Radiation Therapy With or Without Apalutamide in Treating Patients With Recurrent Prostate Cancer, the BALANCE Trial
- Conditions
- Recurrent Prostate CarcinomaStage III Prostate Adenocarcinoma AJCC v7Stage IV Prostate Adenocarcinoma AJCC v7
- Interventions
- Registration Number
- NCT03371719
- Lead Sponsor
- NRG Oncology
- Brief Summary
This phase II trial studies how well radiation therapy with or without apalutamide works in treating patients with prostate cancer that has come back (recurrent). Radiation therapy uses high energy x-ray to kill tumor cells and shrink tumors. Androgen can cause the growth of prostate cancer cells. Drugs, such as apalutamide, may lessen the amount of androgen made by the body. Giving radiation therapy and apalutamide may work better at treating prostate cancer compared to radiation therapy alone.
- Detailed Description
PRIMARY OBJECTIVE:
I. To determine whether, in men with post-prostatectomy prostate-specific antigen (PSA) recurrences, salvage radiation (SRT) with enhanced anti-androgen therapy with apalutamide will improve biochemical progression-free survival (bPFS) compared to SRT alone.
SECONDARY OBJECTIVES:
I. To assess whether molecular stratification by the PAM50 gene expression clustering will identify subsets of prostate cancer (luminal A or basal, luminal B) which derive the greatest benefit from anti-androgen therapy.
II. To assess overall survival. III. To assess cancer-specific mortality. IV. To assess metastasis-free survival. V. To assess distant metastasis. VI. To assess local-regional progression. VII. To assess PSA nadir during first year of treatment and prior to initiation of any hormonal salvage therapy.
VIII. To assess initiation of salvage hormonal therapy. IX. To assess PSA with a non-castrate testosterone at 1 and 3 years post randomization: PSA \< 0.1 ng/ml and testosterone \>= 50 ng/dl.
X. To assess acute and late physician-reported morbidity (per the Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0) after SRT +/- apalutamide.
XI. To assess acute and late patient-reported symptomatic adverse events morbidity (per the patient reported outcomes \[PRO\]-CTCAE) after SRT +/- apalutamide.
XII. To assess testosterone levels at 3, 6, 9, 12, and 36 months post randomization.
EXPLORATORY OBJECTIVE:
I. To assess the prognostic and predictive value of the genomic classifier Decipher.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM 1: Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive placebo orally (PO) once daily (QD) on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
ARM 2: Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive apalutamide PO QD on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years, and then yearly thereafter.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Male
- Target Recruitment
- 324
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Pathologically (histologically) proven diagnosis of prostate adenocarcinoma; prostatectomy must have been performed within 10 years prior to Step 1 registration and any type of radical prostatectomy is permitted, including retropubic, perineal, laparoscopic or robotically assisted
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Post-prostatectomy patients with a detectable serum PSA (>= 0.1, but =< 1.0 ng/mL) at study entry (within 90 days of Step 1 registration) and at least one of the following:
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Gleason score 7-10 (International Society of Urological Pathology [ISUP] grade group 2 to 5)
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ISUP grade group:
- Grade group 1 = Gleason score =< 6,
- Grade group 2 = Gleason score 3 + 4 = 7,
- Grade group 3 = Gleason score 4 + 3 = 7,
- Grade group 4 = Gleason score 8,
- Grade group 5 = Gleason scores 9 and 10
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>= T3a disease
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Persistent elevation of PSA after prostatectomy measured within 90 days after surgery (PSA never became undetectable) of > 0.04 but < 0.2 ng/mL (PSA nadir)
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pN0 or pNx
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History/physical examination within 90 days prior to Step 1 registration
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Karnofsky performance status of 70-100 within 90 days prior to Step 1 registration
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Surgical formalin-fixed paraffin-embedded (FFPE) specimen must be available for submission to GenomeDx for genomic analysis on Decipher GRID platform; Note: if Decipher results have already been obtained, in lieu of tissue, results must be submitted to GenomeDx for validation and for GenomeDx to provide the subtyping needed for stratification
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Prior androgen deprivation therapy (luteinizing hormone-releasing hormone [LHRH] agonist and/or non-steroidal anti-androgen) is allowed if discontinued at least 90 days prior to Step 1 registration and given for =< 90 days duration
- For example: patients on prior LHRH analogs (post-prostatectomy), the discontinuation date should be calculated based on the expected duration of the sustained release injection, not simply the injection date of the drug; for instance, if a 22.5 mg sustained release dose of leuprolide acetate is given (3 month duration), then the expected duration of such a dose would be 90 days after the injection date; for a 7.5 mg leuprolide (1 month duration), the discontinuation date would be 30 days after the injection date
- Please note: finasteride or dutasteride must be stopped before treatment starts but prior usage will not affect eligibility
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Hemoglobin >= 9.0 g/dL, independent of transfusion and/or growth factors within 90 days prior to Step 1 registration
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Platelet count >= 100,000 x 10^9/uL independent of transfusion and/or growth factors within 90 days prior to Step 1 registration
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Serum albumin >= 3.0 g/dL within 90 days prior to Step 1 registration
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Glomerular filtration rate (GFR) >= 35 mL/min estimated by Cockcroft-Gault or measured directly by 24 hour urine creatinine within 90 days prior to Step 1 registration
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Serum total bilirubin =< 1.5 x 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 Step 1 registration
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Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 x ULN within 90 days prior to Step 1 registration
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Testosterone > 50 ng/dL within 90 days prior to Step 1 registration
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Concomitant medications known to lower the seizure threshold discontinued or substituted at least 4 weeks (30 days) prior to Step 1 registration
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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
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The patient must agree not to donate sperm during the study treatment and for 3 months after receiving the last dose of study drug
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The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
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PRIOR TO STEP 1 REGISTRATION:
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Definitive clinical, radiologic, or pathologic evidence of metastatic disease (M1) or lymph node involvement (N1)
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Prior invasive malignancy (except non-melanomatous skin cancer, carcinoma in situ of the male breast, penis, oral cavity, or stage Ta of the bladder, or stage I completely resected melanoma) unless disease free for a minimum of 2 years
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Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable
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Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
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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 Step 1 registration)
- History of documented inflammatory bowel disease
- Transmural myocardial infarction within the last 4 months prior to Step 1 registration
- Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months prior to Step 1 registration
- History of any condition that in the opinion of the investigator, would preclude participation in this study
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Current evidence of any of the following:
- Known gastrointestinal disorder affecting absorption of oral medications
- Active uncontrolled infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis)
- Uncontrolled hypertension
- Any current condition that in the opinion of the investigator, would preclude participation in this study
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Prior whole gland ablative therapy (i.e. cryoablation or high intensity focused ultrasound [HIFU]) for prostate cancer is not allowed
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HIV positive with CD4 count < 200 cells/microliter within 30 days prior to registration
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HIV patients under treatment with highly active antiretroviral therapy (HAART) within 30 days prior to registration regardless of CD4 count; (Note: HIV testing is not required for eligibility for this protocol as it is self-reported; this exclusion criterion is necessary because the treatments involved in this protocol may be immunosuppressive and/or interact with HAART)
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Patients must not plan to participate in any other clinical trials while receiving treatment on this study or being followed post-protocol therapy
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PRIOR TO STEP 2 REGISTRATION:
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For patients who have not undergone prior Decipher analysis, submission of the specimen to GenomeDx should be as soon as possible after study registration (Step 1) as these results can take up 21 days after the specimen is received at GenomeDx; Step 2 registration must occur within 6 weeks (42 days) of Step 1 registration; if Decipher results have already been obtained, in lieu of tissue, results must be submitted to GenomeDx for validation
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm 1 (radiation therapy, placebo) External Beam Radiation Therapy Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive placebo PO QD on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Arm 1 (radiation therapy, placebo) Placebo Administration Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive placebo PO QD on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Arm 2 (radiation therapy, apalutamide) Apalutamide Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive apalutamide PO QD on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Arm 2 (radiation therapy, apalutamide) External Beam Radiation Therapy Patients undergo external beam radiation therapy on day 1 for 7-8 weeks. Beginning on day of radiation therapy, patients receive apalutamide PO QD on days 1-30. Treatment repeats every 30 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
- Primary Outcome Measures
Name Time Method Biochemical progression-free survival (bPFS) From randomization to the first occurrence of a rise in PSA, clinical or radiographic local, regional, or distant metastases, or death from any cause, assessed up to 5 years bPFS curves will be estimated by the Kaplan-Meier (1958) method and compared between the two treatment arms using a one-sided logrank test at the alpha = 0.12 significance level. In addition, a multivariable Cox regression model will be fit incorporating the three stratification factors used in the randomization (surgical margins, pre-salvage radiation \[SRT\] PSA, and molecular subtype) as covariates to estimate the adjusted hazard ratio (HR) between the two treatment groups. Additional regression models will be fit including other pretreatment characteristics as covariates. The goodness-of-fit of the proportional hazards assumption will be evaluating using graphical methods (Kay, 1977), residual plots, and the global test proposed by Grambsch and Therneau (1994). Missing covariates will be handled using multiple imputation as described in White and Royston (1982).
- Secondary Outcome Measures
Name Time Method Initiation of salvage hormonal therapy Up to 5 years Will also be analyzed under a competing risks framework, treating death without experiencing the event in question as a competing risk.
Undetectable PSA with a non-castrate testosterone (PSA < 0.1 ng/ml and testosterone >= 50 ng/dl)) 3 years Will be compared using chi square tests.
Acute patient-reported morbidity symptomatic adverse events (per the patient reported outcomes [PRO]-CTCAE) Up to 5 years Adverse events will also be assessed using PRO-CTCAE items. Assessments will be collected before and at the end of radiotherapy treatment and in follow-up. For each symptom and each domain (i.e., frequency, severity, and interference), counts and frequencies will be provided for the worst score experienced by the patient by treatment arm. The proportion of patients with scores \>= 1 and \>= 3 will be compared between groups using a chi-square test, or Fisher's exact test if cell frequencies are \< 5.
Overall survival (OS) From randomization until death from any cause, assessed up to 5 years OS will be estimated by the Kaplan-Meier method and compared between treatment arms via the logrank test. Cox regression will be used to obtain HRs for this outcome, both unadjusted and adjusted for covariates.
Metastasis-free survival (MFS) From randomization until distant metastasis (clinical and/or radiographic appearance of disseminated disease) or death from any cause, assessed up to 5 years MFS will be estimated by the Kaplan-Meier method and compared between treatment arms via the logrank test. Cox regression will be used to obtain HRs for this outcome, both unadjusted and adjusted for covariates. A competing risks analysis will be performed treating death from prostate cancer as the event of interest and death from all other causes as a competing risk. Cumulative incidence curves will be generated (Gooley et al., 1999; Dignam et al., 2004) along with 95% confidence intervals and compared between the two treatment arms using Gray's method (Gray, 1988). In addition, multivariable analysis will be conducted using Fine and Gray's regression model (Fine and Gray, 1999) to derive covariate-adjusted (subdistribution) HRs and confidence intervals.
Local-regional progression From randomization to local or regional recurrence ignoring biochemical failure and distant recurrence and censoring for death, assessed up to 5 years Will also be analyzed under a competing risks framework, treating death without experiencing the event in question as a competing risk.
Undetectable PSA with a non-castrate testosterone (PSA < 0.1 ng/ml and testosterone >= 50 ng/dl) 1 year Will be compared using chi square tests.
Acute physician-reported morbidity (per the Common Terminology Criteria for Adverse Events [CTCAE] version 5) Up to 30 days after radiation therapy Adverse events will be scored according to the National Cancer Institute (NCI)'s CTCAE version 5.0. For each type of adverse event, counts and frequencies will be provided for the worst grade experienced by the patient by treatment arm. The proportion of patients with grades \>= 1 and \>= 3 will be compared between groups using a chi-square test, or Fisher's exact test if cell frequencies are \< 5, at the two-sided 0.05 significance level. Logistic regression, both univariate and multivariate, will be used to model the probability of grade 3+ acute adverse events as a function of treatment arm and covariates. Both unadjusted and adjusted odds ratios and the respective 95% confidence intervals will be computed.
Late physician-reported morbidity (per the CTCAE version 5) defined as grade 3+ adverse events occurring more than 30 days after the completion of radiation therapy From the time protocol treatment started to the time of the first recorded late grade 3+ adverse event, assessed up to 5 years Adverse events will be scored according to the NCI's CTCAE version 5.0. For each type of adverse event, counts and frequencies will be provided for the worst grade experienced by the patient by treatment arm. The proportion of patients with grades \>= 1 and \>= 3 will be compared between groups using a chi-square test, or Fisher's exact test if cell frequencies are \< 5, at the two-sided 0.05 significance level.
Late patient-reported morbidity symptomatic adverse events (per the PRO-CTCAE) Up to 5 years Adverse events will also be assessed using PRO-CTCAE items. Assessments will be collected before and at the end of radiotherapy treatment and in follow-up. For each symptom and each domain (i.e., frequency, severity, and interference), counts and frequencies will be provided for the worst score experienced by the patient by treatment arm. The proportion of patients with scores \>= 1 and \>= 3 will be compared between groups using a chi-square test, or Fisher's exact test if cell frequencies are \< 5.
PSA nadir during first year of treatment and prior to initiation of any hormonal salvage therapy During first year of treatment Will be compared between the two groups using a two-sample t-test.
Distant metastasis Up to 5 years Will also be analyzed under a competing risks framework, treating death without experiencing the event in question as a competing risk.
Cancer-specific mortality (CSM) From the date of randomization to the date of death due to prostate cancer, assessed up to 5 years CSM will be estimated by the Kaplan-Meier method and compared between treatment arms via the logrank test. Cox regression will be used to obtain HRs for this outcome, both unadjusted and adjusted for covariates. A competing risks analysis will be performed treating death from prostate cancer as the event of interest and death from all other causes as a competing risk. Cumulative incidence curves will be generated (Gooley et al., 1999; Dignam et al., 2004) along with 95% confidence intervals and compared between the two treatment arms using Gray's method (Gray, 1988). In addition, multivariable analysis will be conducted using Fine and Gray's regression model (Fine and Gray, 1999) to derive covariate-adjusted (subdistribution) HRs and confidence intervals.
Testosterone levels Every 3 months until 6 months post treatment Testosterone levels will be assessed.
Trial Locations
- Locations (363)
Arizona Center for Cancer Care - Gilbert
🇺🇸Gilbert, Arizona, United States
Arizona Center for Cancer Care-Peoria
🇺🇸Peoria, Arizona, United States
Arizona Center for Cancer Care - Scottsdale
🇺🇸Scottsdale, Arizona, United States
Arizona Center for Cancer Care-Surprise
🇺🇸Surprise, Arizona, United States
University of Arkansas for Medical Sciences
🇺🇸Little Rock, Arkansas, United States
Alta Bates Summit Medical Center-Herrick Campus
🇺🇸Berkeley, California, United States
Marin General Hospital
🇺🇸Greenbrae, California, United States
Los Angeles General Medical Center
🇺🇸Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
Cedars Sinai Medical Center
🇺🇸Los Angeles, California, United States
Scroll for more (353 remaining)Arizona Center for Cancer Care - Gilbert🇺🇸Gilbert, Arizona, United States