BIOMARKER TRIAL of APALUTAMIDE and RADIATION for RECURRENT PROSTATE CANCER

Study Overview
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Brief Summary
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This phase II trial studies how well radiation therapy with or without apalutamide works in treating patients with stage III-IV prostate cancer. 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 than radiation alone.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine whether, in men with post-prostatectomy 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) after SRT +/- apalutamide. XI. To assess acute and late patient-reported 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. OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: Patients undergo external beam radiation therapy on Day 1 for 7.5 weeks. Beginning on Day 1 of radiation therapy, patients receive placebo orally (PO) once daily (QD) on days 1-30. Treatment repeats every 30 days for up to 6 courses (6 months) in the absence of disease progression or unacceptable toxicity. ARM 2: Patients undergo external beam radiation therapy on Day 1 for 7.5 weeks. Beginning on Day 1 of radiation therapy, patients receive apalutamide PO QD on Days 1-30. Treatment repeats every 30 days for up to 6 courses (6 months) 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.

Official Title
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A Phase II, Double-Blinded, Placebo Controlled Randomized Trial of Salvage Radiotherapy With or Without Enhanced Anti-androgen Therapy With Apalutamide in Recurrent Prostate Cancer

Conditions
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PSA Progression, Stage III Prostate Adenocarcinoma, Stage IV Prostate Adenocarcinoma

Intervention / Treatment
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* Drug: Apalutamide
* Radiation: External Beam Radiation Therapy
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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: Gleason score 7-10 (International Society of Urological Pathology [ISUP] grade group 2 to 5) 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 >= T3a disease 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) pN0 or pNx History/physical examination within 90 days prior to Step 1 registration Karnofsky performance status of 70-100 within 90 days prior to Step 1 registration 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 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 Hemoglobin ≥ 9.0 g/dL, independent of transfusion and/or growth factors within 90 days prior to Step 1 registration Platelet count ≥ 100,000 x 10^9/uL independent of transfusion and/or growth factors within 90 days prior to step 1 registration Serum albumin ≥ 3.0 g/dL within 90 days prior to Step 1 registration 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 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 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 x ULN within 90 days prior to Step 1 registration Testosterone > 50 ng/dL within 90 days prior to Step 1 registration Concomitant medications known to lower the seizure threshold discontinued or substituted at least 4 weeks (30 days) prior to Step 1 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 The patient must agree not to donate sperm during the study treatment and for 3 months after receiving the last dose of study drug The patient or a legally authorized representative must provide study-specific informed consent prior to study entry Exclusion Criteria: Definitive clinical, radiologic, or pathologic evidence of metastatic disease (M1) or lymph node involvement (N1) 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 Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields 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 Current evidence of any of the following: Known gastrointestinal disorder affecting absorption of oral medications Active uncontrolled infection (eg, 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 Prior whole gland ablative therapy (i.e. cryoablation or high intensity focused ultrasound [HIFU]) for prostate cancer is not allowed HIV positive with CD4 count < 200 cells/microliter within 30 days prior to registration 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.) 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 Patients must not plan to participate in any other clinical trials while receiving treatment on this study or being followed post-protocol therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Arm 1 (Radiation Therapy + Placebo)<br>Patients undergo external beam radiation therapy on Day 1 for 7.5 weeks. Beginning on Day 1 of radiation therapy, patients receive placebo PO QD on Days 1-30. Treatment repeats every 30 days for up to 6 courses (6 months) in the absence of disease progression or unacceptable toxicity. | Radiation: External Beam Radiation Therapy<br>* Undergo external beam radiation therapy<br>* Other names: external-beam radiation;Other: Placebo<br>* Given PO<br>* Other names: sham therapy;|
| Experimental: Arm 2 (Radiation Therapy + Apalutamide)<br>Patients undergo external beam radiation therapy on Day 1 for 7.5 weeks. Beginning on Day 1 of radiation therapy, patients receive apalutamide PO QD on Days 1-30. Treatment repeats every 30 days for up to 6 courses (6 months)in the absence of disease progression or unacceptable toxicity. | Drug: Apalutamide<br>* Given PO<br>* Other names: JNJ-56021927;Radiation: External Beam Radiation Therapy<br>* Undergo external beam radiation therapy<br>* Other names: external-beam radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. Analysis will include evaluation of a potential predictive biomarker (molecular subtype) to inform the design of a subsequent, phase III clinical trial. In addition, a multivariable Cox (1972) 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. | 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 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Patient-Reported Morbidity (per the patient reported outcomes [PRO]- Common Terminology Criteria for Adverse Events [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. | Up to 30 days after radiation therapy | 
| 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, 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. | Up to 30 days after radiation therapy | 
| Late Patient-Reported Morbidity (per the patient reported outcomes [PRO]- Common Terminology Criteria for Adverse Events [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. | From the end of radiation therapy + 30 days up to 6 years | 
| Late Physician-Reported Morbidity (per the Common Terminology Criteria for Adverse Events [CTCAE] version 4) 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. | From the end of radiation therapy + 30 days to the time of the first recorded late grade 3+ adverse event, assessed up to 6 years | 
| Cancer-Specific Mortality (CSM) | CSM will be estimated by the Kaplan-Meier method and compared between treatment arms via the logrank test. Patients dying from other causes will be censored as of the date of death. Cox regression will be used to obtain HRs for this outcome, both unadjusted and adjusted for covariates. A competing risks analysis will also be performed treating death from prostate cancer and death from all other causes as competing risks. 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). | From the date of randomization to the date of death due to prostate cancer, assessed up to 6 years | 
| Distant Metastasis | Will also be analyzed under a competing risks framework, treating death without experiencing the event in question as a competing risk. | Up to 6 years | 
| 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. | Up to 6 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. | From randomization to local or regional recurrence, assessed up to 6 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. | From randomization until distant metastasis (clinical and/or radiographic appearance of disseminated disease) or death from any cause, assessed up to 6 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. | From randomization until death from any cause, assessed up to 6 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. | During first year of treatment | 
| Testosterone Levels | Testosterone levels over time will be assessed using mixed effects regression modeling. | Every 3 months until 36 months post randomization | 
| Undetectable PSA with a Non-Castrate Testosterone (PSA < 0.1 ng/ml and testosterone >= 50 ng/dl) | The proportion of patients with undetectable PSA and non-castrate testosterone level will be compared between the two treatment arms using chi square tests. | 1 year | 
| Undetectable PSA with a Non-Castrate testosterone (PSA < 0.1 ng/ml and testosterone >= 50 ng/dl)) | The proportion of patients with undetectable PSA and non-castrate testosterone level will be compared between the two treatment arms using chi square tests. | 3 years |