Intermittent Androgen Deprivation Therapy in the Era of AR Pathway Inhibitors

NCT ID: NCT05974774

Last Updated: 2025-09-19

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 1600 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-05-23
• Study Completion Date: 2039-06-01

Brief Summary

This study addresses the global topic of treatment optimization, i.e. achieving similar benefit while reducing the duration of treatment, hence hoping to decrease the burden of side-effects, improve quality-of life and reduce resource utilization.

The primary goal of de-escalation is to investigate whether using an intermittent regime results in a similar OS to continuous treatment.

Detailed Description

Prostate cancer is known to be dependent on testicular and adrenal androgens and the earliest identified treatments were the suppression of the body's production of testosterone. Then came the development of drugs able to block the androgen receptors that multiplied on the cancer cell membranes. The combination of these drugs presently approved by the EMA for first line treatment of mHNPC are understood to be given maximum androgen blockage and to be used until progression. All have been shown to positively impact overall survival. For patients, however, the consequences of continuous intensified MAB, and thereby testosterone suppression, have impacted their quality of life, especially in the form of fatigue, emotional distress, decrease of libido and loss of sexual function. This is in addition to toxicities linked to the mechanisms of these drugs which include cardiovascular diseases, cognitive effects and loss of bone mineral density.

Treatment optimization is rarely addressed by clinical trials run for registration purposes. Toxicity is subsumed under efficacy and keeping the cancer at bay or controlled at any cost. Overall patient experience is not taken into account when determining what is an acceptable trade-off. Intermittent treatment or drug holiday are options to manage drug toxicities but longer off-treatment periods remain rare due to the fear of losing efficacy.

Prostate cancer is an ideal setting to study the benefits of intermittent treatment as PSA levels have been shown to be a good indicator of cancer status. By holding androgen blockade after good PSA response, patients get the opportunity of seeing an improvement in their quality of life as testosterone levels slowly recover. The longer a patient stays off treatment, the more improvements to his overall wellbeing can be felt. Monitoring PSA levels provides an early signal to cancer regrowth and allows for the restart of MAB when it becomes necessary.

While improving the patient's quality of life, there is as yet no indication as to the possible impact of this approach on overall survival. Alternating off/on treatment could delay both the start of the next line of treatment and the development of castration resistance but the absence of constant androgen suppression could also have the opposite effect and precipitate new alternatives to cancer cells testosterone dependence.

This trial will randomize patients to either continue with their treatment as prescribed or to stop treatment until PSA levels indicate the necessity of restarting suppression. The latter group can stop treatment again when PSA levels reaches 0.2 ng/mL or lower. There is a need to investigate whether the benefit to patient's lives of holding long-term treatment will outweigh the risks of shortening overall survival. This trial is being done to allow both patients and their treating teams to have the data needed to make an informed decision on the best treatment approach.

Conditions

Prostate Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A - continuous treatment

Arm A (cMAB): ADT (LHRH agonist or antagonist) + ARPI (abiraterone or enzalutamide or apalutamide or darolutamide) continuously until start of a new anti-cancer therapy.

Group Type: ACTIVE_COMPARATOR

cMAB

Intervention Type: DRUG

LHRH agonist or antagonist + ARPI (abiraterone or enzalutamide or apalutamide or darolutamide)

Arm B - intermittent treatment

Arm B (iMAB): no further treatment, including ADT and ARPI; decision to restart ADT (LHRH agonist or antagonist) and the initial ARPI (abiraterone, enzalutamide, apalutamide or darolutamide) is left at Investigator discretion.

Group Type: EXPERIMENTAL

iMAB

Intervention Type: DRUG

no treatment until significant PSA increase as per treating physician at which point patient restarts ADT (LHRH agonist or antagonist) + ARPI (abiraterone or enzalutamide or apalutamide or darolutamide). Once PSA \< 0.2 ng/mL, treatment stops again.

Interventions

iMAB

no treatment until significant PSA increase as per treating physician at which point patient restarts ADT (LHRH agonist or antagonist) + ARPI (abiraterone or enzalutamide or apalutamide or darolutamide). Once PSA \< 0.2 ng/mL, treatment stops again.

Intervention Type: DRUG

cMAB

LHRH agonist or antagonist + ARPI (abiraterone or enzalutamide or apalutamide or darolutamide)

Intervention Type: DRUG

Other Intervention Names

intermittent maximum androgen blockade; continuous maximum androgen blockade

Eligibility Criteria

Inclusion Criteria

• Patient treated with ADT and an ARPI for mHNPC for 6-12 months and presenting with a PSA ≤ 0.2 ng/mL Note: Patient may have received docetaxel and radiotherapy of the prostate and metastases Note: Patients with synchronous or metachronous metastases, high volume/risk or low volume/risk who fulfil the criteria can be included.
• Before patient 's enrolment, written informed consent must be given according to ICH/GCP, and national/local regulations

Exclusion Criteria

• Patients with M1a on modern imaging technique (PET-Choline or -PSMA or Whole Body MRI) for whom radiation therapy and 2-3 years of hormone therapy is planned
• Patients who underwent or will undergo a bilateral orchiectomy
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment for this trial
• Patients who have received a systemic anti-prostate cancer treatment not approved by EMA together with MAB or a radical prostatectomy for M1 disease
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed and discussed with the patient before the enrolment in the trial

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Cancer Trials Ireland

NETWORK

Sponsor Role: collaborator

UNICANCER

OTHER

Sponsor Role: collaborator

Spanish Oncology Genito-Urinary Group

OTHER

Sponsor Role: collaborator

European Organisation for Research and Treatment of Cancer - EORTC

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bertrand Tombal, Prof

Role: STUDY_CHAIR

Cliniques Universitaires de Saint Luc

Silke Gillessen, Prof

Role: STUDY_CHAIR

Oncology Institute of Southern Switzerland - Ospedale San Giovanni

Locations

University Hospitals Copenhagen - Rigshospitalet

Copenhagen, , Denmark

Site Status: RECRUITING

Centre Francois Baclesse

Caen, , France

Site Status: RECRUITING

Institut Daniel Hollard

Grenoble, , France

Site Status: RECRUITING

Clinique La Croix Du Sud

Quint-Fonsegrives, , France

Site Status: RECRUITING

CHU de Toulouse - Institut Claudius Regaud - IUCT oncopole

Toulouse, , France

Site Status: RECRUITING

Gustave Roussy

Villejuif, , France

Site Status: RECRUITING

Hospital De La Santa Creu I Sant Pau

Barcelona, , Spain

Site Status: RECRUITING

Hospital Universitario San Carlos

Madrid, , Spain

Site Status: RECRUITING

Hospital Universitario Puerta De Hierro

Majadahonda, , Spain

Site Status: RECRUITING

Countries

Denmark; France; Spain

Central Contacts

EORTC

Role: CONTACT

eortc@eortc.org

+3227741611

Facility Contacts

Martin Andreas Roeder Martin Andreas, Dr

Role: primary

Florence Joly, Dr

Role: primary

Valentine Ruste, Dr

Role: primary

Guillaume Ploussard, Dr

Role: primary

Loic Mourey, Dr

Role: primary

Anna Patrikidou, Dr

Role: primary

Pablo Maroto, Dr

Role: primary

Javier Puente, Dr

Role: primary

Aranzazu Gonzalez del Alba, Dr

Role: primary

Other Identifiers

EORTC 2238

Identifier Type: -

Identifier Source: org_study_id