An Efficacy and Safety Study of JNJ-56021927 (Apalutamide) in High-risk Prostate Cancer Subjects Receiving Primary Radiation Therapy: ATLAS

Study Overview
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Brief Summary
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The purpose of this study is to determine if apalutamide plus gonadotropin releasing hormone (GnRH) agonist in participants with high-risk, localized or locally advanced prostate cancer receiving primary radiation therapy results in an improvement of metastasis-free survival.

Detailed Description
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This is a randomized, double-blind, placebo-controlled, multicenter study of apalutamide plus GnRH agonist compared with GnRH agonist among participants with high-risk, localized or locally advanced prostate cancer receiving primary radiation therapy (RT). The study will include a Screening Phase, Treatment Phase, a Posttreatment Phase, and a Long-term Follow-up Phase. Participants will either receive either apalutamide (experimental) or bicalutamide 50 milligram (mg) capsule plus placebo as control group. Safety will be monitored throughout the study.

Official Title
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ATLAS: A Randomized, Double-blind, Placebo-controlled Phase 3 Study of JNJ-56021927 in Subjects With High-risk, Localized or Locally Advanced Prostate Cancer Receiving Treatment With Primary Radiation Therapy

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: Apalutamide
* Drug: Bicalutamide
* Drug: Bicalutamide Placebo
* Drug: Apalutamide Placebo
* Drug: GnRH (agonist)
* Radiation: 74-80 Grays (units of radiation)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years Indicated and planned to receive primary radiation therapy for prostate cancer Histologically confirmed adenocarcinoma of an intact prostate, and 1 of the following at diagnosis: 1) Gleason score >=8 and >=cT2c, 2) Gleason score >=7, PSA >=20 nanogram per milliliters (ng/mL), and >=cT2c Charlson index (CCI) <=3 An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) grade of 0 or 1 Adequate organ function: (1) aspartate aminotransferase (AST), alanine aminotransferase (ALT), within normal limits (WNL), (2) serum creatinine less than (<) 1.5 milligram/deciliter (mg/dL) (<133 micromoles/Liter [mcmol/L]), (3) platelets greater than or equal to (>=)140,000/microLiter (mcL), independent of transfusion and/or growth factors within 3 months prior to randomization, (4) Hemoglobin >= 12.0 gram/deciliter (g/dL) (7.4 millimloes [mmol], independent of transfusion and/or growth factors within 3 months prior to randomization Participants who are sexually active (even men with vasectomies) and willing to use a condom and agree not to donate sperm during the trial Signed, written, informed consent Be able to swallow whole study drug tablets Exclusion Criteria: - Presence of distant metastasis, (clinical stage M1). Isolated pelvic nodal disease below the iliac bifurcation (clinical stage N1) is not an exclusion. Diagnosis of distant metastasis (clinical M stage; M0 versus M1a, M1b, M1c) and pelvic nodal disease (clinical N stage; N1 versus N0) will be assessed by central radiological review. Patients are considered eligible only if the central radiological review confirms clinical stage M0. Prior treatment with gonadotropin releasing hormone (GnRH) analogue or anti-androgen or both for >3 months prior to randomization Bilateral orchiectomy History of pelvic radiation Prior systemic (example [e.g.], chemotherapy) or local (e.g. radical prostatectomy, cryotherapy) treatment for prostate cancer History of seizure or any condition that may predispose to seizure (including, but not limited to prior stroke, transient ischemic attack or loss of consciousness <= 1 year prior to randomization; brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect) Prior treatment with enzalutamide, abiraterone acetate, orteronel, galeterone, ketoconazole, aminoglutethimide, estrogens, megestrol acetate, and progestational agents (including cyproterone acetate) for prostate cancer Prior treatment with radiopharmaceutical agents (e.g., strontium-89) or immunotherapy (e.g., sipuleucel-T) for prostate cancer Prior treatment with systemic glucocorticoids ≤4 weeks prior to randomization or is expected to require long-term use of corticosteroids during the study Use of 5-alpha reductase inhibitors (e.g., dutasteride, finasteride) <=4 weeks prior to randomization Use of any investigational agent <=4 weeks prior to randomization Current chronic use of opioid analgesics for >=3 weeks for oral or >7 days for non-oral formulations Major surgery <=4 weeks prior to randomization Current or prior treatment with anti-epileptic medications for the treatment of seizures Gastrointestinal conditions affecting absorption Known or suspected contraindications or hypersensitivity to apalutamide, bicalutamide or GnRH agonists or any of the components of the formulations Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject

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 |
| --- | --- |
| Experimental: Apalutamide<br>Participants will receive apalutamide (240 mg), by mouth, once daily for overall 30 months, plus bicalutamide placebo, by mouth, once daily, for four months from randomization. All participants are treated with gonadotropin releasing hormone (GnRH) agonist for 30 months from randomization and radiation therapy to the prostate started at about 8 weeks after randomization. | Drug: Apalutamide<br> <br> Drug: Bicalutamide Placebo<br> <br> Drug: GnRH (agonist)<br> <br> Radiation: 74-80 Grays (units of radiation)<br> <br> |
| Active Comparator: Control group<br>Participants will receive apalutamide placebo, by mouth, once daily for overall 30 months, plus bicalutamide (50 mg), by mouth, once daily, for four months from randomization. All participants are treated with gonadotropin releasing hormone (GnRH) agonist for 30 months from randomization and radiation therapy to the prostate started at about 8 weeks after randomization. | Drug: Bicalutamide<br> <br> Drug: Apalutamide Placebo<br> <br> Drug: GnRH (agonist)<br> <br> Radiation: 74-80 Grays (units of radiation)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metastasis-free survival | Metastasis-free survival is defined as the time from randomization to the date of the first occurrence of radiographic bone or soft tissue distant metastasis based on conventional imaging by blinded independent central review (BICR), histopathologic diagnosis of distant metastasis, or death from any cause, whichever occurs first. | 108 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival | Event-free survival is defined as the time from randomization to the date of the first occurrence of prostate specific antigen (PSA) failure by the Phoenix definition, local or regional disease recurrence on conventional imaging by BICR or histopathologic diagnosis, distant metastasis on conventional imaging by BICR or histopathologic diagnosis, or death. | 108 Months | 
| Time to Prostate Specific Antigen (PSA) Progression | Time to PSA progression is defined as time from randomization to the date of PSA nadir plus (+) 0.5 nanograms per milliliter (ng/mL) and rising. | 108 Months | 
| Overall Survival (OS) | OS is defined as the time from randomization to date of death from any cause. | 108 Months | 
| Time to Distant Metastasis | Time to distant metastasis is defined as the time from randomization to the date of the first occurrence of radiographic or pathological bone or soft tissue distant metastasis on conventional imaging by BICR or histopathologic diagnosis of distant metastasis. | 108 Months | 
| Time to Next Local or Systemic Treatment | Time to next local or systemic treatment defined as time from randomization to first subsequent therapy, including re-initiation of androgen deprivation therapy (ADT) and local treatments for local-regional recurrence or distant metastasis. | 108 Months | 
| MFS by Conventional or Positron Emission Tomography (PET) Imaging | MFS by conventional or PET imaging is defined as time from randomization to the date of the first occurrence of radiographic bone or soft tissue distant metastasis based on conventional imaging or PET imaging, histopathologic diagnosis of distant metastasis, or death from any cause, whichever occurs first. | 108 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostatic neoplasms, Prostate Cancer, High-Risk prostate cancer, JNJ-56021927, Apalutamide, ATLAS, Radiation, Long-term hormone therapy, Localized or locally advanced prostate cancer, Janssen