Evaluation of Apalutamide with Androgen Deprivation Therapy Versus Androgen Deprivation Therapy Alone in High-Risk Oligometastatic Prostate Cancer

Trial ID: 2024-515049-41-00
Sponsor: Universita' Degli Studi Di Torino

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Diseases & Conditions

Prostate cancer metastatic

Objectives

The primary objective of this study is to determine if treatment with **apalutamide** plus androgen deprivation therapy (ADT) after radical prostatectomy (RP) results in an improvement in radiographic progression-free survival (RPFS) based on PSMA PET/CT, as compared to ADT alone. This is clinically relevant as it may provide insights into the potential benefits of adding apalutamide to standard ADT in patients with high-risk prostate cancer, potentially improving outcomes in terms of disease progression.

Secondary objectives include:

To characterize the safety profile of treatment with apalutamide plus ADT after RP.
To explore measures of efficacy.
To evaluate treatment-related symptoms and tolerability.

These objectives aim to provide a comprehensive understanding of the treatment's safety, efficacy, and tolerability, which are crucial for assessing the overall benefit-risk profile of the therapeutic regimen in this patient population.

Participants

The clinical trial focuses on **metastatic prostate cancer** and involves a study population exclusively composed of male subjects, aged between 18 and 79 years. The participants are required to have a histologically confirmed adenocarcinoma of the prostate and must be candidates for radical prostatectomy with pelvic lymph node dissection. The trial does not include vulnerable populations. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on specific inclusion criteria, such as the ability to receive androgen deprivation therapy (ADT) for at least 18 months and adequate organ function. Conventional imaging must be negative for metastases, and participants should have low volume metastatic disease as defined by PSMA PET/CT. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations, such as diet and physical activity, are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **apalutamide** in combination with androgen deprivation therapy (ADT) following radical prostatectomy (RP) in patients with high-risk **metastatic prostate cancer**. This Phase 4 trial is structured as a randomized, double-blind, controlled study, aiming to assess improvements in radiological progression-free survival (RPFS) using PSMA PET/CT imaging compared to ADT alone. The trial is expected to commence recruitment on July 12, 2024, and conclude by July 12, 2027, with a maximum treatment period of 18 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 age, ability to receive ADT, and histologically confirmed adenocarcinoma of the prostate. Following successful screening, participants will be randomized to receive either the investigational treatment or control. Regular follow-up visits will be scheduled to monitor safety, efficacy, and adherence to the treatment protocol. These visits will include assessments of adverse events, biochemical progression-free survival, and overall survival, among other secondary endpoints. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Participant involvement is anticipated to last up to 18 months, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. The trial's primary endpoint is RPFS, with secondary endpoints encompassing adverse events, biochemical progression-free survival, and changes in quality of life measures. The study aims to provide valuable insights into the potential benefits of adding apalutamide to standard ADT in the treatment of high-risk metastatic prostate cancer.

Treatment

The clinical trial involves the administration of **apalutamide**, a nonsteroidal antiandrogen, as the experimental medication. Apalutamide is provided in the form of film-coated tablets, marketed under the name Erleada, with each tablet containing 60 mg of the active substance. The pharmaceutical form is specifically designed for **oral** administration. Participants in the trial are instructed to take a maximum daily dose of 240 mg, which equates to four tablets per day. The treatment period is set for a maximum of 18 months. The chemical origin of apalutamide is confirmed, and it is identified by the ATC code L02BB05. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, the study includes a comparator treatment involving androgen deprivation therapy (ADT) alone. This standard-of-care therapy serves as a control to evaluate the efficacy of apalutamide in combination with ADT. The trial aims to determine if the combination therapy results in an improvement in radiographic progression-free survival (RPFS) based on PSMA PET/CT, compared to ADT alone. The administration of ADT follows standard clinical guidelines, and participant compliance is similarly monitored to maintain the integrity of the study outcomes.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the evaluation of **radiological progression-free survival (RPFS)**, utilizing PSMA PET/CT imaging. This primary endpoint aims to determine the effectiveness of apalutamide in combination with androgen deprivation therapy (ADT) following radical prostatectomy (RP) in subjects with high-risk prostate cancer. The trial will compare this combination treatment to ADT alone, focusing on improvements in RPFS.

Secondary endpoints include the assessment of adverse events (AEs), biochemical progression-free survival (BPFS), progression-free survival 2 (PFS2), time to castration-resistant prostate cancer (CRPC), the percentage of subjects receiving postoperative radiotherapy, and overall survival (OS). Additionally, changes from baseline over time in the Expanded Prostate Cancer Index (EPIC-26) and EQ-5D-5L will be measured to evaluate patient-reported outcomes. These parameters will be collected and analyzed at specified intervals throughout the trial to provide a comprehensive understanding of the treatment's efficacy and impact on quality of life.

Inclusion and Exclusion Criteria

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Inclusion Criteria

≥ 18 years of age, < 80 years of age
Signed informed consent form (ICF) indicating that the subject understands the purpose and procedures required for the study and is willing to participate in the study; subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol
Histologically confirmed adenocarcinoma of the prostate
High-risk disease defined by a total Gleason Sum Score ≥ 4+4 (=Grade Groups [GG] 4-5), PSA >20 ng/ml, or ≥cT2c based on digital rectal examination or ≥cT3 or cN+ based on preoperative imaging
Conventional imaging negative for metastases
Presence of low volume metastatic disease at pre-surgery PSMA PET/CT. The metastatic burden is classified according to the definition used in the CHARTEED trial applied to PSMA PET/CT, where high metastatic burden was defined as four or more bone metastases with one or more outside the vertebral bodies or pelvis, or visceral metastases, or both; all other assessable patients were considered to have low metastatic burden
Candidate to RP with PLND
Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
Adequate organ function
Able to receive ADT for at least 18 months, based on cardiovascular risk assessment and the investigator’s assessment
Be able to swallow whole study drug tablets

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Exclusion Criteria

Distant metastasis based on conventional imaging (CT scan or bone scintigraphy). Nodal disease below the iliac bifurcation (clinical stage N1 at CT scan) is not an exclusion criterion.
Prior hormonal treatment (GnRHa, agonist or antagonist)
Prior bilateral orchiectomy
History of prior systemic or local therapy for prostate cancer, including pelvic radiation and whole gland or focal ablative modalities for prostate cancer
Use of any investigational agent ≤4 weeks prior to RP or any therapeutic procedure for prostate cancer at any time
Major surgery ≤4 weeks prior to RP
Any of the following within 12 months prior to first dose of study drug: severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias or New York Heart Association Class II to IV heart disease; uncomplicated deep vein thrombosis is not considered exclusionary
Human immunodeficiency virus-positive subjects with 1 or more of the following: (1) not receiving highly active antiretroviral therapy; (2) had a change in antiretroviral therapy within 6 months of the start of screening; (3) receiving antiretroviral therapy that may interfere with study drug (consult Sponsor for review of medication prior to enrolment); (4) CD4 count <350 at screening; (5) AIDS-defining opportunistic infection within 6 months of start of screening; (6) active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction
History of seizure; any condition that may predispose to seizure
Patients taking any prohibited medications (as reported in the protocol) should not be included
Gastrointestinal conditions affecting absorption
Known or suspected contraindications or hypersensitivity to apalutamide, GnRHa 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
Active malignancies other than prostate cancer. The only allowed exceptions are: non-muscle invasive bladder cancer (NMIBC); skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured; breast cancer (adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence); malignancy that is considered cured with minimal risk of recurrence.