October 18, 2019
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October 22, 2019
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February 7, 2024
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March 5, 2020
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November 1, 2026 (Final data collection date for primary outcome measure)
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Metastasis-free survival (MFS) [ Time Frame: From randomization to detection of metastatic disease or death from any cause, assessed up to 7.5 years ] Kaplan-Meier 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 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 and graphical methods. 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 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. Patients alive and metastasis free will be censored as of the time of the last negative examination.
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Metastasis-free survival (MFS) [ Time Frame: From randomization to detection of metastatic disease or death from any cause, assessed up to 7.5 years ] 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).
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- Quality of life (QOL) between the two treatment arms [ Time Frame: Up to 3 years post treatment ]
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.
- Overall survival (OS) [ Time Frame: From randomization until date of death or censored at last date known alive, assessed up to 7.5 years ]
Will be summarized by Kaplan-Meier curves and compared between treatment groups via logrank tests and Cox regression modeling.
- Biochemical progression-free survival (bPFS) [ Time Frame: From randomization until biochemical recurrence or death from prostate cancer, assessed up to 7.5 years ]
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. Patients who die from non-prostate cancer related causes will be censored as of the date of death.
- Time to local-regional progression [ Time Frame: Up to 7.5 years ]
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.
- Time to castrate resistance [ Time Frame: Up to 7.5 years ]
Will be summarized by Kaplan-Meier curves and compared between treatment groups via logrank tests and Cox regression modeling. Patients who die prior to resistance will be censored.
- Cancer-specific survival [ Time Frame: Up to 7.5 years ]
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. Patients who die from non-prostate cancer related causes will be censored as of the date of death.
- Incidence of adverse events [ Time Frame: Up to 7.5 years ]
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.
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- Quality of life (QOL) between the two treatment arms [ Time Frame: Up to 3 years post treatment ]
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.
- Overall survival [ Time Frame: From randomization until date of death or censored at last date known alive, assessed up to 7.5 years ]
Will be summarized by Kaplan-Meier curves and compared between treatment groups via logrank tests and Cox regression modeling.
- Biochemical progression-free survival (bPFS) [ Time Frame: From randomization until biochemical recurrence or death from prostate cancer, assessed up to 7.5 years ]
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.
- Time to local-regional progression [ Time Frame: Up to 7.5 years ]
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.
- Time to castrate resistance [ Time Frame: Up to 7.5 years ]
Will be summarized by Kaplan-Meier curves and compared between treatment groups via logrank tests and Cox regression modeling.
- Cancer-specific survival [ Time Frame: Up to 7.5 years ]
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.
- Incidence of adverse events [ Time Frame: Up to 7.5 years ]
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.
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- MFS by Decipher genomic score [ Time Frame: Up to 7.5 years ]
Will determine the ability of the Decipher test to predict for metastasis in a purely node-positive population. Subgroup analyses of MFS by Decipher genomic score (high risk or low/intermediate risk) will be performed and tests for treatment-by-risk group interaction conducted via Cox regression to explore whether any benefits of apalutamide is limited to the high (or low/intermediate) risk stratum.
- OS by Decipher genomic score [ Time Frame: Up to 7.5 years ]
Will determine the ability of the Decipher test to predict for metastasis in a purely node-positive population. Subgroup analyses of OS by Decipher genomic score (high risk or low/intermediate risk) will be performed and tests for treatment-by-risk group interaction conducted via Cox regression to explore whether any benefits of apalutamide is limited to the high (or low/intermediate) risk stratum.
- PAM50-based classification of prostate cancer [ Time Frame: Up to 7.5 years ]
Will validate the PAM50-based classification of prostate cancer into luminal A, luminal B, and basal subtypes as prognostic markers. Classifications of prostate cancer into Luminal A, Luminal B, and basal subtypes using the PAM50 method of classification. Subgroup analyses will be performed and tests for treatment-by-risk group interaction conducted via Cox regression to explore whether any benefits of apalutamide is limited to the high (or low/intermediate) risk stratum.
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- MFS by Decipher genomic score [ Time Frame: Up to 7.5 years ]
Will determine the ability of the Decipher test to predict for metastasis in a purely node-positive population. Subgroup analyses of MFS and overall survival by Decipher genomic score (high risk or low/intermediate risk) will be performed and tests for treatment-by-risk group interaction conducted via Cox regression to explore whether any benefits of abiraterone acetate with prednisone and apalutamide are limited to the high (or low/intermediate) risk stratum.
- PAM50-based classification of prostate cancer [ Time Frame: Up to time of recurrence, assessed up to 7.5 years ]
Will validate the PAM50-based classification of prostate cancer into luminal A, luminal B, and basal subtypes as prognostic markers. Classifications of prostate cancer into Luminal A, Luminal B, and basal subtypes using the PAM50 method of classification. Subgroup analyses will be performed and tests for treatment-by-risk group interaction conducted via Cox regression to explore whether any benefits of abiraterone acetate with prednisone and apalutamide are limited to the high (or low/intermediate) risk stratum.
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Testing the Addition of the Drug Apalutamide to the Usual Hormone Therapy and Radiation Therapy After Surgery for Prostate Cancer
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Randomized Phase III Trial Incorporating Apalutamide and Advanced Imaging Into Salvage Treatment for Patients With Node-Positive Prostate Cancer After Radical Prostatectomy (INNOVATE*) *INtensifying Treatment for NOde Positive Prostate Cancer by VArying the Hormonal ThErapy
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This phase III trial studies whether adding apalutamide to the usual treatment improves outcome in patients with lymph 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 reduce the growth of prostate cancer cell growth by blocking the attachment of androgen to its receptors on cancer cells, a mechanism similar to stopping the entrance of a key into its lock. Adding apalutamide to the usual hormone therapy and radiation therapy after surgery may stabilize prostate cancer and prevent it from spreading and extend time without disease spreading compared to the usual approach.
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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 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 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 5-6 or 7-8 weeks beginning within 90 days of randomization 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) 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.
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Interventional
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Phase 3
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Allocation: Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment
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- Prostate Adenocarcinoma
- 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
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- Active Comparator: Arm I (hormone therapy, radiation therapy)
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 5-6 or 7-8 weeks beginning within 90 days of randomization in the absence of disease progression or unacceptable toxicity.
Interventions:
- Drug: Hormone Therapy
- Other: Quality-of-Life Assessment
- Other: Questionnaire Administration
- Radiation: Radiation Therapy
- Experimental: Arm II (hormone therapy, radiation therapy, apalutamide)
Patients undergo standard of care hormone therapy and radiation therapy as in Arm I. Patients also receive apalutamide PO QD on days 1-90. Cycles repeat every 90 days for 8 cycles in the absence of disease progression or unacceptable toxicity.
Interventions:
- Drug: Apalutamide
- Drug: Hormone Therapy
- Other: Quality-of-Life Assessment
- Other: Questionnaire Administration
- Radiation: Radiation Therapy
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Not Provided
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Recruiting
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586
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Same as current
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November 1, 2026
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November 1, 2026 (Final data collection date for primary outcome measure)
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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 (American Joint Committee on Cancer [AJCC] 8th edition [ed])
- 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; however, if the patient has already had a recent F-18 PSMA PET (PyLarify) scan or 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); peri-prostatic and peri-rectal nodes can also be considered regional lymphadenopathy and are allowed
- 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 180 days of registration and before start of GnRH agonist/antagonist
- Patients who have already started on post-prostatectomy GnRH agonist/antagonist for =< 180 days prior to registration are eligible (Note: patients who started on an oral antiandrogen are eligible if started =< 180 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 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, Ronald Chen, Doctor of Medicine (MD)
- The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
Exclusion Criteria:
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Sexes Eligible for Study: |
Male |
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18 Years and older (Adult, Older Adult)
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No
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United States
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NCT04134260
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NRG-GU008 NCI-2019-06838 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) NRG-GU008 ( Other Identifier: NRG Oncology ) NRG-GU008 ( Other Identifier: CTEP ) U10CA180868 ( U.S. NIH Grant/Contract )
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Yes
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Studies a U.S. FDA-regulated Drug Product: |
Yes |
Studies a U.S. FDA-regulated Device Product: |
No |
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Not Provided
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NRG Oncology
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Same as current
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NRG Oncology
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Same as current
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National Cancer Institute (NCI)
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Principal Investigator: |
Ronald C Chen |
NRG Oncology |
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NRG Oncology
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February 2024
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