Phase 3 Randomized Trial of Enzalutamide with Androgen Deprivation and Radiation Therapy in High-Risk Localized Prostate Cancer
- Trial ID
- 2024-514808-13-00
- Sponsor
- Cancer Trials Ireland
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effects of enzalutamide in combination with androgen deprivation therapy and radiation therapy on **metastasis-free survival** (MFS) in patients with high-risk, clinically localized prostate cancer. Metastasis-free survival is a critical endpoint as it directly correlates with the progression of the disease and overall patient prognosis, providing valuable insights into the efficacy of the treatment regimen in preventing the spread of cancer.
Secondary objectives include determining the effects on:
- **Overall survival** (OS), which assesses the impact of the treatment on mortality from any cause.
- **Prostate cancer-specific survival**, focusing on mortality directly attributable to prostate cancer.
- **PSA progression-free survival** (PSA-PFS), using Phoenix criteria or death from any cause, to evaluate biochemical recurrence.
- **Clinical progression-free survival** (clinical-PFS), considering imaging, symptoms, signs, initiation of other anti-cancer treatments, or death from any cause.
- Time to subsequent hormonal therapy, specifically the time to restarting androgen deprivation therapy (ADT).
- Time to **castration-resistant disease**, as defined by PCWG2 criteria, to assess the development of resistance to hormonal therapy.
- **Safety**, by monitoring adverse events according to CTCAE v4.03.
- **Health-related quality of life**, using EORTC QLQC-30 & PR-25, EQ-5D-FL, to evaluate the impact of treatment on patient well-being.
- Health outcomes relative to costs, through the incremental cost-effectiveness ratio, to assess the economic impact of the treatment.
- Identification of **biomarkers** that are prognostic and/or predictive of response to treatment, safety, and resistance, to understand associations with clinical outcomes.
Participants
The clinical trial involves a total of **721 participants** diagnosed with **localized prostate cancer** at high risk of recurrence. The study population is exclusively male, with an age range of 18 years and older. Participants were selected based on specific inclusion criteria, including a pathological diagnosis of adenocarcinoma of the prostate with a high risk for recurrence, adequate bone marrow, liver, and renal function, and an ECOG performance status of 0-1. The trial does not include a vulnerable population. Participants are required to have a lifestyle that allows them to comply with all study requirements, including treatment and attending necessary assessments. The selection process ensures that participants are willing and able to start the study treatment within seven days of randomization. The trial does not include female subjects, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy of **enzalutamide** in combination with androgen deprivation therapy and radiation therapy for patients with high-risk, clinically localized **prostate cancer**. The primary objective is to assess **metastasis-free survival**, while secondary endpoints include overall survival, prostate cancer-specific survival, and safety, among others. The trial is categorized as a Phase III study and is not considered low intervention.
The trial is expected to run until December 31, 2025, with recruitment having started on April 1, 2015. Participants will be involved in the study for a maximum treatment period of 96 weeks. The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a pathological diagnosis of adenocarcinoma of the prostate, adequate organ function, and an ECOG performance status of 0-1. Following randomization, study treatment is to commence within seven days.
Participants will undergo regular follow-up visits to monitor treatment efficacy and safety, with assessments including imaging, laboratory tests, and health-related quality of life questionnaires. The end-of-study visit will conclude the participant's involvement, where final evaluations will be conducted to assess the primary and secondary endpoints. Conditions that may lead to early termination from the study include non-compliance with study requirements, adverse events, or withdrawal of consent.
Treatment
The clinical trial involves the administration of **ANANDRON 150 mg** tablets, containing the active substance **nilutamide**. This medication is formulated as a tablet and is administered orally. The maximum daily dose is 150 mg, with a total maximum dose of 25,200 mg over a treatment period of up to 24 months. Nilutamide functions as an androgen receptor blocker, and its chemical origin is confirmed. The product is manufactured by CHEPLAPHARM ARZNEIMITTEL GMBH and is not a paediatric formulation.
**Xtandi - 40 mg soft capsules** are also utilized in the trial, containing the active substance **enzalutamide**. These capsules are administered orally, with a maximum daily dose of 160 mg and a total maximum dose of 107,520 mg over a treatment period of up to 96 months. Enzalutamide is an androgen receptor blocker of chemical origin, produced by ASTELLAS PHARMA EUROPE B.V. This formulation is not intended for paediatric use.
The trial includes **Casodex® 50 mg film-coated tablets**, which contain **bicalutamide** as the active ingredient. These tablets are administered orally, with a maximum daily dose of 50 mg and a total maximum dose of 8,400 mg over a 24-month treatment period. Bicalutamide is a chemical androgen receptor blocker, manufactured by LABORATOIRES JUVISE PHARMACEUTICALS, and is not a paediatric formulation.
Additionally, **Flutamide 250 mg tablets** are part of the study, containing the active substance **flutamide**. These tablets are administered orally, with a maximum daily dose of 750 mg and a total maximum dose of 126,000 mg over a 24-month treatment period. Flutamide is a chemical androgen receptor blocker, produced by GENERICS [UK] LIMITED, and is not formulated for paediatric use.
All medications in this trial are administered orally and are classified as androgen receptor blockers. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed treatment regimen. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Metastasis-free survival (MFS)**, which includes metastasis or death from any cause. Secondary endpoints include overall survival (OS), prostate cancer-specific survival, PSA progression-free survival (PSA-PFS) based on the Phoenix criteria, clinical progression-free survival (clinical-PFS), time to subsequent hormonal therapy, time to castration-resistant disease, safety as measured by adverse events using CTCAE v4.03, health-related quality of life assessed with EORTC QLQC-30 & PR-25 and EQ-5D-5L, and health outcomes relative to costs, specifically the incremental cost-effectiveness ratio.
The trial will involve the use of androgen receptor blockers, including **nilutamide**, **enzalutamide**, **bicalutamide**, and **flutamide**, administered orally in various formulations such as tablets and soft capsules. The maximum treatment period for these medications ranges from 24 to 96 weeks, depending on the specific product. The trial aims to determine the effects of enzalutamide in combination with androgen deprivation therapy and radiation therapy for high-risk, clinically localized prostate cancer. The study will follow a randomized phase 3 design, with efficacy parameters collected and analyzed at specified intervals throughout the trial duration, which is estimated to conclude by December 31, 2025.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Pathological diagnosis of adenocarcinoma of the prostate, judged to be at high risk for recurrence based on any of the following (in accordance with the ISUP Consensus 2005 (16) see Appendix 3): Gleason score 8-10 OR Gleason score of 4+3 AND clinical T2b-4 AND PSA >20ng/mL OR N1 disease (involvement of lymph nodes at or below the bifurcation of the common iliac arteries) defined radiologically as greater than 10mm on short axis using standard CT or MRI, or biopsy proven.
- Age ≥ 18 yrs
- Adequate bone marrow function: Hb ≥100g/L and WCC ≥ 4.0 x 109/L and platelets ≥100 x 109/L
- Adequate liver function: ALT < 2 x ULN and bilirubin < 1.5 x ULN, (or if bilirubin is between 1.5 - 2 x ULN, they must have a normal conjugated bilirubin).
- Adequate renal function: calculated creatinine clearance > 30 mL/min (Cockroft-Gault)
- ECOG performance status of 0-1
- Study treatment both planned and able to start within 7 days of randomisation.
- Willing and able to comply with all study requirements, including treatment, and attending required assessments
- Has completed the baseline HRQL questionnaires UNLESS is unable to complete because of literacy or limited vision
- Signed, written, informed consent
Exclusion Criteria
- Prostate cancer with significant sarcomatoid or spindle cell or neuroendocrine small cell components
- Involvement of lymph nodes superior to the common iliac bifurcation, and/or outside the pelvis (distant lymph nodes). Lymph node involvement is defined by histopathological confirmation, or by a short axis measurement >10mm on standard imaging (CT or MRI, but not PET).
- Any contraindication to external beam radiotherapy
- History of a. seizure or any condition that may predispose to seizure (e.g. prior cortical stroke or significant brain trauma). b. loss of consciousness or transient ischemic attack within 12 months of randomization. c. significant cardiovascular disease within the last 3 months:including myocardial infarction, unstable angina, congestive heart failure (NYHA grade II or greater, see Appendix 4), ongoing arrhythmias of Grade > 2 (NCI CTCAE, version 4.03) , thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism). Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed.
- Evidence of metastatic disease: minimum imaging required is a CT and/or MRI of the abdomen and pelvis, and a whole body bone scan (WBBS). If equivocal bone scan, follow-up plain films are required to show NO evidence of cancer if not covered by CT/MRI
- PSA > 100 ng/mL
- History of another malignancy within 5 years prior to randomisation except for non-melanomatous carcinoma of the skin; or, adequately treated, non-muscle-invasive urothelial carcinoma of the bladder (i.e. Tis, Ta and low grade T1 tumours).
- Concurrent illness, including severe infection that might jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety a. HIV-infection is not an exclusion criterion if it is controlled with anti-retroviral drugs that are unaffected by concomitant enzalutamide.
- Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse;
- Patients who are sexually active and not willing/able to use medically acceptable forms of barrier contraception.
- Use of hormonal therapy or androgen deprivation therapy, including enzalutamide, except in the following setting: a. Use of LHRHA (with or without anti-androgens) for less than 30 days prior to randomisation in the trial.
- Bilateral orchidectomy or radical prostatectomy
- Prior brachytherapy or other radiotherapy that would result in an overlap of radiotherapy fields
- Participation in other clinical trials of investigational agents for the treatment of prostate cancer or other diseases.
- Major surgery within 21 days prior to randomisation
- Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of enzalutamide, including difficulty swallowing tablets
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Apr 2015 | 9 |
 Ireland | Not Recruiting | 01 Apr 2015 | 67 |
 Spain | Not Recruiting | 01 Apr 2015 | 3 |
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 |
|---|---|---|---|---|---|---|
Casodex® 50 mg Film-coated Tablets | Comparator | FILM-COATED TABLETS | ORAL | 50 | 24 | PRD9243928 |
ANANDRON 150 mg, comprimé | Comparator | COMPRIMÉ | ORAL | 150 | 24 | PRD7953284 |
Flutamide 250 mg Tablets | Comparator | TABLETS | ORAL | 750 | 24 | PRD438630 |
Xtandi - 40 mg soft capsules | Test | SOFT CAPSULES | ORAL | 160 | 96 | PRD1863628 |