Efficacy and Safety Evaluation of Enzalutamide and Leuprorelin Acetate in High-Risk Nonmetastatic Prostate Cancer Post-Definitive Therapy
- Trial ID
- 2024-513521-23-00
- Protocol
- C3431004/MDV3100-13
- Sponsor
- Medivation Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of enzalutamide plus leuprolide and enzalutamide monotherapy compared to placebo plus leuprolide in men with high-risk nonmetastatic **prostate cancer** progressing after definitive therapy. This is clinically relevant as it aims to determine the most effective treatment regimen for delaying disease progression in this patient population.
Secondary objectives include assessing all **safety** parameters by comparing enzalutamide plus leuprolide and enzalutamide monotherapy against placebo plus leuprolide. This is crucial for understanding the safety profile and potential adverse effects associated with these treatment options.
Participants
The clinical trial involves a total of **702 male participants** diagnosed with **prostate cancer**. The study population is composed exclusively of males aged **18 years or older**, with no female subjects included. Participants were selected based on specific criteria, including a histologically or cytologically confirmed adenocarcinoma of the prostate, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening. The trial does not include a vulnerable population. Participants are required to have an estimated life expectancy of at least 12 months and must be able to swallow the study drug and comply with study requirements. Lifestyle considerations include the use of two acceptable methods of birth control throughout the study, with one being a condom as a barrier method. The trial population was selected to ensure that participants have a prostate-specific antigen (PSA) doubling time of 9 months or less, and a serum testosterone level of at least 150 ng/dL at screening. The study aims to compare the efficacy of enzalutamide plus leuprolide and enzalutamide monotherapy versus placebo plus leuprolide.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, controlled study designed to evaluate the efficacy and safety of **enzalutamide** plus **leuprolide**, enzalutamide monotherapy, and placebo plus leuprolide in men with high-risk nonmetastatic **prostate cancer** progressing after definitive therapy. The trial is structured to include three arms: one receiving enzalutamide plus leuprolide, another receiving enzalutamide alone, and a third receiving placebo plus leuprolide. The primary endpoint is to assess the efficacy of the combination of enzalutamide plus leuprolide versus placebo plus leuprolide, as measured by metastasis-free survival (MFS). Secondary endpoints include time to PSA progression, time to first use of new antineoplastic therapy, and overall survival.
The trial is expected to run from October 2015 to October 2026, with participants involved for a maximum treatment period of 90 days. The study begins with a screening visit to confirm eligibility based on criteria such as age, histologically confirmed adenocarcinoma of the prostate, and specific PSA levels. Participants must also meet conditions related to contraceptive use and agree not to donate sperm during the study and for three months after the last dose of the study drug. Following the screening, participants will be randomized into one of the three study arms.
Study visits are scheduled at regular intervals to monitor the participants' health, adherence to the study protocol, and response to the treatment. These visits include assessments of PSA levels, serum testosterone, and performance status, among other health indicators. The end-of-study visit will occur after the completion of the treatment period, where final evaluations will be conducted to assess the outcomes of the trial.
Participants may be withdrawn from the study early if they experience unacceptable adverse effects, if they choose to withdraw consent, or if they do not comply with the study protocol. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.
Treatment
The clinical trial involves the administration of **enzalutamide**, marketed under the name Xtandi, which is provided in the form of 40 mg **soft capsules**. The pharmaceutical form is a soft capsule, and the route of administration is **oral use**. The maximum daily dose of enzalutamide is 160 mg, and the treatment period is set for a maximum of 90 days. The enzalutamide capsules used in the trial are identical to the commercial product, with modifications in the packaging and labeling sites, container closure system, and supporting stability data for the container closure system. The active substance, enzalutamide, is of chemical origin and is also known by the synonym MDV3100.
**Leuprorelin acetate** is used as a comparator treatment in the study. It is provided as a powder and solvent for solution for injection. The route of administration is **subcutaneous use**. The maximum total dose of leuprorelin acetate is 22.5 mg, administered over a treatment period of up to 90 days. The active substance, leuprorelin acetate, is of chemical origin.
A **placebo** for enzalutamide 40 mg soft gelatin capsule is also utilized in the study. The placebo is designed to match the enzalutamide capsules in appearance but does not contain the active substance. The placebo is used to assess the efficacy and safety of enzalutamide in combination with leuprorelin acetate and as a monotherapy compared to placebo plus leuprorelin acetate.
Efficacy
The efficacy of the clinical trial will be assessed by comparing the combination of **enzalutamide** plus leuprolide and enzalutamide monotherapy against placebo plus leuprolide in men with high-risk nonmetastatic prostate cancer. The primary endpoint for evaluating efficacy is the measurement of metastasis-free survival (MFS). Secondary endpoints include the time to prostate-specific antigen (PSA) progression, the time to the first use of new antineoplastic therapy, and overall survival. These endpoints will provide a comprehensive assessment of the treatment's impact on disease progression and patient survival.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age 18 years or older and willing and able to provide informed consent.
- Histologically or cytologically confirmed adenocarcinoma of the prostate at initial biopsy, without neuroendocrine differentiation, signet cell, or small cell features.
- Prostate cancer initially treated by radical prostatectomy or radiotherapy (including brachytherapy) or both, with curative intent. Prostate cryoablation is not considered definitive therapy for this study, but its prior use is not exclusionary.
- PSA doubling time ≤9 months as calculated by the sponsor.
- Screening PSA by the central laboratory ≥1 ng/mL for patients who had radical prostatectomy (with or without radiotherapy) as primary treatment for prostate cancer and at least 2 ng/mL above the nadir for patients who had radiotherapy only as primary treatment for prostate cancer.
- Serum testosterone ≥150 ng/dL (5.2 nmol/L) at screening.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening.
- Estimated life expectancy of ≥12 months.
- Able to swallow the study drug and comply with study requirements.
- Throughout study, the patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (1 of which must include a condom as a barrier method of contraception) from screening through 3 months after the last dose of study drug or per local guidelines where these require additional description of contraceptive methods. Two acceptable methods of birth control thus include the following: ● Condom (barrier method is required) AND ● One of the following is required: – Established and ongoing use of oral, injected, or implanted hormonal method of contraception by the female partner – Placement of an intrauterine device or intrauterine system by the female partner – Additional barrier method including contraceptive sponge and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the female partner – Tubal ligation in the female partner performed at least 6 months before screening – Vasectomy or other procedure resulting in infertility (eg, bilateral orchiectomy), performed at least 6 months before screening
- Throughout the study, the patient must use a condom if having sex with a pregnant woman.
- Must agree not to donate sperm from first dose of study drug through 3 months after the last dose of study drug.
Exclusion Criteria
- Prior or present evidence of distant metastatic disease as assessed by computed tomography (CT) or magnetic resonance imaging (MRI) or chest x-ray for soft tissue disease and whole-body radionuclide bone scan for bone disease. Patients with soft tissue pelvic disease may be eligible if the short axis of the largest lymph node is < 20 mm for lymph nodes below aortic bifurcation. If the screening bone scan shows a lesion suggestive of metastatic disease, the patient will be eligible only if a second imaging modality (plain film, CT, MRI) does not show bone metastasis. If the imaging results are equivocal or consistent with metastasis by central radiology review, the patient is not eligible for enrollment. Positron-emission tomography (PET) is not an evaluable imaging modality for this study.
- Prior hormonal therapy. Neoadjuvant/adjuvant therapy to treat prostate cancer ≤36 months in duration and ≥9 months before randomization, or a single dose or a short course (≤6 months) of hormonal therapy given for rising PSA ≥9 months before randomization is allowed.
- Prior cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone acetate, or enzalutamide for prostate cancer.
- Prior systemic biologic therapy, including immunotherapy, for prostate cancer.
- Major surgery within 4 weeks before randomization date.
- Treatment with 5-alfa reductase inhibitors (finasteride, dutasteride) within 4 weeks of randomization.
- For patients who had a prior prostatectomy, a suitable candidate for salvage radiotherapy as determined by the investigator in consideration of appropriate guidelines (eg, American Society for Radiation Oncology/American Urological Association [ASTRO/AUA]; European Association of Urology [EAU]).
- Participation in a clinical study of an investigational agent that inhibits the androgen receptor or androgen synthesis (eg, TAK-700, ARN-509, ODM-201); patients who received placebo are allowed.
- Use of any other investigational agent within 4 weeks before randomization date.
- Known or suspected brain metastasis or active leptomeningeal disease.
- History of another invasive cancer within 3 years before screening, with the exception of fully treated cancers with a remote probability of recurrence. The medical monitor and investigator must agree that the possibility of recurrence is remote.
- Absolute neutrophil count <1500/µL, platelet count <100,000/µL, or hemoglobin <10 g/dL (6.2 mmol/L) at screening. NOTE: May not have received any growth factors or blood transfusions within 7 days before the hematology values obtained at screening.
- Total bilirubin (TBili) ≥1.5-times the upper limit of normal (except patients with documented Gilbert’s disease), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2.5-times the upper limit of normal at screening.
- Creatinine >2 mg/dL (177 µmol/L) at screening.
- Albumin <3.0 g/dL (30 g/L) at screening.
- History of seizure or any condition that may predispose to seizure (eg, prior cortical stroke or significant brain trauma). History of loss of consciousness (unless of cardiac origin) or transient ischemic attack within 12 months before randomization.
- Clinically significant cardiovascular disease including the following: -Myocardial infarction within 6 months before screening; -Unstable angina within 3 months before screening; -New York Heart Association class III or IV congestive heart failure or a history of New York Heart Association class III or IV congestive heart failure unless a screening echocardiogram or multigated acquisition scan performed within 3 months before the randomization date demonstrates a left ventricular ejection fraction ≥45%; -History of clinically significant ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes); -History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place; -Hypotension as indicated by systolic blood pressure <86 mm Hg at screening; -Bradycardia as indicated by a heart rate of ≤45 beats per minute on the screening electrocardiogram (ECG); -Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure >170 mm Hg or diastolic blood pressure >105 mm Hg at screening.
- Gastrointestinal disorder affecting absorption.
- Hypersensitivity reaction to enzalutamide or any of the capsule components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene.
- Contraindication to the use of leuprolide, such as a previous hypersensitivity reaction to an LHRH analogue or any of the excipients in the leuprolide injection.
- Ongoing drug or alcohol abuse as per investigator judgment.
- Any concurrent disease, infection, or comorbid condition that interferes with the ability of the patient to participate in the study, which places the patient at undue risk, or complicates the interpretation of data, in the opinion of the investigator or medical monitor.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 05 Oct 2015 | 6 |
 Denmark | Not Recruiting | 05 Oct 2015 | 30 |
 Finland | Not Recruiting | 05 Oct 2015 | 57 |
 France | Not Recruiting | 05 Oct 2015 | 44 |
 Italy | Not Recruiting | 05 Oct 2015 | 30 |
 The Netherlands | Not Recruiting | 05 Oct 2015 | — |
 Poland | Not Recruiting | 05 Oct 2015 | 6 |
 Slovakia | Not Recruiting | 05 Oct 2015 | 45 |
 Spain | Not Recruiting | 05 Oct 2015 | 74 |
 Sweden | Not Recruiting | 05 Oct 2015 | 39 |
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 |
|---|---|---|---|---|---|---|
LEUPRORELIN ACETATE | Comparator | — | SUBCUTANEOUS USE | 22.5 | 90 | SUB02900MIG |
Xtandi - 40 mg soft capsules | Test | SOFT CAPSULES | ORAL USE | 160 | 90 | PRD894075 |
Placebo for Enzalutamide 40 mg soft gelatin capsule | Placebo | N/A | — | — | — | N/A |