Evaluation of Apalutamide in Non-Metastatic Castration-Resistant Prostate Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial
- Trial ID
- 2023-509221-47-00
- Protocol
- ARN-509-003
- Sponsor
- Aragon Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the superiority in the **metastasis-free survival (MFS)** of men with high-risk non-metastatic castration-resistant prostate cancer (NM-CRPC) treated with Apalutamide compared to placebo. This is clinically relevant as MFS is a critical endpoint in assessing the efficacy of treatments in delaying the progression of prostate cancer, which can significantly impact patient outcomes and quality of life.
Secondary objectives include:
- Comparing the overall survival (OS) of men with high-risk NM-CRPC treated with Apalutamide versus placebo.
- Comparing the time to symptomatic progression in men with high-risk NM-CRPC treated with Apalutamide versus placebo.
- Comparing the time to initiation of cytotoxic chemotherapy in men with high-risk NM-CRPC treated with Apalutamide versus placebo.
- Comparing the progression-free survival (PFS) of men with high-risk NM-CRPC treated with Apalutamide versus placebo.
- Comparing the time to metastasis (TTM) in men with high-risk NM-CRPC treated with Apalutamide versus placebo.
- Evaluating the safety and tolerability of Apalutamide.
Participants
The clinical trial involves a total of **44 participants** diagnosed with **Castration-Resistant Prostate Cancer**. The study population consists exclusively of male subjects, aged **18 years and older**, who are not considered part of a vulnerable population. Participants were selected based on specific inclusion criteria, including a histologically or cytologically confirmed adenocarcinoma of the prostate, with a high risk for metastasis development. All participants have demonstrated castration-resistant prostate cancer during continuous androgen deprivation therapy (ADT) and are either surgically or medically castrated. The trial does not include female subjects. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status grade of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Lifestyle considerations such as diet and physical activity are not specified, but participants must be willing and able to comply with scheduled visits and study procedures. The trial aims to assess the efficacy of Apalutamide versus placebo in improving metastasis-free survival in this specific patient population.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, placebo-controlled, Phase III study designed to evaluate the efficacy of **apalutamide** in men with non-metastatic castration-resistant prostate cancer (NM-CRPC). The primary objective is to demonstrate superiority in metastasis-free survival (MFS) of participants treated with apalutamide compared to placebo. The trial is expected to run from November 2013 to June 2027, with a maximum treatment period of 48 months for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed adenocarcinoma of the prostate, castration-resistant status, and adequate organ function. Following randomization, participants will receive either apalutamide or placebo, administered orally in the form of film-coated tablets. The study includes regular follow-up visits to monitor safety, efficacy, and compliance with the treatment regimen. These visits will involve laboratory assessments, radiographic evaluations, and completion of patient-reported outcomes questionnaires.
The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. Conditions that may lead to early termination include significant adverse events, disease progression, or withdrawal of consent. The trial also incorporates secondary endpoints, such as time to metastasis, progression-free survival, and overall survival, which will be assessed through hierarchical testing. Participants are expected to comply with all study procedures, including long-term follow-up visits, to ensure comprehensive data collection and analysis.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The primary experimental medication is **Apalutamide**, marketed under the sponsor product code JNJ-56021927. It is provided in the form of a **film-coated tablet** and is administered orally. The maximum daily dose is 240 mg, with a total treatment period of up to 48 months. Apalutamide is a chemical substance used to evaluate its efficacy in improving metastasis-free survival in men with non-metastatic castration-resistant prostate cancer (NM-CRPC).
Another treatment used in the trial is **Abiraterone Acetate**, available in two formulations: ZYTIGA 250 mg tablets and ZYTIGA 500 mg film-coated tablets. Both formulations are administered orally. The 500 mg film-coated tablets have a maximum daily dose of 1000 mg. The treatment period for Abiraterone Acetate is also up to 48 months. This medication is used as part of the androgen deprivation therapy regimen in the study.
The trial also includes a **placebo** for Apalutamide, referred to as Apalutamide placebo. This placebo is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know who is receiving the active medication versus the placebo.
Additionally, **Prednisone** is used as a non-experimental treatment in the study. It is provided in tablet form and administered orally, with a maximum daily dose of 10 mg. Prednisone is included as part of the standard-of-care therapy for participants receiving Abiraterone Acetate.
Participant compliance with the dosing schedules is monitored throughout the study to ensure adherence to the treatment protocols. The trial aims to assess the superiority of Apalutamide over placebo in terms of metastasis-free survival in the target patient population.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the measurement of **Metastasis-Free Survival (MFS)** in men with high-risk non-metastatic castration-resistant prostate cancer (NM-CRPC) treated with Apalutamide versus placebo. The primary endpoint, MFS, will be evaluated to demonstrate the superiority of Apalutamide in extending the time patients remain free from metastasis.
Secondary endpoints will be assessed using a hierarchical testing approach, including Time to Metastasis (TTM), Progression-Free Survival (PFS), Time to symptomatic progression, Overall Survival (OS), and Time to initiation of cytotoxic chemotherapy. These endpoints will provide a comprehensive evaluation of the treatment's efficacy in delaying disease progression and improving survival outcomes.
The trial is designed as a multicenter, randomized, double-blind, placebo-controlled, Phase III study. The efficacy parameters will be collected and analyzed at specified intervals throughout the study duration, which is estimated to conclude by June 2027. The trial will ensure rigorous data collection and analysis to validate the efficacy of Apalutamide in the target patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features, with high risk for development of metastases, defined as PSADT ≤ 10 months. PSADT is calculated using at least 3 PSA values obtained during continuous ADT (see Section 5.1).
- Castration-resistant prostate cancer demonstrated during continuous ADT, defined as 3 PSA rises at least 1 week apart, with the last PSA > 2 ng/mL
- Surgically or medically castrated, with testosterone levels of <50 ng/dL. If the patient is medically castrated, continuous dosing with GnRHa must have been initiated at least 4 weeks prior to randomization and must be continued throughout the study to maintain castrate levels of testosterone.
- 4.Patients receiving bone loss prevention treatment with bone-sparing agents indicated for the treatment of osteoporosis at doses and dosing schedule appropriate for the treatment of osteoporosis (e.g., denosumab [Prolia®], zoledronic acid [Reclast®]) must be on stable doses for at least 4 weeks prior to randomization.
- Patients who received a first generation anti-androgen (e.g., bicalutamide, flutamide, nilutamide) must have at least a 4-week washout prior to randomization AND must show continuing disease (PSA) progression (an increase in PSA) after washout.
- At least 4 weeks must have elapsed from the use of 5-α reductase inhibitors (e.g., dutasteride, finasteride), estrogens (irrespective of dose used), and any other anti-cancer therapy prior to randomization, including chemotherapy given in the adjuvant/neoadjuvant setting (e.g.,clinical trial)
- At least 4 weeks must have elapsed from major surgery or radiation therapy prior to randomization
- Age ≥ 18 years
- Eastern Cooperative Oncology Group (ECOG) Performance Status grade 0 or 1.
- Resolution of all acute toxic effects of prior therapy or surgical procedure to Grade 1 or baseline prior to randomization.
- Adequate organ function as defined by the following criteria: -Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x upper limit of normal (ULN) -Total serum bilirubin ≤1.5 x ULN. Total serum bilirubin >1.5 x ULN is allowed if Gilbert's disease is documented prior to end of screening procedures -Serum creatinine ≤ 2 x ULN -Absolute neutrophil count (ANC) ≥ 1500/μL -Platelets ≥ 100,000/μL -Hemoglobin ≥ 9.0 g/dL -Administration of growth factors or blood transfusions will not be allowed within 4 weeks of the hematology labs required to confirm eligibility.
- Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to randomization
- Willingness and ability to comply with scheduled visits, treatment plans, laboratory and radiographic assessments, and other study procedures, including ability to swallow study drug tablets, the completion of patient reported outcomes questionnaires and long-term follow-up visits
Exclusion Criteria
- Presence of distant metastases confirmed by blinded independent central review (BICR), including CNS and vertebral or meningeal involvement, or history of distant metastases. Exception: Pelvic lymph nodes <2 cm in short axis (N1) located below the iliac bifurcation are allowed
- Symptomatic loco-regional disease requiring medical intervention, such as moderate or severe urinary obstruction or hydronephrosis due to primary tumor (e.g., tumor obstruction of bladder trigone)
- Prior treatment with second generation anti-androgens (e.g., enzalutamide)
- Prior treatment with CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galerterone, ketoconazole, aminoglutethimide)
- Prior treatment with radiopharmaceutical agents (e.g., Strontium-89), immunotherapy (e.g., sipuleucel-T), or any other investigational agent for NM-CRPC
- Prior chemotherapy for prostate cancer except if administered in the adjuvant/neoadjuvant setting
- History of seizure or condition that may pre-dispose to seizure (e.g., stroke within 1 year prior to randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign CNS or meningeal disease which may require treatment with surgery or radiation therapy)
- Concurrent therapy with any of the following (all must have been discontinued or substituted for at least 4 weeks prior to randomization): Medications known to lower the seizure threshold (for a complete list please see Appendix 5) Herbal (e.g. saw palmetto) and non-herbal (e.g. pomegranate) products that may decrease PSA levels Systemic (oral/IV/IM) corticosteroids. Short term use (≤ 4 weeks) of corticosteroids during the study is allowed if clinically indicated, but it should be tapered off as soon as possible Any other experimental treatment on another clinical trial Agents indicated for the prevention of skeletal-related events in patients with solid tumors (e.g., denosumab [Xgeva®])
- History or evidence of any of the following conditions: Any prior malignancy (other than adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) within 5 years prior to randomization Any of the following within 6 months prior to randomization: Severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias Uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic BP≥100 mmHg). Patients with a history of uncontrolled hypertension are allowed provided blood pressure is controlled by antihypertensive treatment. Gastrointestinal disorder affecting absorption Active infection, such as human immunodeficiency virus (HIV) Any other condition that, in the opinion of the Investigator, would impair the patient's ability to comply with study procedures.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 11 Nov 2013 | 1 |
 Belgium | Not Recruiting | 11 Nov 2013 | 1 |
 Czechia | Not Recruiting | 11 Nov 2013 | 5 |
 Denmark | Not Recruiting | 11 Nov 2013 | 2 |
 France | Not Recruiting | 11 Nov 2013 | 1 |
 Germany | Not Recruiting | 11 Nov 2013 | 1 |
 Italy | Not Recruiting | 11 Nov 2013 | 3 |
 The Netherlands | Not Recruiting | 11 Nov 2013 | — |
 Poland | Not Recruiting | 11 Nov 2013 | 4 |
 Romania | Not Recruiting | 11 Nov 2013 | 1 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ZYTIGA 250 mg tablets | Other | TABLETS | ORAL USE | 0 | 48 | PRD732825 |
- | Other | PHF00243MIG | ORAL USE | 0 | 48 | L02AE |
PREDNISONE | Other | — | ORAL USE | 10 | 48 | SUB10020MIG |
Apalutamide placebo | Placebo | N/A | — | — | — | N/A |
ZYTIGA 500 mg film-coated tablets | Other | FILM-COATED TABLETS | ORAL USE | 1000 | 48 | PRD4502160 |
JNJ-56021927 | Test | FILM-COATED TABLET | ORAL | 240 | 48 | PRD4402768 |