Phase III Randomized Trial of Intermittent vs. Continuous Androgen Deprivation Therapy with AR Pathway Inhibitors in Metastatic Hormone-Naïve Prostate Cancer

The primary objective of this phase III trial is to evaluate the **risk/benefit ratio** of intermittent maximum androgen blockade (iMAB) compared to continuous maximum androgen blockade (cMAB) in patients with metastatic hormone-naïve prostate cancer (mHNPC) who have achieved a deep prostate-specific antigen (PSA) response (PSA ≤ 0.2 ng/mL) after 6 to 12 months of androgen deprivation therapy (ADT) combined with one of the registered androgen receptor pathway inhibitors (ARpI). This objective is clinically relevant as it aims to determine whether iMAB can maintain efficacy while potentially reducing treatment-related side effects and improving quality of life.

The primary objective will be addressed through the following co-primary objectives:

• To demonstrate that at least 70% of patients in the iMAB arm do not restart hormonal therapy within one year of interrupting their MAB therapy, which serves as a feasibility endpoint.
• To establish that the overall survival (OS) from randomization using an iMAB regimen is non-inferior to continuous treatment, which is considered a pertinence endpoint.

The clinical trial focuses on **metastatic hormone naïve prostate cancer (mHNPC)** and involves a study population exclusively composed of male subjects. The age range of participants falls within categories 3 and 4, which typically correspond to adult and older adult age groups. The trial does not include a vulnerable population. Participants were selected based on their treatment history with androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARpI) for a duration of 6 to 12 months, achieving a prostate-specific antigen (PSA) level of ≤ 0.2 ng/mL. The trial does not provide specific information regarding the total number of participants or detailed lifestyle considerations such as diet or physical activity. The sponsor has not disclosed the total number of participants involved in the study.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the risk/benefit ratio of intermittent maximum androgen blockade (iMAB) versus continuous maximum androgen blockade (cMAB) in patients with metastatic hormone-naïve prostate cancer (mHNPC). The trial aims to enroll 1600 participants and is expected to span from April 2025 to June 2039. Participants will be randomly assigned to either the iMAB or cMAB treatment arm, with the primary objective being to assess the proportion of patients in the iMAB arm who do not restart hormonal therapy within one year of interruption and to compare overall survival between the two groups.

The study will include several key visits: an initial **screening** visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require patients to have been treated with androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARpI) for 6-12 months, with a prostate-specific antigen (PSA) level of ≤ 0.2 ng/mL. Participants will be involved in the study for a maximum treatment period of 60 months, with conditions for early termination including withdrawal of consent, adverse events, or disease progression.

Throughout the trial, safety will be monitored according to the CTCAE Version 5.0, and secondary endpoints will include health-related quality of life (HRQoL) assessments, time to next systemic prostate cancer therapy, and recovery of testosterone levels. The trial will utilize a variety of medicinal products, including **darolutamide**, **goserelin acetate**, **abiraterone**, **apalutamide**, **enzalutamide**, **triptorelin acetate**, **relugolix**, and **leuprorelin acetate**, administered either orally or via subcutaneous injection, depending on the specific product. The study's findings are anticipated to have significant implications for the management of mHNPC, potentially influencing future clinical practice.

**Degarelix** is administered as a **subcutaneous injection** with a pharmaceutical form identified as PHF00231MIG. The treatment involves a maximum total dose of 4960 mg over a period of 60 days. The administration is part of an **endocrine therapy** regimen. Monitoring of participant compliance is essential to ensure adherence to the dosing schedule.

**Darolutamide** is provided in an **oral** form, designated as PHF00082MIG. The maximum daily dose is 1200 mg, with a total dose of 2190000 mg over the course of 60 days. It is used in conjunction with **endocrine therapy and anti-androgens**. Compliance is monitored to maintain the therapeutic regimen.

**Goserelin Acetate** is delivered via **subcutaneous injection**, with a pharmaceutical form of PHF00104MIG. The total dose does not exceed 237.6 mg over 60 days. It is categorized under **gonadotropin releasing hormone analogues**. Adherence to the dosing schedule is critical for efficacy.

**Abiraterone** is administered **orally**, with a pharmaceutical form of PHF00245MIG. The maximum daily dose is 1000 mg, with a total dose of 1825000 mg over 60 days. It is part of **endocrine therapy and other hormone antagonists and related agents**. Participant compliance is monitored to ensure proper dosing.

**Apalutamide** is available in an **oral** form, identified as PHF00082MIG. The maximum daily dose is 240 mg, with a total dose of 438000 mg over 60 days. It is used alongside **endocrine therapy and anti-androgens**. Monitoring of compliance is necessary to maintain the treatment protocol.

**Enzalutamide** is administered **orally**, with a pharmaceutical form of PHF00007MIG. The maximum daily dose is 160 mg, with a total dose of 292000 mg over 60 days. It is part of **hormone antagonists and related agents, anti-androgens**. Ensuring participant adherence to the dosing schedule is crucial.

**Triptorelin Acetate** is given as an **injection**, with a pharmaceutical form of PHF00231MIG. The total dose is limited to 225 mg over 60 days. It is classified under **hormones and related agents**. Compliance monitoring is essential for effective treatment.

**Relugolix** is administered **orally**, with a pharmaceutical form of PHF00082MIG. The maximum daily dose is 360 mg, with a total dose of 219360 mg over 60 days. It is used in **endocrine therapy and other hormone antagonists and related agents**. Participant adherence to the dosing regimen is monitored.

**Leuprorelin Acetate** is delivered via **injection**, with a pharmaceutical form of PHF00231MIG. The total dose does not exceed 450 mg over 60 days. It is part of **gonadotropin releasing hormone analogues**. Monitoring compliance is necessary to ensure the effectiveness of the treatment.

The efficacy of the clinical trial will be assessed using co-primary endpoints, which include the proportion of patients who do not restart their hormonal therapy within one year of interrupting their maximum androgen blockade (MAB) therapy, and overall survival (OS) from randomization. These endpoints are designed to evaluate the feasibility and pertinence of intermittent MAB (iMAB) compared to continuous MAB (cMAB) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) who have achieved a deep **PSA** response (PSA ≤ 0.2 ng/mL) after 6 to 12 months of androgen deprivation therapy (ADT) and one of the registered androgen receptor pathway inhibitors (ARpI).

Secondary endpoints will include safety assessments according to the CTCAE Version 5.0 for toxicity of grade 3 or higher adverse events, changes in health-related quality of life (HRQoL) using the EORTC QLQ-C30 and IL249 item list, time spent on MAB treatment, time to next systemic prostate cancer therapy, and health utility derived from patient-reported QLQ-C30 data. Additionally, the trial will measure the proportion of patients with recovered testosterone levels and PSA ≤ 0.2 ng/mL at specified time points, as well as testosterone and PSA value profiles during the first three years. These efficacy parameters will be collected and analyzed at various time points throughout the trial to provide comprehensive insights into the treatment's impact on patient outcomes.