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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
324
Given PO
Undergo external beam radiation therapy
Given PO
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
Biochemical progression-free survival (bPFS)
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).
Time frame: 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
Overall survival (OS)
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.
Time frame: From randomization until death from any cause, assessed up to 5 years
Cancer-specific mortality (CSM)
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.
Time frame: From the date of randomization to the date of death due to prostate cancer, assessed up to 5 years
Metastasis-free survival (MFS)
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.
Time frame: From randomization until distant metastasis (clinical and/or radiographic appearance of disseminated disease) or death from any cause, assessed up to 5 years
Distant metastasis
Will also be analyzed under a competing risks framework, treating death without experiencing the event in question as a competing risk.
Time frame: Up to 5 years
Local-regional progression
Will also be analyzed under a competing risks framework, treating death without experiencing the event in question as a competing risk.
Time frame: From randomization to local or regional recurrence ignoring biochemical failure and distant recurrence and censoring for death, assessed up to 5 years
PSA nadir during first year of treatment and prior to initiation of any hormonal salvage therapy
Will be compared between the two groups using a two-sample t-test.
Time frame: During first year of treatment
Initiation of salvage hormonal therapy
Will also be analyzed under a competing risks framework, treating death without experiencing the event in question as a competing risk.
Time frame: Up to 5 years
Undetectable PSA with a non-castrate testosterone (PSA < 0.1 ng/ml and testosterone >= 50 ng/dl)
Will be compared using chi square tests.
Time frame: 1 year
Undetectable PSA with a non-castrate testosterone (PSA < 0.1 ng/ml and testosterone >= 50 ng/dl))
Will be compared using chi square tests.
Time frame: 3 years
Acute physician-reported morbidity (per the Common Terminology Criteria for Adverse Events [CTCAE] version 5)
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.
Time frame: Up to 30 days after radiation therapy
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
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.
Time frame: From the time protocol treatment started to the time of the first recorded late grade 3+ adverse event, assessed up to 5 years
Testosterone levels
Testosterone levels will be assessed.
Time frame: Every 3 months until 6 months post treatment
Acute patient-reported morbidity symptomatic adverse events (per the patient reported outcomes [PRO]-CTCAE)
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.
Time frame: Up to 5 years
Late patient-reported morbidity symptomatic adverse events (per the PRO-CTCAE)
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.
Time frame: Up to 5 years
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