Phase III Randomized Study of Apalutamide with Radiotherapy and LHRH Agonist in High-Risk Biochemically Relapsed Prostate Adenocarcinoma Post-Prostatectomy

Trial ID: 2024-514829-36-00
Sponsor: Unicancer

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Diseases & Conditions

Prostate cancer

Objectives

The primary objective of this study is to evaluate the clinical benefit of adding the androgen receptor competitive inhibitor **apalutamide** in combination with a Luteinizing Hormone Releasing Hormone (LHRH) agonist concomitantly to salvage radiotherapy (SRT) after biochemical progression following radical prostatectomy in patients with high-risk prostate adenocarcinoma. The clinical benefit will be assessed using the progression-free survival (PFS) rate at 5 years. This is clinically relevant as it aims to improve outcomes in patients with high-risk biochemically-relapsed prostate adenocarcinoma, a condition with limited treatment options and significant risk of disease progression.

Secondary objectives include:

Evaluating the prostate-cancer specific survival rate.
Assessing the overall survival rate at 10 years.
Determining the biochemical relapse rate.
Evaluating the time to castration-resistant prostate cancer.
Assessing safety.
Evaluating patients' quality of life.

These objectives aim to provide a comprehensive understanding of the treatment's impact on survival, disease progression, safety, and quality of life, which are critical factors in the management of prostate cancer.

Participants

The clinical trial involves a study population of **male** participants aged between 18 and 80 years, diagnosed with high-risk biochemically-relapsed **prostate adenocarcinoma** following radical prostatectomy. The sponsor has not provided the total number of participants. The trial population was selected based on specific inclusion criteria, including adequate renal and hepatic function, an ECOG performance status of 0 or 1, and no clinical or radiological signs of metastatic disease. Participants are required to have a histologically confirmed diagnosis of prostate adenocarcinoma, with tumor stages pT2, pT3, or pT4 (only in case of bladder neck involvement). Lifestyle considerations such as diet and physical activity are not specified. The study does not include female or vulnerable populations. Key inclusion criteria include a PSA level of at least 0.2 ng/mL at randomization, with high-risk features such as a PSA at relapse greater than 0.5 ng/mL, a Gleason score greater than 7, or a PSA doubling time of 6 months or less.

Plans and Procedures

The clinical trial is designed as an open-label, randomized, Phase III study to evaluate the efficacy of combining **apalutamide** with radiotherapy and a Luteinizing Hormone Releasing Hormone (LHRH) agonist in patients with high-risk biochemically-relapsed prostate adenocarcinoma following radical prostatectomy. The primary objective is to assess the clinical benefit of this combination therapy by measuring the progression-free survival (PFS) rate at five years. The trial will follow a randomized, controlled design, ensuring that participants are randomly assigned to either the treatment or control group, with neither the participants nor the investigators blinded to the treatment allocation.

The trial is expected to last until December 31, 2034, with recruitment having commenced on January 9, 2020. Participants will be involved in the study for a maximum treatment period of 24 months, with the possibility of early termination if specific conditions arise, such as adverse events or withdrawal of consent. The study includes several key visits: an initial screening visit to confirm eligibility based on inclusion criteria, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to have a histologically confirmed diagnosis of prostate adenocarcinoma, adequate renal and hepatic function, and no clinical or radiological signs of metastatic disease, among other conditions.

Primary endpoints include the 5-year progression-free survival, defined by PERCIST 1.0 and RECIST 1.1 criteria, while secondary endpoints encompass cancer-specific overall survival, overall survival assessed at 10 years, biochemical relapse-free survival, time to castration resistance, and safety evaluations. Safety assessments will be conducted according to the NCI CTCAE version 5.0, with acute and late toxicities related to radiotherapy being monitored. Patient-reported outcomes, including quality of life, will be evaluated using standardized questionnaires at baseline, the end of salvage radiotherapy, the end of treatment, and during follow-up visits until disease progression. Participants must be willing and able to comply with the protocol, including attending scheduled visits and undergoing examinations throughout the study duration.

Treatment

The clinical trial involves the administration of the experimental medication **apalutamide**, marketed under the product name JNJ-56021927. This medication is provided in the form of a **film-coated tablet** and is intended for **oral** administration. The maximum daily dose of apalutamide is 240 mg, with a total maximum dose of 40,320 mg over the course of the treatment period. The treatment duration is set for a maximum of 24 months. Apalutamide is a chemical substance developed by Janssen-Cilag International N.V. and functions as an androgen receptor competitive inhibitor. The primary objective of the trial is to assess the clinical benefit of apalutamide in combination with a Luteinizing Hormone Releasing Hormone (LHRH) agonist and salvage radiotherapy (SRT) in patients with high-risk prostate adenocarcinoma who have experienced biochemical progression following radical prostatectomy.

In addition to the experimental treatment, the study protocol includes the use of a **Luteinizing Hormone Releasing Hormone (LHRH) agonist** as part of the combination therapy. The LHRH agonist is administered concomitantly with apalutamide and salvage radiotherapy. The specific LHRH agonist used in the study is not detailed in the provided data, but it is a standard component of the therapeutic regimen for prostate cancer. The combination of these treatments aims to improve progression-free survival (PFS) rates at 5 years in the target patient population.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The study is designed to evaluate the efficacy of the combination therapy in a controlled setting, with careful documentation of dosing schedules and participant responses to the treatment. The trial is conducted in accordance with regulatory standards and ethical guidelines to ensure the safety and well-being of all participants.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the measurement of the **progression-free survival (PFS)** rate at 5 years. PFS is defined as the time from the date of randomization to the date of first evidence of loco-regional recurrences, distant metastases, or death from any cause, whichever occurs first, or the date of last known follow-up alive without any such events. Evidence of loco-regional recurrences and distant metastases will be evaluated using PET CT scans, following PERCIST 1.0 and RECIST 1.1 criteria.

Secondary endpoints include cancer-specific overall survival, overall survival (OS), biochemical relapse-free survival, time to castration resistance, safety, and patient-reported outcomes. Cancer-specific overall survival is defined as the time from randomization to death related to prostate cancer or last known follow-up alive. OS will be assessed at 10 years, defined as the time from randomization to death from any cause or last known follow-up alive. Biochemical relapse-free survival is retrospectively defined by the interval between randomization and the first PSA elevation following the 6-month treatment in both arms, with PSA measurements every 6 months for 5 years and annually thereafter if no relapse is observed. Time to castration resistance is defined as the time from randomization to the appearance of castration resistance, as per EAU guidelines.

Safety will be evaluated by assessing the frequency, nature, and severity of adverse events according to NCI CTCAE version 5.0. Acute toxicity related to radiotherapy is defined as occurring during radiotherapy and up to 3 months after completion, while late toxicity is defined as occurring later than 3 months post-radiotherapy. Patient-reported outcomes will be assessed using the EORTC QLQ-C30, EORTC QLQ-PR25, IIEF-5 questionnaires, and the IADL scale for patients aged 75 and older. These assessments will occur at baseline, end of salvage radiotherapy (SRT), end of treatment visit, and at every follow-up visit until disease progression.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patients must have signed a written informed consent form prior to any trial specific procedures
Age ≥ 18 years old and ≤ 80 years old
Histologically confirmed diagnosis of prostate adenocarcinoma treated primarily with radical prostatectomy
Tumor stage pT2, pT3 or pT4* (*only in case of bladder neck involvement)
Patients should have no clinical and radiological signs (18FCH-PET CT-scan or 68Ga-PSMA-PET CT-scan) of metastatic disease. Patients with a local relapse or pelvic nodal relapse (N1) detected on PET CT-scan can be randomized
ECOG performance status ≤ 1
PSA ≥ 0.2 ng/mL at the time of randomization with an elevation of PSA over three consecutive PSA increases over a 1-month interval minimum
At least 3 months between radical prostatectomy and randomization
High-risk features as defined by at least one of these characteristics: PSA at relapse > 0.5 ng/mL or Gleason score > 7 or tumor stage pT3b or resection margins R0 or PSA doubling time ≤ 6 months or pelvic lymph node relapse (N1, ≤ 5 lymph nodes)
Adequate renal function: serum creatinine < 1.5 x upper limit of normal (ULN) or a calculated corrected creatinine clearance ≥ 60 mL/min according to the Cockcroft-Gault formula, creatinemia < 2 ULN
Adequate hepatic function: total bilirubin ≤ 1.5 x ULN (unless documented Gilbert’s syndrome), AST and ALT ≤ 2.5 x ULN
Patients with QTc prolongation < 500 ms*, inclusion should considered after close benefit/risk assessment and cardiologist advice *In patients with a history or risk factors for QT prolongation, and in patients receiving concomitant medicines that may prolong the QT interval, a cardiologist should assess the benefit / risk balance taking into account the potential risk of torsade de pointes before initiating treatment with apalutamide
Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
Patients must be affiliated to the Social Security System

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Exclusion Criteria

Previous treatment with hormone therapy for prostate cancer
Uncontrolled hypertension (defined as systolic blood pressure (BP) ≥ 160 mmHg or diastolic BP ≥ 100 mmHg). Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
History of seizure or condition that may pre-dispose 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)
Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to study entry
Clinically significant history of liver disease consistent with Child-Pugh class B or C
Histology other than adenocarcinoma
Surgical or chemical castration
Other malignancy except adequately treated basal cell carcinoma of the skin or other malignancy from which the patient has been cured for at least 5 years
Previous pelvic radiotherapy
More than 5 (>5) pelvic lymph node relapses
Paraaortic, thoracic or supaclavicular nodal relapse (M1a)
History of Inflammatory bowel disease or any malabsorption syndrome or conditions that would interfere with enteral absorption
Severe or 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 within 6 months prior to randomization
Certain risk factors for abnormal heart rhythmas/QT prolongation: torsade de pointes ventricular arrhythmias (e.g, heart failure, hypokalemia, or a family history of a long QT syndrome), a QT or corrected QT (QTc) interval > 500 ms at baseline
Medications known to prolong QTc
Known hypersensitivity to apalutamide or to any of its components
Galactosemia, Glucose-galactose malabsorption or lactase deficiency
Inability or willingness to swallow oral medication
Individual deprived of liberty or placed under the authority of a tutor
Patients already included in another therapeutic trial with an experimental drug or having been given an experimental drug within the 30 days before inclusion