Two Studies for Patients With High Risk Prostate Cancer Testing Less Intense Treatment for Patients With a Low Gene Risk Score and Testing a More Intense Treatment for Patients With a High Gene Risk Score, The PREDICT-RT Trial

• ClinicalTrials.gov Identifier: NCT04513717
• Recruitment Status: Recruiting
• First Posted: August 14, 2020
• Last Update Posted: February 7, 2024
• Sponsor: NRG Oncology
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): NRG Oncology

Tracking Information

• First Submitted Date: August 7, 2020
• First Posted Date: August 14, 2020
• Last Update Posted Date: February 7, 2024
• Actual Study Start Date: December 15, 2020
• Estimated Primary Completion Date: December 31, 2033 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 19, 2022)

Metastasis-free survival (MFS) [ Time Frame: From randomization to the date of detection of distant metastasis on standard imaging or date of death from any cause, assessed up to 13 years ]

Assessed based on conventional imaging. MFS will be estimated using the Kaplan-Meier method (Kaplan 1958).

Original Primary Outcome Measures (submitted: August 11, 2020)

Metastasis-Free Survival (MFS) [ Time Frame: From randomization to the date of detection of distant metastasis on standard imaging or date of death from any cause, assessed up to 13 years ]

Assessed based on conventional imaging. MFS will be estimated using the Kaplan-Meier method (Kaplan 1958).

Current Secondary Outcome Measures (submitted: January 19, 2022)

• MFS [ Time Frame: From randomization to the date of detection of distant metastasis on standard imaging or date of death from any cause, assessed up to 13 years ]
  Assessed based on standard or molecular, if available, imaging. MFS will be estimated using the Kaplan-Meier method (Kaplan 1958)
• Overall survival [ Time Frame: From the date of randomization to the date of death or last known follow-up date, with patients alive at the last known follow-up time treated as censored, assessed up to 13 years ]
  Will be estimated using the Kaplan-Meier method and treatment arms compared using the stratified log-rank test (Kaplan 1958).
• Prostate cancer specific mortality (PCSM) [ Time Frame: From the date of randomization to the date of prostate cancer death, assessed up to 13 years ]
• Prostate specific antigen (PSA) failure-free survival with non-castrate testosterone and no additional therapies [ Time Frame: From the date of randomization to the date event, or death or censored at the last known follow-up date, assessed up to 13 years ]
  PSA failure-free survival will be estimated using the Kaplan-Meier method and treatment arms compared using the stratified log-rank test (Kaplan 1958).
• Time to testosterone recovery [ Time Frame: Up to 13 years ]
  Defined as testosterone that is non-castrate.
• Time to PSA failure or salvage therapy [ Time Frame: Up to 13 years ]
• Testosterone levels at the time of PSA failure and metastases [ Time Frame: Up to 13 years ]
• Incidence of adverse events [ Time Frame: Up to 13 years ]
  Measured by the Common Terminology Criteria for Adverse Events (CTCAE ) version (v) 5.0 and Patient Reported Outcomes (PRO)-CTCAE.

Original Secondary Outcome Measures (submitted: August 11, 2020)

• MFS [ Time Frame: From randomization to the date of detection of distant metastasis on standard imaging or date of death from any cause, assessed up to 13 years ]
  Assessed based on standard or molecular, if available, imaging. MFS will be estimated using the Kaplan-Meier method (Kaplan 1958)
• Overall Survival [ Time Frame: From the date of randomization to the date of death or last known follow-up date, with patients alive at the last known follow-up time treated as censored, assessed up to 13 years ]
  Will be estimated using the Kaplan-Meier method and treatment arms compared using the stratified log-rank test (Kaplan 1958).
• Prostate Cancer Specific Mortality (PCSM) [ Time Frame: From the date of randomization to the date of prostate cancer death, assessed up to 13 years ]
• Prostate Specific Antigen (PSA) failure-free survival with non-castrate testosterone and no additional therapies [ Time Frame: From the date of randomization to the date event, or death or censored at the last known follow-up date, assessed up to 13 years ]
  PSA failure-free survival will be estimated using the Kaplan-Meier method and treatment arms compared using the stratified log-rank test (Kaplan 1958).
• Time to testosterone recovery [ Time Frame: Up to 13 years ]
  Defined as testosterone that is non-castrate.
• Time to PSA failure or salvage therapy [ Time Frame: Up to 13 years ]
• Testosterone levels at the time of PSA failure and metastases [ Time Frame: Up to 13 years ]
• Incidence of Adverse Events [ Time Frame: Up to 13 years ]
  Measured by the Common Terminology Criteria for Adverse Events (CTCAE ) version (v) 5.0 and Patient Reported Outcomes (PRO)-CTCAE.

Current Other Pre-specified Outcome Measures (submitted: January 19, 2022)

• Cardio-metabolic markers including body mass index and waist circumference [ Time Frame: Up to 13 years ]
• Machine learning/artificial intelligence algorithm [ Time Frame: Up to 13 years ]
• Bowel and urinary quality of life (De-intensification study) [ Time Frame: Up to 13 years ]
  Measured by EPIC-26 bowel and urinary domains.
• Cognition (De-intensification study) [ Time Frame: Up to 13 years ]
  Measured by the Functional Assessment of Chronic Illness Therapy-Cognition (FACIT-Cog) perceived cognitive abilities subscale.
• Sexual, hormonal, bowel, and urinary quality of life (Intensification study) [ Time Frame: Up to 13 years ]
  Measured by Expanded Prostate Cancer Index Composite-26.
• Cognition (Intensification study) [ Time Frame: Up to 13 years ]
  Measured by the FACIT-Cog perceived cognitive abilities subscale.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Two Studies for Patients With High Risk Prostate Cancer Testing Less Intense Treatment for Patients With a Low Gene Risk Score and Testing a More Intense Treatment for Patients With a High Gene Risk Score, The PREDICT-RT Trial
• Official Title: Parallel Phase III Randomized Trials for High Risk Prostate Cancer Evaluating De-Intensification for Lower Genomic Risk and Intensification of Concurrent Therapy for Higher Genomic Risk With Radiation (PREDICT-RT*)
• Brief Summary: This phase III trial compares less intense hormone therapy and radiation therapy to usual hormone therapy and radiation therapy in treating patients with high risk prostate cancer and low gene risk score. This trial also compares more intense hormone therapy and radiation therapy to usual hormone therapy and radiation therapy in patients with high risk prostate cancer and high gene risk score. Apalutamide may help fight prostate cancer by blocking the use of androgen by the tumor cells. Radiation therapy uses high energy rays to kill tumor cells and shrink tumors. Giving a shorter hormone therapy treatment may work the same at controlling prostate cancer compared to the usual 24 month hormone therapy treatment in patients with low gene risk score. Adding apalutamide to the usual treatment may increase the length of time without prostate cancer spreading as compared to the usual treatment in patients with high gene risk score.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine whether men with National Comprehensive Cancer Network (NCCN) high risk prostate cancer who are in the lower 2/3 of Decipher genomic risk (=< 0.85) can be treated with 12 months androgen deprivation therapy (ADT) plus radiation therapy (RT) instead of 24 months ADT+RT and experience non-inferior metastasis-free survival. (De-intensification study) II. To determine whether men with NCCN high risk prostate cancer who are in the upper 1/3 of Decipher genomic risk (> 0.85) or have node-positive disease by conventional imaging (magnetic resonance imaging [MRI] or computed tomography [CT] scan) will have a superior metastasis-free survival (MFS) through treatment intensification with apalutamide added to the standard of RT plus 24 month ADT. (Intensification study)

SECONDARY OBJECTIVES:

I. To compare overall survival (OS) between the standard of care (RT plus 24 months of ADT) and either the de-intensification (RT plus 12 months of ADT) or intensification arm (RT plus 24 months of ADT plus apalutamide). (De-intensification and intensification studies) II. To compare time to prostate specific antigen (PSA) failure or start of salvage treatment between the standard of care (RT plus 24 months of ADT) and either the de-intensification arm (RT plus 12 months of ADT) or intensification arm (RT plus 24 months of ADT plus apalutamide). (De-intensification and intensification studies) III. To compare PSA failure-free survival with non-castrate testosterone and no additional therapies between the standard of care (RT plus 24 months of ADT) and either the de-intensification arm (RT plus 12 months of ADT) or intensification arm (RT plus 24 months of ADT plus apalutamide). (De-intensification and intensification studies) IV. To compare MFS judged based on either standard or molecular imaging between the standard of care (RT plus 24 months of ADT) and either the de-intensification arm (RT plus 12 months of ADT) or intensification arm (RT plus 24 months of ADT plus apalutamide). (De-intensification and intensification studies) V. To compare prostate cancer-specific mortality between the standard of care (RT plus 24 months of ADT) and either the de-intensification arm (RT plus 12 months of ADT) or intensification arm (RT plus 24 months of ADT plus apalutamide). (De-intensification and intensification studies) VI. To compare testosterone levels at the time of PSA failure and metastases between the standard of care (RT plus 24 months of ADT) and either the de-intensification arm (RT plus 12 months of ADT) or intensification arm (RT plus 24 months of ADT plus apalutamide). (De-intensification and intensification studies) VII. To compare time to testosterone recovery (defined as a T > 200) between the standard of care (RT plus 24 months of ADT) and either the de-intensification arm (RT plus 12 months of ADT) or intensification arm (RT plus 24 months of ADT plus apalutamide). (De-intensification and intensification studies) VIII. To compare adverse events, both clinician-reported using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 and patient-reported using Patient Reported Outcome (PRO)-CTCAE items, between the standard of care (RT plus 24 months of ADT) and either the de-intensification arm (RT plus 12 months of ADT) or intensification arm (RT plus 24 months of ADT plus apalutamide). (De-intensification and intensification studies)

EXPLORATORY OBJECTIVES:

I. To compare changes in cardio-metabolic markers, including body mass index, and waist circumference, between the standard of care (RT plus 24 months of ADT) and either the de-intensification arm (RT plus 12 months of ADT) or intensification arm (RT plus 24 months of ADT plus apalutamide). (De-intensification and intensification studies) II. To determine a machine learning/artificial intelligence algorithm for radiotherapy quality assurance. (De-intensification and Intensification studies) III. To perform future translational correlative studies using biological and imaging data. (De-intensification and intensification studies) IV. Impact of PET use in high-risk prostate cancer

PATIENT-REPORTED OUTCOMES OBJECTIVES:

PRIMARY OBJECTIVES:

I. To compare sexual and hormonal function related quality of life, as measured by the Expanded Prostate Cancer Index Composite-26 (EPIC), between the standard of care (RT plus 24 months of ADT) and the de-intensification arm (RT plus 12 months of ADT). (De-Intensification Study) II. To compare fatigue, as measured by the Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue instrument, between the standard of care (RT plus 24 months of ADT) and the intensification arm (RT plus 24 months of ADT plus apalutamide). (Intensification Study)

SECONDARY OBJECTIVES:

I. To compare depression, as measured by the PROMIS-depression, between the standard of care (RT plus 24 months of ADT) and the de-intensification arm (RT plus 12 months of ADT). (De-Intensification Study) II. To compare depression, as measured by the PROMIS-depression, between the standard of care (RT plus 24 months of ADT) and the intensification arm (RT plus 24 months of ADT plus apalutamide). (Intensification Study)

EXPLORATORY OBJECTIVES:

I. To compare cognition, as measured by the Functional Assessment of Chronic Illness Therapy-Cognitive (FACT-Cog) perceived cognitive abilities subscale, between the standard of care (RT plus 24 months of ADT) and the de-intensification arm (RT plus 12 months of ADT). (De-Intensification Study) II. To compare bowel and urinary function related quality of life, as measured by the Expanded Prostate Cancer Index Composite-26 (EPIC), between the standard of care (RT plus 24 months of ADT) and the de-intensification arm (RT plus 12 months of ADT). (De-Intensification Study) III. To compare fatigue, as measured by the PROMIS-Fatigue instrument, between the standard of care (RT plus 24 months of ADT) and the de-intensification arm (RT plus 12 months of ADT). (De-Intensification Study) IV. To compare sexual and hormonal function related quality of life, as measured by the Expanded Prostate Cancer Index Composite-26 (EPIC), between the standard of care (RT plus 24 months of ADT) and the intensification arm (RT plus 24 months of ADT plus apalutamide). (Intensification Study) V. To compare bowel and urinary function related quality of life, as measured by the Expanded Prostate Cancer Index Composite-26 (EPIC), between the standard of care (RT plus 24 months of ADT) and the intensification arm (RT plus 24 months of ADT plus apalutamide). (Intensification Study) VI. To compare cognition, as measured by the Functional Assessment of Chronic Illness Therapy-Cognitive (FACT-Cog) perceived cognitive abilities subscale, between the standard of care (RT plus 24 months of ADT) and the intensification arm (RT plus 24 months of ADT plus apalutamide). (Intensification Study)

OUTLINE: Patients are randomized to 1 of 4 arms.

DE-INTENSIFICATION STUDY (DECIPHER SCORE =< 0.85):

ARM I: Patients undergo radiation therapy (RT) over 2-11 weeks and receive ADT (consisting of either leuprolide, goserelin, triptorelin, degarelix, buserelin or histrelin and bicalutamide or flutamide) for 24 months in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo RT over 2-11 weeks and receive ADT (consisting of either leuprolide, goserelin, triptorelin, degarelix, buserelin or histrelin and bicalutamide or flutamide) for 12 months in the absence of disease progression or unacceptable toxicity.

INTENSIFICATION STUDY (DECIPHER SCORE > 0.85 OR NODE POSITIVE):

ARM III: Patients undergo RT over 2-11 weeks and receive ADT (consisting of either leuprolide, goserelin, triptorelin, degarelix, buserelin or histrelin and bicalutamide or flutamide) for 24 months in the absence of disease progression or unacceptable toxicity.

ARM IV: Patients undergo RT over 2-11 weeks and receive ADT (consisting of either leuprolide, goserelin, triptorelin, degarelix, buserelin or histrelin) for 24 months in the absence of disease progression or unacceptable toxicity. Patients also receive apalutamide orally (PO) once daily (QD). Treatment repeats every 90 days for up to 8 cycles (24 months) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up annually.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Metastatic Malignant Neoplasm in the Bone
• Prostate Adenocarcinoma
• Stage III Prostate Cancer AJCC v8
• Stage IIIA Prostate Cancer AJCC v8
• Stage IIIB Prostate Cancer AJCC v8
• Stage IIIC Prostate Cancer AJCC v8
• Stage IVA Prostate Cancer AJCC v8

Intervention

• Drug: Apalutamide
  Nonsteroidal Antiandrogen
  Other Names:

  • ARN 509
  • ARN-509
  • ARN509
  • Erleada
  • JNJ 56021927
  • JNJ-56021927
• Drug: Bicalutamide
  Antiandrogen
  Other Names:

  • Casodex
  • Cosudex
  • ICI 176,334
  • ICI 176334
• Drug: Buserelin
  Luteinizing hormone-releasing hormone (LHRH) agonist
  Other Names:

  • 6-[O-(1,1-Dimethylethyl)-D-serine]-9-(N-ethyl-L-prolinamide)-10-deglycinamide-luteinizing Hormone-releasing Factor (Pig)
  • BSRL
  • Busereline
  • Etilamide
  • HOE 766
  • ICI 123215
  • S74-6766
• Drug: Degarelix
  Gonadotropin-releasing hormone (GnRH) antagonist
  Other Names:

  • FE200486
  • Firmagon
• Drug: Flutamide
  Antiandrogen
  Other Names:

  • 4'-Nitro-3'-trifluoromethylisobutyranilide
  • Apimid
  • Cebatrol
  • Chimax
  • Cytomid
  • Drogenil
  • Euflex
  • Eulexine
  • Flucinom
  • Flucinome
  • Flugerel
  • Fluken
  • Flulem
  • FLUT
  • Fluta-Gry
  • Flutabene
  • Flutacan
  • Flutamex
  • Flutamin
  • Flutan
  • Flutaplex
  • Fugerel
  • Grisetin
  • Niftolide
  • Oncosal
  • Profamid
  • Propanamide, 2-Methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)-
  • Prostacur
  • Prostadirex
  • Prostica
  • Prostogenat
  • Sch 13521
  • Tafenil
  • Tecnoflut
  • Testotard
• Drug: Goserelin
  Gonadotropin-releasing hormone (GnRH) agonist
  Other Name: ICI-118630
• Drug: Histrelin
  Gonadotropin-releasing hormone (GnRH) agonist
• Drug: Leuprolide
  Gonadotropin-releasing hormone (GnRH) agonist
  Other Name: Leuprorelin
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment
• Other: Questionnaire Administration
  Ancillary studies
• Radiation: Radiation Therapy
  Undergo radiation therapy
  Other Names:

  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation
• Drug: Triptorelin
  Gonadotropin-releasing hormone (GnRH) agonist
  Other Names:

  • 6-D-Tryptophan-LH-RH
  • 6-D-Tryptophanluteinizing Hormone-releasing Factor
  • AY-25650
  • CL-118,532
  • Detryptoreline

Study Arms

• Active Comparator: Arm I (de-intensification study)
  Patients undergo RT over 2-11 weeks and receive ADT (consisting of either leuprolide, goserelin, triptorelin, degarelix, buserelin or histrelin and bicalutamide or flutamide) for 24 months in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Bicalutamide
  • Drug: Buserelin
  • Drug: Degarelix
  • Drug: Flutamide
  • Drug: Goserelin
  • Drug: Histrelin
  • Drug: Leuprolide
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
  • Radiation: Radiation Therapy
  • Drug: Triptorelin
• Experimental: Arm II (de-intensification study)
  Patients undergo RT over 2-11 weeks and receive ADT (consisting of either leuprolide, goserelin, triptorelin, degarelix, buserelin or histrelin and bicalutamide or flutamide) for 12 months in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Bicalutamide
  • Drug: Buserelin
  • Drug: Degarelix
  • Drug: Flutamide
  • Drug: Goserelin
  • Drug: Histrelin
  • Drug: Leuprolide
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
  • Radiation: Radiation Therapy
  • Drug: Triptorelin
• Active Comparator: Arm III (intensification study)
  Patients undergo RT over 2-11 weeks and receive ADT as in Arm I.
  Interventions:

  • Drug: Bicalutamide
  • Drug: Buserelin
  • Drug: Degarelix
  • Drug: Flutamide
  • Drug: Goserelin
  • Drug: Histrelin
  • Drug: Leuprolide
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
  • Radiation: Radiation Therapy
  • Drug: Triptorelin
• Experimental: Arm IV (intensification study)
  Patients undergo RT over 2-11 weeks and receive ADT (consisting of either leuprolide, goserelin, triptorelin, degarelix, buserelin or histrelin) for 24 months in the absence of disease progression or unacceptable toxicity. Patients also receive apalutamide PO QD. Treatment repeats every 90 days for up to 8 cycles (24 months) in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Apalutamide
  • Drug: Buserelin
  • Drug: Degarelix
  • Drug: Goserelin
  • Drug: Histrelin
  • Drug: Leuprolide
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
  • Radiation: Radiation Therapy
  • Drug: Triptorelin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 11, 2020): 2478
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2033
• Estimated Primary Completion Date: December 31, 2033 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• PRIOR TO STEP 1 REGISTRATION
• Pathologically proven diagnosis of adenocarcinoma of prostate cancer within 180 days prior to registration

• High-risk disease defined as having at least one or more of the following:

  • PSA > 20 ng/mL prior to starting ADT Note: Patients receiving a 5-alpha reductase inhibitor (ex. finasteride) at the time of enrollment are eligible. The baseline PSA value should be doubled for PSAs taken while on 5-alpha reductase inhibitors and the medication should be discontinued prior to randomization but a washout period is not required.
  • cT3a-T4 by digital exam or imaging (American Joint Committee on Cancer [AJCC] 8th edition [Ed.])
  • Gleason score of 8-10
  • Node positive by conventional imaging with a short axis of at least 1.0 cm

• Appropriate stage for study entry based on the following diagnostic workup:

  • History/physical examination within 120 days prior to registration;

  • Bone imaging within 120 days prior to registration;

    • Note: To be eligible, patient must have no definitive evidence of bone metastases (M0) on bone scan or sodium fluoride (NaF) PET within 120 days prior to registration (negative NaF PET/CT or negative Axumin or choline PET or negative fluciclovine, choline or prostate-specific membrane antigen (PSMA) PET within 120 days prior to registration is an acceptable substitute if they have been performed). Patients who have bone metastases established only fluciclovine, choline, or PSMA PET but not definitive on bone scan or NaF PET will still be eligible
  • CT or MRI of the pelvis within 120 days prior to registration (negative fluciclovine, choline, or PSMA PET within 120 days prior to registration is an acceptable substitute). As with bone staging, nodal staging for trial purposes will be based off of conventional imaging findings only
  • Patients with confirmed N1 metastases on conventional imaging (CT/MRI) as defined by ≥10 mm on short axis are eligible but will be automatically assigned to the intensification study. Patients who are positive by fluciclovine, choline, or PSMA PET (i.e. N1), but whose nodes do not meet traditional size criteria for positivity (i.e. they measure ≥ 10 mm on either the CT or MRI portion of the PET or on a dedicated CT or MRI) will not be considered N1 for the trial and will not automatically be assigned to the intensification study
• Age ≥ 18
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 120 days prior to registration
• Hemoglobin ≥ 9.0 g/dL, independent of transfusion and/or growth factors (within 120 days prior to registration)
• Platelet count ≥ -100 x 10^3/uL independent of transfusion and/or growth factors (within 120 days prior to registration)

• Creatinine clearance (CrCl) ≥ 30 mL/min estimated by Cockcroft-Gault equation (within 120 days prior to registration)

  • For Black patients whose renal function is not considered adequate by Cockcroft-Gault formula, an alternative formula that takes race into account (Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula) may be used for calculating creatinine clearance for trial eligibility
  • Either a CrCl ≥ 30 ml/min or calculated glomerular filtration rate (GFR) ≥ 30 will make a patient eligible

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 120 days prior to registration)

  • Note: In subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤ 1.5 x ULN, subject is eligible
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x institutional ULN (within 120 days prior to registration)
• Serum albumin ≥ 3.0 g/dL (within 120 days prior to registration)
• The patient must agree to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agree to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial and have a CD4 count ≥ 200 cells/microliter within 60 days prior to registration. Note: HIV testing is not required for eligibility for this protocol. Of note, for patients with HIV in the intensification trial randomized to apalutamide, highly active antiretroviral therapy (HAART) may need to be adjusted to medications that do not interact with apalutamide
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable after or on suppressive therapy within 60 days prior to registration, if indicated. Note: HBV viral testing is not required for eligibility for this protocol
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Note: Any patient with a cancer (other than keratinocyte carcinoma or carcinoma in situ or low-grade non-muscle invasive bladder cancer) who has been disease-free for less than 3 years must contact the principal investigator
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
• PRIOR TO STEP 2 RANDOMIZATION
• Confirmation of Decipher score
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load within 60 days prior. Note: Apalutamide may interfere with HCV drugs. Patients on HCV medications should alert their infectious diseases physician if they get randomized to apalutamide due to the possibility that apalutamide can affect the bioavailability of some HCV medications. HCV viral testing is not required for eligibility for this protocol
• For patients entering the Intensification Cohort ONLY: Patients must discontinue or substitute concomitant medications known to lower the seizure threshold at least 30 days prior to Step 2 randomization

Exclusion Criteria:

• PRIOR TO STEP 1 REGISTRATION:
• Definitive radiologic evidence of metastatic disease outside of the pelvic nodes (M1a, M1b or M1c) on conventional imaging (i.e. bone scan, CT scan, MRI)
• Prior systemic chemotherapy within ≤ 3 years prior to registration; note that prior chemotherapy for a different cancer is allowed (completed > 3 years prior to registration
• Prior radical prostatectomy
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
• Current use of 5-alpha reductase inhibitor. NOTE: If the alpha reductase inhibitor is stopped prior to randomization the patient is eligible

• History of any of the following:

  • Seizure disorder
  • Current severe or unstable angina
  • New York Heart Association Functional Classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.)
  • History of any condition that in the opinion of the investigator, would preclude participation in this study

• Evidence of any of the following at registration:

  • Active uncontrolled infection requiring IV antibiotics
  • Baseline severe hepatic impairment (Child Pugh Class C)
  • Inability to swallow oral pills
  • Any current condition that in the opinion of the investigator, would preclude participation in this study
• Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation (both luteinizing hormone-releasing hormone [LHRH] agonist and oral anti-androgen) is ≤ 60 days prior to registration; Please note: baseline PSA must be obtained prior to the start of any ADT
• PRIOR TO STEP 2 RANDOMIZATION:
• Evidence of known gastrointestinal disorder affecting absorption of oral medications at registration
• For patients entering the Intensification Cohort ONLY: Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] ≥ 160 mmHg or diastolic BP ≥ 100 mmHg). Subjects with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT04513717
• Other Study ID Numbers: NRG-GU009; NCI-2020-04705 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); NRG-GU009 ( Other Identifier: NRG Oncology ); NRG-GU009 ( Other Identifier: CTEP ); U10CA180868 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: NRG Oncology
• Original Responsible Party: Same as current
• Current Study Sponsor: NRG Oncology
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Paul L Nguyen; NRG Oncology

• PRS Account: NRG Oncology
• Verification Date: February 2024