Evaluation of Shortened 12-Month Androgen Receptor Signaling Inhibitor Therapy with Androgen Deprivation in Low-Volume Metastatic Castration-Sensitive Prostate Cancer

The primary objective of this study is to evaluate whether the discontinuation of **androgen receptor signaling inhibitors (ARSIs)** 12 months after initiation in patients with low-volume metastatic castration-sensitive prostate cancer (mCSPC), with the option to restart treatment, is non-inferior to continued ARSI therapy. This approach aims to reduce significant toxicity and costs associated with prolonged ARSI use, which is clinically relevant for improving patient quality of life and healthcare resource management.

Secondary objectives include:

• To prospectively evaluate time to PSA increase.
• To prospectively evaluate time to first-line therapy for metastatic castration-resistant prostate cancer (mCRPC).
• To prospectively evaluate overall survival (OS).
• To correlate circulating DNA (ctDNA) levels to PSA levels.
• To evaluate whether ctDNA levels could serve as a better treatment response marker than PSA.
• To predict patients who will need continued ARSI treatment with ctDNA levels.
• To identify resistance mechanisms in ctDNA occurring with ARSI treatment.
• To assess the value of ctDNA quantification during ARSI treatment to predict tumor progression.
• To explore quality of life (QoL) benefits by the interruption of ARSIs and potential changes during rechallenge, and to explore QoL with functional assessment.

The clinical trial focuses on **low-volume metastatic castration-sensitive prostate cancer** and involves a study population exclusively composed of male participants aged 18 years and older. The participants are required to have a histological diagnosis of prostate adenocarcinoma and must not have started androgen deprivation therapy (ADT). The trial does not include a vulnerable population, and participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, indicating they are fit for treatment with apalutamide or enzalutamide as per the treating physician's assessment. The selection criteria ensure that participants have low-volume de novo metastatic disease, confirmed by imaging and evaluated by a local multidisciplinary team. The sponsor has not provided information regarding the total number of participants. The trial does not include female subjects, and no specific lifestyle considerations such as diet or physical activity are mentioned.

The clinical trial is designed to evaluate the efficacy of discontinuing **androgen receptor signaling inhibitors (ARSI)** after 12 months in patients with low-volume metastatic castration-sensitive prostate cancer, compared to continued treatment. This is a randomized, nationwide trial with a double-blind, controlled design. The trial is expected to last until October 2029, with recruitment starting in September 2023. Participants will be involved for a maximum of 60 months, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, diagnosis of prostate adenocarcinoma, and disease volume. Follow-up visits will occur at regular intervals to assess primary and secondary endpoints, including time to clinical progression-free survival and overall survival. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.

Participants will be randomly assigned to either continue ARSI treatment or discontinue after 12 months, with the option to restart if necessary. The trial will utilize various pharmaceutical forms, including **subcutaneous injections** and **oral** administration, depending on the specific medication. The trial's primary endpoint is the time to clinical progression-free survival, with secondary endpoints including overall survival and quality of life assessments. The trial is categorized as a low-intervention study, as the investigational products are used within their authorized indications, and additional procedures pose minimal risk compared to standard clinical practice.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **ELIGARD 7.5 mg** is provided as a powder and solvent for solution for injection, containing **leuprorelin acetate** as the active substance. It is administered via **subcutaneous injection** with a maximum daily dose of 7.5 mg and a total dose of 450 mg over a treatment period of 60 days. This medication is part of hormone therapy.

**GOSERELIN ACETATE** is available in an implant form, administered through **implantation**. The maximum daily dose is 10.8 mg, with a total dose of 234 mg over 60 days. This medication is also used in hormone therapy.

**Pamorelin 22.5 mg** is a prolonged-release suspension for injection containing **triptorelin**. It is administered via **intramuscular injection** with a maximum daily dose of 22.5 mg and a total dose of 225 mg over the treatment period. This medication is part of hormone therapy.

**CAMCEVI 42 mg** is a prolonged-release suspension for injection containing **leuprorelin**. It is administered through **implantation** with a maximum daily dose of 42 mg and a total dose of 420 mg over 60 days. This medication is used in hormone therapy.

**APALUTAMIDE** is provided as a film-coated tablet for **oral** administration. The maximum daily dose is 240 mg, with a total dose of 438,000 mg over the treatment period. This medication is categorized under androgen receptor signaling inhibitors (ARSI).

**ENZALUTAMIDE** is also a film-coated tablet for **oral** administration, with a maximum daily dose of 160 mg and a total dose of 292,000 mg over 60 days. It is classified as an ARSI.

**Suprefact Depot 9.45 mg** is an implant containing **buserelin**, administered via **implantation**. The maximum daily dose is 9.9 mg, with a total dose of 198 mg over the treatment period. This medication is part of hormone therapy.

**Gonapeptyl Depot 3.75 mg** is a suspension for injection containing **triptorelin**, administered via **subcutaneous injection**. The maximum daily dose is 3.75 mg, with a total dose of 450 mg over 60 days. This medication is used in hormone therapy.

**Decapeptyl-CR 3.75 mg** is a suspension for injection containing **triptorelin**, administered as an **injectable solution**. The maximum daily dose is 3.75 mg, with a total dose of 245 mg over the treatment period. This medication is part of hormone therapy.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to evaluate the efficacy and safety of these medications in the context of low-volume metastatic castration-sensitive prostate cancer.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the time to clinical progression-free survival (cPFS) in both arms of the study. Secondary endpoints include overall survival (OS), time to prostate-specific antigen (PSA) increase as defined by PCWG3 criteria, time to first-line therapy for metastatic castration-resistant prostate cancer (mCRPC), correlation of circulating tumor DNA (ctDNA) levels with PSA levels, and the value of ctDNA quantification during androgen receptor signaling inhibitor (ARSI) treatment to predict tumor progression. Additionally, quality of life (QoL) in relation to ARSI treatment, correlation of PSMA-PET scan results to clinical outcomes, and the correlation of genomic profiles of previously taken prostate cancer tissue biopsies with clinical outcomes will be evaluated.

The efficacy parameters will be measured and collected at specified timepoints throughout the trial. The trial is designed to assess the non-inferiority of discontinuing ARSIs 12 months after initiation in patients with low-volume metastatic castration-sensitive prostate cancer (mCSPC), with the possibility to restart treatment. This approach aims to spare significant toxicity and costs while maintaining efficacy. The trial will utilize standard imaging protocols and validated criteria for assessing disease progression and treatment response.