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Testing the Addition of the Drugs, Apalutamide and Abiraterone Acetate With Prednisone, to the Usual Hormone Therapy and Radiation Therapy After Surgery for Prostate Cancer

NCT04134260

Description:

This phase III trial studies how well adding apalutamide, abiraterone acetate, and prednisone to the usual hormone therapy and radiation therapy works compared to the usual hormone therapy and radiation therapy in treating patients with node-positive prostate cancer after surgery. Radiation therapy uses high energy x-ray to kill tumor cells and shrink tumors. Androgens, or male sex hormones, can cause the growth of prostate cancer cells. Drugs, such as apalutamide, may help stop or slow the growth of prostate cancer cell growth by blocking the androgens. Abiraterone acetate blocks some of the enzymes needed for androgen production and may cause the death of prostate cancer cells that need androgens to grow. Prednisone may help abiraterone acetate work better by making tumor cells more sensitive to the drug. Adding apalutamide and abiraterone acetate with prednisone to the usual usual hormone therapy and radiation therapy after surgery may stabilize prostate cancer and prevent it from spreading or extend time without disease spreading compared to the usual approach.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of the Drugs, Apalutamide and Abiraterone Acetate With Prednisone, to the Usual Hormone Therapy and Radiation Therapy After Surgery for Prostate Cancer
  • Official Title: Randomized Phase III Trial Incorporating Abiraterone Acetate With Prednisone and Apalutamide and Advanced Imaging Into Salvage Treatment for Patients With Node-Positive Prostate Cancer After Radical Prostatectomy

Clinical Trial IDs

  • ORG STUDY ID: NRG-GU008
  • SECONDARY ID: NCI-2019-06838
  • SECONDARY ID: NRG-GU008
  • SECONDARY ID: NRG-GU008
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT04134260

Conditions

  • Positive Lymph Node
  • Prostate Adenocarcinoma
  • PSA Level Greater Than Zero
  • Stage I Prostate Cancer AJCC v8
  • Stage II Prostate Cancer AJCC v8
  • Stage IIA Prostate Cancer AJCC v8
  • Stage IIB Prostate Cancer AJCC v8
  • Stage IIC Prostate Cancer AJCC v8
  • 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

Interventions

DrugSynonymsArms
Abiraterone AcetateCB7630, Yonsa, ZytigaArm II (apalutamide, abiraterone acetate, prednisone)
ApalutamideARN 509, ARN-509, ARN509, Erleada, JNJ 56021927, JNJ-56021927Arm II (apalutamide, abiraterone acetate, prednisone)
Hormone TherapyChemotherapy-Hormones/Steroids, Endocrine Therapy, hormonal therapy, hormone treatmentArm I (hormone therapy, radiation therapy)
Prednisone.delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, Perrigo Prednisone, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisone Intensol, Prednisonum, Prednitone, Promifen, Rayos, Servisone, SK-PrednisoneArm II (apalutamide, abiraterone acetate, prednisone)

Purpose

This phase III trial studies how well adding apalutamide, abiraterone acetate, and prednisone to the usual hormone therapy and radiation therapy works compared to the usual hormone therapy and radiation therapy in treating patients with node-positive prostate cancer after surgery. Radiation therapy uses high energy x-ray to kill tumor cells and shrink tumors. Androgens, or male sex hormones, can cause the growth of prostate cancer cells. Drugs, such as apalutamide, may help stop or slow the growth of prostate cancer cell growth by blocking the androgens. Abiraterone acetate blocks some of the enzymes needed for androgen production and may cause the death of prostate cancer cells that need androgens to grow. Prednisone may help abiraterone acetate work better by making tumor cells more sensitive to the drug. Adding apalutamide and abiraterone acetate with prednisone to the usual usual hormone therapy and radiation therapy after surgery may stabilize prostate cancer and prevent it from spreading or extend time without disease spreading compared to the usual approach.

Detailed Description

      PRIMARY OBJECTIVE:

      I. Compare metastasis-free survival (MFS) of salvage radiation therapy (RT) and gonadotropin
      releasing hormone (GnRH) agonist/antagonist versus (vs.) RT/GnRH agonist/antagonist with
      abiraterone acetate with prednisone and apalutamide for patients with pathologic
      node-positive prostate cancer after radical prostatectomy with detectable prostate-specific
      antigen (PSA).

      SECONDARY OBJECTIVES:

      I. Compare health-related quality of life (Expanded Prostate Cancer Index Composite
      [EPIC]-26, EuroQol [EQ]-5 Dimension [D]-5 Level [L]), Brief Pain Inventory, Patient Reported
      Outcome Measurement Information System [PROMIS]-Fatigue) among the treatment arms.

      II. Compare overall survival, biochemical progression-free survival, time to local-regional
      progression, time to castrate resistance, and cancer-specific survival among the treatment
      arms.

      III. Compare the short-term and long-term treatment-related adverse events among the
      treatment arms.

      EXPLORATORY OBJECTIVES:

      I. Validate Decipher score for an exclusively node-positive population and use additional
      genomic information from Affymetrix Human Exon 1.0st array to develop and validate novel
      prognostic and predictive biomarkers.

      II. Validate the PAM50-based classification of prostate cancer into luminal A, luminal B, and
      basal subtypes as prognostic markers and determine whether the luminal B subtype is a
      predictive marker for having a larger improvement in outcome from the addition of abiraterone
      acetate with prednisone and apalutamide.

      III. To optimize quality assurance methodologies and processes for radiotherapy and imaging
      with machine learning strategies.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive standard of care hormone therapy per physician discretion for 24
      months. Patients also undergo standard of care pelvis and prostate bed radiation therapy 5
      days per week over 7-8 weeks beginning within 56 days after first hormone injection if the
      injection is not started prior to registration or within 90 days after first hormone
      injection if the injection is started prior to registration in the absence of disease
      progression or unacceptable toxicity.

      ARM II: Patients undergo standard of care hormone therapy and radiation therapy as in Arm I.
      Patients also receive apalutamide orally (PO) once daily (QD), abiraterone acetate PO QD, and
      prednisone PO QD or twice daily (BID) on days 1-90. Cycles repeat every 90 days for 8 cycles
      in the absence of disease progression or unacceptable toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Arm I (hormone therapy, radiation therapy)Active ComparatorPatients receive standard of care hormone therapy per physician discretion for 24 months. Patients also undergo standard of care pelvis and prostate bed radiation therapy 5 days per week over 7-8 weeks beginning within 56 days after first hormone injection if the injection is not started prior to registration or within 90 days after first hormone injection if the injection is started prior to registration in the absence of disease progression or unacceptable toxicity.
  • Hormone Therapy
Arm II (apalutamide, abiraterone acetate, prednisone)ExperimentalPatients receive standard of care hormone therapy and radiation therapy as in Arm I. Patients also receive apalutamide PO QD, abiraterone acetate PO QD, and prednisone PO QD or BID on days 1-90. Cycles repeat every 90 days for 8 cycles in the absence of disease progression or unacceptable toxicity.
  • Abiraterone Acetate
  • Apalutamide
  • Hormone Therapy
  • Prednisone

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologically (histologically) proven diagnosis of prostate adenocarcinoma. Any type
             of radical prostatectomy is permitted, including retropubic, perineal, laparoscopic or
             robotically assisted

          -  Any T-stage is eligible

          -  Appropriate stage for study entry based on fluciclovine F-18 positron emission
             tomography (PET) scan (FACBC, Axumin) within 90 days prior to registration that is
             negative for distant metastatic (M1a, M1b, M1c) disease; (Note that though every
             effort should be made to obtain a fluciclovine F-18 PET [FACBC, Axumin] scan, if the
             patient has already had a recent gallium Ga 68-labeled PSMA-11 [Ga-68 PSMA] PET scan
             or C-11 or F-18 choline PET scan within 90 days prior to registration [to include scan
             report] then repeat molecular imaging with a fluciclovine F-18 PET [FACBC, Axumin]
             scan will not be required.)

          -  Pathologically node positive disease with nodal involvement only in the pelvis in the
             prostatectomy specimen (including external iliacs, internal iliacs, and/or obturator
             nodes)

          -  History/physical examination within 90 days prior to registration

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 90 days
             prior to registration

          -  Detectable PSA after radical prostatectomy. Detectable PSA is defined as serum PSA > 0
             ng/mL at least 30 days after prostatectomy and within 90 days of registration and
             before start of GnRH agonist/antagonist

          -  Patients who have already started on post-prostatectomy GnRH agonist/antagonist for =<
             45 days prior to registration are eligible (Note: patients who started on an oral
             antiandrogen are eligible if started =< 45 days and stopped prior to registration)

          -  Hemoglobin >= 9.0 g/dL, independent of transfusion and/or growth factors (within 90
             days prior to registration)

          -  Platelet count >= 100,000 x 10^9/uL independent of transfusion and/or growth factors
             (within 90 days prior to registration)

          -  Serum potassium >= 3.5 mmol/L within 90 days prior to registration

          -  Creatinine clearance (CrCl) >= 30 mL/min estimated by Cockcroft-Gault (please use
             actual weight for calculation unless greater than 30% above ideal body weight then use
             the adjusted body weight) (within 90 days prior to registration)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (Note: In subjects
             with Gilbert?s syndrome, if total bilirubin is > 1.5 x ULN, measure direct and
             indirect bilirubin and if direct bilirubin is =< 1.5 x ULN, subject is eligible)
             (within 90 days prior to registration)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             institutional ULN (within 90 days prior to registration)

          -  Serum albumin >= 3.0 g/dL (within 90 days prior to registration)

          -  Discontinue or substitute concomitant medications known to lower the seizure threshold
             at least 30 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 (didanosine [DDI] is not permitted) with undetectable viral load within 6
             months are eligible for this trial and have a CD4 count >= 200 cells/microliter within
             30 days prior to registration. Note: HIV testing is not required for eligibility for
             this protocol

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy within 30 days prior to registration,
             if indicated. Note: HBV viral testing is not required for eligibility for this
             protocol

          -  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 30 days prior to
             registration

          -  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) who has no evidence of
             disease for < 3 years must contact the principal investigator, Ron Chen, Doctor of
             Medicine (MD)

          -  The patient or a legally authorized representative must provide study-specific
             informed consent prior to study entry

        Exclusion Criteria:

          -  Definitive radiologic evidence of metastatic disease (M1a, M1b or M1c) on molecular
             imaging (e.g. fluciclovine F-18 PET, PSMA, F-18 choline 11)

          -  Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a
             different cancer is allowed (completed > 3 years prior to registration)

          -  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

          -  Didanosine (DDI) antiretroviral therapy is not permitted

          -  History of any of the following:

               -  Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke
                  within 1 year prior to registration, brain arteriovenous malformation,
                  Schwannoma, meningioma, or other benign central nervous system [CNS] or meningeal
                  disease which may require treatment with surgery or radiation therapy)

               -  Severe or unstable angina, myocardial infarction, arterial or venous
                  thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident
                  including transient ischemic attacks), or clinically significant ventricular
                  arrhythmias within 6 months prior to registration

               -  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

          -  Current evidence of any of the following:

               -  Known gastrointestinal disorder affecting absorption of oral medications

               -  Active uncontrolled infection

               -  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

               -  Any chronic medical condition requiring a higher dose of corticosteroid than 10
                  mg prednisone/prednisolone once daily

               -  Baseline moderate and severe hepatic impairment (Child-Pugh Class B & C)

               -  Inability to swallow oral pills

               -  Any current condition that in the opinion of the investigator, would preclude
                  participation in this study

          -  Patients must not plan to participate in any other therapeutic clinical trials while
             receiving treatment on this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Metastasis-free survival (MFS)
Time Frame:From randomization to detection of metastatic disease or death from any cause, assessed up to 7.5 years
Safety Issue:
Description:Kaplan-Meier (1958) curves will be generated and metastasis-free survival compared between the two treatment groups by a logrank test, stratified by prostate specific antigen (PSA) level after prostatectomy (never detectable or rising). Cox (1972) regression modeling to assess and adjust for the effects of PSA stratum and other baseline covariates will also be performed. The proportional hazards assumption will be tested using Schoenfeld residuals (Grambsch and Therneau, 1994) and graphical methods (Kay, 1997). Martingale residual plots will be examined to determine the best functional form for incorporating covariates into the model. A competing risks analysis will also be performed (Dignam et al, 2012) with time to distant metastasis or death from prostate cancer as the event of interest and death from other causes as the competing risk. Cumulative incidence curves will be generated along with Fine-Gray?s test (1999).

Secondary Outcome Measures

Measure:Quality of life (QOL) between the two treatment arms
Time Frame:Up to 3 years post treatment
Safety Issue:
Description:Quality of life scores will be derived by constructing summary measures across domains from the various quality of life instruments (Expanded Prostate Cancer Index Composite-26, EuroQol (EQ)-5 Dimension (D)-5 Level (L), Brief Pain Inventory, and Patient Reported Outcome Measurement Information System-Fatigue). Calculated health utilities will be derived from the EQ-5D-5L instrument and used to produce a quality-adjusted life year survival estimate post-treatment. The area under the curve provides an estimate of the quality-adjusted, restricted mean survival time and will be compared between the two treatment arms as described in Glasziou et al (1990). QOL scores will be analyzed using mixed effects regression for longitudinal data to compare the profiles over time between the two treatment groups (Gibbons and Hedeker, 2000). The models will include treatment, time, and treatment-by-time interaction terms as fixed effects and subjects as a random effect.
Measure:Overall survival
Time Frame:From randomization until date of death or censored at last date known alive, assessed up to 7.5 years
Safety Issue:
Description:Will be summarized by Kaplan-Meier curves and compared between treatment groups via logrank tests and Cox regression modeling.
Measure:Biochemical progression-free survival (bPFS)
Time Frame:From randomization until biochemical recurrence or death from prostate cancer, assessed up to 7.5 years
Safety Issue:
Description:Will be summarized by Kaplan-Meier curves and compared between treatment groups via logrank tests and Cox regression modeling. In addition, competing risks analyses will be performed and cumulative incidence curves generated for bPFS with death from other (i.e., non-prostate cancer) causes treated as a competing event.
Measure:Time to local-regional progression
Time Frame:Up to 7.5 years
Safety Issue:
Description:Competing risks analyses will be performed and cumulative incidence curves generated for local-regional progression with death from other (i.e., non-prostate cancer) causes treated as a competing event.
Measure:Time to castrate resistance
Time Frame:Up to 7.5 years
Safety Issue:
Description:Will be summarized by Kaplan-Meier curves and compared between treatment groups via logrank tests and Cox regression modeling.
Measure:Cancer-specific survival
Time Frame:Up to 7.5 years
Safety Issue:
Description:Will be summarized by Kaplan-Meier curves and compared between treatment groups via logrank tests and Cox regression modeling. In addition, competing risks analyses will be performed and cumulative incidence curves generated for cancer-specific survival with death from other (i.e., non-prostate cancer) causes treated as a competing event.
Measure:Incidence of adverse events
Time Frame:Up to 7.5 years
Safety Issue:
Description:Will be assessed by Common Terminology Criteria for Adverse Events version 5.0. Adverse events will be tabulated by type, level of severity, and attribution for each treatment arm and the rate of events compared between treatment groups using chi-square or Fisher?s exact tests.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:NRG Oncology

Trial Keywords

  • Prostate Cancer
  • Apalutamide
  • Abiraterone Acetate

Last Updated

November 26, 2019