 New York, New York, United States

Mount Sinai Chelsea; 🇺🇸 New York, New York, United States

Mount Sinai West; 🇺🇸 New York, New York, United States

Lenox Hill Hospital; 🇺🇸 New York, New York, United States

Mount Sinai Hospital; 🇺🇸 New York, New York, United States

Manhattan Eye Ear and Throat Hospital; 🇺🇸 New York, New York, United States

Phelps Memorial Hospital Center; 🇺🇸 Sleepy Hollow, New York, United States

Stony Brook University Medical Center; 🇺🇸 Stony Brook, New York, United States

Westchester Medical Center; 🇺🇸 Valhalla, New York, United States

ECU Health Oncology Kenansville; 🇺🇸 Kenansville, North Carolina, United States

ECU Health Oncology Kinston; 🇺🇸 Kinston, North Carolina, United States

ECU Health Oncology Richlands; 🇺🇸 Richlands, North Carolina, United States

University of Cincinnati Cancer Center-UC Medical Center; 🇺🇸 Cincinnati, Ohio, United States

Good Samaritan Hospital - Cincinnati; 🇺🇸 Cincinnati, Ohio, United States

Bethesda North Hospital; 🇺🇸 Cincinnati, Ohio, United States

Ohio State University Comprehensive Cancer Center; 🇺🇸 Columbus, Ohio, United States

University of Cincinnati Cancer Center-West Chester; 🇺🇸 West Chester, Ohio, United States

University of Oklahoma Health Sciences Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Mercy Hospital Oklahoma City; 🇺🇸 Oklahoma City, Oklahoma, United States

Saint Charles Health System; 🇺🇸 Bend, Oregon, United States

Clackamas Radiation Oncology Center; 🇺🇸 Clackamas, Oregon, United States

Providence Cancer Institute Clackamas Clinic; 🇺🇸 Clackamas, Oregon, United States

Bay Area Hospital; 🇺🇸 Coos Bay, Oregon, United States

Legacy Mount Hood Medical Center; 🇺🇸 Gresham, Oregon, United States

Providence Newberg Medical Center; 🇺🇸 Newberg, Oregon, United States

Providence Willamette Falls Medical Center; 🇺🇸 Oregon City, Oregon, United States

Legacy Good Samaritan Hospital and Medical Center; 🇺🇸 Portland, Oregon, United States

Providence Portland Medical Center; 🇺🇸 Portland, Oregon, United States

Providence Saint Vincent Medical Center; 🇺🇸 Portland, Oregon, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

Legacy Meridian Park Hospital; 🇺🇸 Tualatin, Oregon, United States

UPMC Altoona; 🇺🇸 Altoona, Pennsylvania, United States

UPMC-Heritage Valley Health System Beaver; 🇺🇸 Beaver, Pennsylvania, United States

Crozer-Keystone Regional Cancer Center at Broomall; 🇺🇸 Broomall, Pennsylvania, United States

Carlisle Regional Cancer Center; 🇺🇸 Carlisle, Pennsylvania, United States

Delaware County Memorial Hospital; 🇺🇸 Drexel Hill, Pennsylvania, United States

Fox Chase Cancer Center - East Norriton Hospital Outpatient Center; 🇺🇸 East Norriton, Pennsylvania, United States

UPMC Hillman Cancer Center Erie; 🇺🇸 Erie, Pennsylvania, United States

UPMC Cancer Center at UPMC Horizon; 🇺🇸 Farrell, Pennsylvania, United States

Fox Chase Cancer Center Buckingham; 🇺🇸 Furlong, Pennsylvania, United States

Crozer Regional Cancer Center at Brinton Lake; 🇺🇸 Glen Mills, Pennsylvania, United States

UPMC Cancer Centers - Arnold Palmer Pavilion; 🇺🇸 Greensburg, Pennsylvania, United States

UPMC Pinnacle Cancer Center/Community Osteopathic Campus; 🇺🇸 Harrisburg, Pennsylvania, United States

Penn State Milton S Hershey Medical Center; 🇺🇸 Hershey, Pennsylvania, United States

UPMC-Johnstown/John P. Murtha Regional Cancer Center; 🇺🇸 Johnstown, Pennsylvania, United States

UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion; 🇺🇸 Mechanicsburg, Pennsylvania, United States

UPMC Cancer Center - Monroeville; 🇺🇸 Monroeville, Pennsylvania, United States

UPMC Hillman Cancer Center in Coraopolis; 🇺🇸 Moon, Pennsylvania, United States

UPMC Cancer Center-Natrona Heights; 🇺🇸 Natrona Heights, Pennsylvania, United States

UPMC Hillman Cancer Center - New Castle; 🇺🇸 New Castle, Pennsylvania, United States

Penn Presbyterian Medical Center; 🇺🇸 Philadelphia, Pennsylvania, United States

University of Pennsylvania/Abramson Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Thomas Jefferson University Hospital; 🇺🇸 Philadelphia, Pennsylvania, United States

Fox Chase Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Temple University Hospital; 🇺🇸 Philadelphia, Pennsylvania, United States

UPMC-Magee Womens Hospital; 🇺🇸 Pittsburgh, Pennsylvania, United States

UPMC-Saint Margaret; 🇺🇸 Pittsburgh, Pennsylvania, United States

University of Pittsburgh Cancer Institute (UPCI); 🇺🇸 Pittsburgh, Pennsylvania, United States

UPMC-Shadyside Hospital; 🇺🇸 Pittsburgh, Pennsylvania, United States

UPMC-Passavant Hospital; 🇺🇸 Pittsburgh, Pennsylvania, United States

UPMC-Saint Clair Hospital Cancer Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

UPMC Cancer Center at UPMC Northwest; 🇺🇸 Seneca, Pennsylvania, United States

UPMC Cancer Center-Uniontown; 🇺🇸 Uniontown, Pennsylvania, United States

UPMC Uniontown Hospital Radiation Oncology; 🇺🇸 Uniontown, Pennsylvania, United States

UPMC Washington Hospital Radiation Oncology; 🇺🇸 Washington, Pennsylvania, United States

UPMC Susquehanna; 🇺🇸 Williamsport, Pennsylvania, United States

UPMC Memorial; 🇺🇸 York, Pennsylvania, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, 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

UT Southwestern Simmons Cancer Center - RedBird; 🇺🇸 Dallas, Texas, United States

UT Southwestern/Simmons Cancer Center-Dallas; 🇺🇸 Dallas, Texas, United States

Tarrant County Hospital District/JPS Health Network; 🇺🇸 Fort Worth, Texas, United States

UT Southwestern/Simmons Cancer Center-Fort Worth; 🇺🇸 Fort Worth, Texas, United States

UT Southwestern Clinical Center at Richardson/Plano; 🇺🇸 Richardson, Texas, 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

University of Virginia Cancer Center; 🇺🇸 Charlottesville, Virginia, United States

Virginia Commonwealth University/Massey Cancer Center; 🇺🇸 Richmond, Virginia, United States

Providence Regional Cancer System-Aberdeen; 🇺🇸 Aberdeen, Washington, United States

PeaceHealth Saint Joseph Medical Center; 🇺🇸 Bellingham, Washington, United States

Providence Regional Cancer System-Centralia; 🇺🇸 Centralia, Washington, United States

Swedish Cancer Institute-Edmonds; 🇺🇸 Edmonds, Washington, United States

Providence Regional Cancer Partnership; 🇺🇸 Everett, Washington, United States

Swedish Cancer Institute-Issaquah; 🇺🇸 Issaquah, Washington, United States

Kadlec Clinic Hematology and Oncology; 🇺🇸 Kennewick, Washington, United States

Providence Regional Cancer System-Lacey; 🇺🇸 Lacey, Washington, United States

PeaceHealth Saint John Medical Center; 🇺🇸 Longview, Washington, United States

Skagit Regional Health Cancer Care Center; 🇺🇸 Mount Vernon, Washington, United States

Swedish Medical Center-Ballard Campus; 🇺🇸 Seattle, Washington, United States

FHCC South Lake Union; 🇺🇸 Seattle, Washington, United States

Fred Hutchinson Cancer Center; 🇺🇸 Seattle, Washington, United States

Swedish Medical Center-First Hill; 🇺🇸 Seattle, Washington, United States

FHCC at Northwest Hospital; 🇺🇸 Seattle, Washington, United States

University of Washington Medical Center - Montlake; 🇺🇸 Seattle, Washington, United States

PeaceHealth United General Medical Center; 🇺🇸 Sedro-Woolley, Washington, United States

Saint Michael Cancer Center; 🇺🇸 Silverdale, Washington, United States

PeaceHealth Southwest Medical Center; 🇺🇸 Vancouver, Washington, United States

Legacy Cancer Institute Medical Oncology and Day Treatment; 🇺🇸 Vancouver, Washington, United States

Legacy Salmon Creek Hospital; 🇺🇸 Vancouver, Washington, United States

Providence Saint Mary Regional Cancer Center; 🇺🇸 Walla Walla, Washington, United States

Langlade Hospital and Cancer Center; 🇺🇸 Antigo, Wisconsin, United States

Marshfield Medical Center-EC Cancer Center; 🇺🇸 Eau Claire, Wisconsin, United States

University of Wisconsin Carbone Cancer Center - Johnson Creek; 🇺🇸 Johnson Creek, Wisconsin, United States

William S Middleton VA Medical Center; 🇺🇸 Madison, Wisconsin, United States

University of Wisconsin Carbone Cancer Center - University Hospital; 🇺🇸 Madison, Wisconsin, United States

Marshfield Medical Center-Marshfield; 🇺🇸 Marshfield, Wisconsin, United States

Marshfield Clinic-Minocqua Center; 🇺🇸 Minocqua, Wisconsin, United States

Cancer Center of Western Wisconsin; 🇺🇸 New Richmond, Wisconsin, United States

Ascension Saint Mary's Hospital; 🇺🇸 Rhinelander, Wisconsin, United States

Marshfield Medical Center-Rice Lake; 🇺🇸 Rice Lake, Wisconsin, 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

Aspirus Regional Cancer Center; 🇺🇸 Wausau, Wisconsin, United States

Marshfield Medical Center - Weston; 🇺🇸 Weston, Wisconsin, United States

Aspirus Cancer Care - Wisconsin Rapids; 🇺🇸 Wisconsin Rapids, Wisconsin, United States

Welch Cancer Center; 🇺🇸 Sheridan, Wyoming, United States