Metastasis-directed therapy for oligorecurrent prostate cancer : A randomized phase III trial.

The primary objective of this randomized phase III trial is to evaluate whether the addition of short-term androgen deprivation therapy (ADT) for either 1 month or 6 months, combined with an **androgen receptor** targeted therapy (ARTA), to metastasis-directed therapy (MDT) significantly prolongs progression-free survival in patients with oligorecurrent hormone-sensitive prostate cancer. This is clinically relevant as it aims to delay the onset of metastatic castration-refractory prostate cancer (mCRPC), which is a critical progression point in the disease course, impacting patient survival and quality of life.

Secondary objectives include:

• Biochemical progression-free survival, calculated from the last day of MDT until biochemical relapse, defined by specific prostate-specific antigen (PSA) criteria.
• Clinical progression-free survival, determined from the last day of MDT until progression is observed on PSMA PET-CT/MRI.
• Cancer-specific survival, measured from the last day of treatment until death due to prostate cancer.
• Overall survival, calculated from the last day of treatment until death from any cause.
• Assessment of acute and late toxicity resulting from radiotherapy, using the Common Toxicity Criteria Version 5.0.
• Quality of life evaluation using the EORTC QLQ-C30 supplemented with QLQ-PR25, and quality-of-life-years assessed with the EuroQOL classification system (EQ-5D-5L).

The clinical trial involves **male** participants diagnosed with **oligorecurrent hormone-sensitive prostate cancer**. The study population is composed of individuals aged 18 years and older, with a **World Health Organization (WHO) performance status** ranging from 0 to 2, indicating they are generally in good health. The trial does not include female subjects or vulnerable populations. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of prostatic adenocarcinoma, prior treatment and control of the primary tumor, and a biochemical recurrence defined by prostate-specific antigen (PSA) levels. The trial also considers lifestyle factors such as the use of highly effective birth control methods. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of adding short-term androgen deprivation therapy (ADT) and androgen receptor targeted therapy (ARTA) to metastasis-directed therapy (MDT) in patients with **oligorecurrent hormone-sensitive prostate cancer**. This is a randomized, phase III trial with a double-blind, controlled design. The trial is expected to run from April 25, 2022, to April 16, 2024, with recruitment having started on April 25, 2022. The estimated end date for the trial is June 1, 2032.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven prostatic adenocarcinoma, prior treatment of the primary tumor, and a maximum of five extracranial metastases. Follow-up visits will occur at regular intervals to monitor the primary endpoint of poly-metastatic free survival and secondary endpoints, including metastatic castration-refractory prostate cancer free survival, biochemical progression-free survival, and overall survival. The end-of-study visit will assess the final outcomes and any adverse events.

The expected length of participant involvement is up to six months, with conditions for early termination including non-compliance with the study protocol or the occurrence of significant adverse events. Participants will be required to use highly effective birth control methods and maintain a WHO performance status of 0-2. The trial will adhere to the Common Toxicity Criteria Version 5.0 for scoring acute and late toxicity, and quality of life will be assessed using the EORTC QLQ-C30 and EQ-5D-5L systems at specified intervals.

The clinical trial involves several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Decapeptyl Sustained Release 22.5 mg** is a prolonged-release suspension for injection containing the active substance **triptorelin**. It is administered via injection with a maximum total dose of 22.5 mg over a treatment period of 6 months. The formulation is provided as a powder and solvent for suspension for injection.

**DEPO-ELIGARD 45 mg** and **DEPO-ELIGARD 7.5 mg** are solutions for injection containing **leuprorelin acetate**. Both are administered via injection, with maximum total doses of 45 mg and 7.5 mg, respectively, over a 6-month treatment period. These formulations are provided as a powder and solvent for solution for injection.

**FIRMAGON 80 mg** and **FIRMAGON 120 mg** are solutions for injection containing **degarelix**. FIRMAGON 80 mg is administered subcutaneously with a maximum total dose of 400 mg over 5 months, while FIRMAGON 120 mg is administered with a maximum total dose of 240 mg over 1 month. Both are provided as a powder and solvent for solution for injection.

**Enzalutamide 40 mg** is provided as soft capsules containing the active substance **enzalutamide**. It is administered orally with a maximum daily dose of 160 mg over a 6-month treatment period.

**Decapeptyl-CR 3.75 mg** is a suspension for injection containing **triptorelin**. It is administered via injection with a maximum total dose of 3.75 mg over a 6-month treatment period. The formulation is provided as a powder and solvent for suspension for injection.

**Orgovyx 120 mg** is a film-coated tablet containing **relugolix**. It is administered orally with a maximum daily dose of 120 mg over a 6-month treatment period.

**ZOLADEX LA 10.8 mg** and **ZOLADEX 3.6 mg** are implants containing **goserelin acetate**. Both are administered via injection, with maximum total doses of 10.8 mg and 3.6 mg, respectively, over a 6-month treatment period.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is poly-metastatic free survival, which will be calculated from the last day of metastasis-directed therapy (MDT) until the first day of poly-progression, defined as the detection of more than five new lesions on PSMA PET-CT/MRI. Secondary endpoints include metastatic castration-refractory prostate cancer free survival (mCRPC-FS), biochemical progression-free survival (bPFS), clinical progression-free survival (cPFS), cancer-specific survival (CSS), overall survival (OS), and quality of life assessments.

mCRPC-FS will be calculated from the last day of MDT until the first diagnosis of castration-resistant prostate cancer (CRPC), defined by biochemical and/or clinical progression at castrate testosterone levels. bPFS will be measured from the last day of the first stereotactic body radiation therapy (SBRT) or metastasectomy until biochemical relapse, defined by two consecutive prostate-specific antigen (PSA) rises. cPFS will be determined from the last day of MDT until progression on PSMA PET-CT/MRI. CSS and OS will be calculated from the last day of treatment until prostate cancer-specific death and death from any cause, respectively.

Quality of life will be assessed using the EORTC QLQ-C30 supplemented with QLQ-PR25, and the EuroQOL classification system (EQ-5D-5L). These assessments are scheduled at baseline, the last day of treatment, and during follow-up consultations at months 1, 3, 6, 12, and 24. Additionally, acute and late toxicity resulting from radiotherapy will be scored using the Common Toxicity Criteria Version 5.0 at every follow-up visit.