Evaluation of Ultra-Hypofractionated Radiotherapy Combined with Oral Relugolix in Patients with Intermediate Risk Prostate Cancer

The primary objective of this study is to evaluate the rate of complete **biochemical response** after 6 months of treatment in patients with unfavorable intermediate-risk localized **prostate cancer**. This is defined as achieving a prostate-specific antigen (PSA) level of less than 0.5 ng/mL following prostate radiotherapy (36.25 Gy in 5 fractions) combined with a short course of oral **relugolix**. This objective is clinically relevant as it aims to determine the efficacy of this treatment regimen in achieving a significant reduction in PSA levels, which is a critical marker for disease control in prostate cancer management.

The secondary objectives include:

• Biochemical relapse-free survival (BRFS) at 2 years post-radiotherapy, defined by a PSA rise of 2 ng/mL or more above the nadir according to the RTOG-ASTRO Phoenix Consensus Conference.
• Rate of patients with testosterone recovery at 90 days post-androgen deprivation therapy (ADT), with eugonadal levels defined as testosterone >150 ng/dL.
• Rate of patients experiencing non-pathological fractures at 2 years.
• Rate of cardiovascular events, including myocardial infarction and stroke, at 48 weeks.
• Erectile dysfunction rate measured with the International Index of Erectile Function (IIEF) at 2 years post-treatment.
• Quality of life assessed using the EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires.

The clinical trial involves a study population of **male** participants exclusively, with an age range of 18 years and older. The participants are individuals diagnosed with **intermediate risk prostate cancer**, specifically those with unfavorable intermediate risk localized prostate cancer. The trial does not include a vulnerable population. Participants were selected based on specific criteria, including a histological confirmation of prostate adenocarcinoma and suitability for ultrahypofractionated treatment, with an International Prostate Symptom Score (IPSS) of less than 15 and a prostate volume of less than 90 cc. Additionally, candidates must be suitable for androgen deprivation therapy. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **relugolix**, a nonpeptide GnRH receptor antagonist, in combination with ultra-hypofractionated radiotherapy for the treatment of intermediate risk prostate cancer. This is a prospective, no-profit, single-arm phase II, interventional multicentric trial. The primary objective is to assess the rate of complete biochemical response after six months of treatment, defined as a prostate-specific antigen (PSA) level of less than 0.5 ng/mL. The trial will also evaluate secondary endpoints such as biochemical relapse-free survival at two years, testosterone recovery rate at 90 days post-androgen deprivation therapy, and quality of life metrics.

The trial will follow a structured sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 18, histological confirmation of prostate adenocarcinoma, and suitability for ultrahypofractionated treatment. Participants will undergo prostate radiotherapy (36.25 GY in 5 fractions) alongside a short course of oral relugolix. Follow-up visits will be scheduled to monitor treatment response and adverse events, with the end-of-study visit marking the conclusion of participant involvement. The overall trial duration is estimated to extend until March 2028, with recruitment starting in March 2025.

Participant involvement is expected to last for a maximum treatment period of six months, with conditions for early termination including withdrawal of consent or adverse events that compromise safety. The trial is not categorized as low intervention and is conducted under phase 4, ensuring rigorous monitoring and data collection to achieve the outlined objectives. The study's design and methodology adhere to high standards of clinical research, ensuring the reliability and validity of the findings.

The clinical trial involves the administration of **Relugolix**, a nonpeptide GnRH receptor antagonist, as the experimental medication. **Relugolix** is provided in an oral pharmaceutical form, identified by the code PHF00082MIG. The maximum daily dose is 360 mg, with the same amount being the maximum total dose allowed. The treatment period is set for a maximum of 6 months. The administration route is oral, and the medication is taken daily. **Relugolix** is a chemical substance, also known by the synonym TAK-385, and is classified under the ATC code L02BX04.

In addition to the experimental treatment, participants will undergo standard-of-care therapy, which includes prostate radiotherapy. The radiotherapy is delivered at a dose of 36.25 Gy in 5 fractions. This combination aims to assess the rate of complete biochemical response in patients with unfavorable intermediate-risk localized prostate cancer. The study does not involve the use of a placebo or comparator treatment. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed primarily by evaluating the rate of complete biochemical response after 6 months of treatment. This is defined as achieving a **prostate-specific antigen (PSA)** level of less than 0.5 ng/mL in patients with unfavorable intermediate-risk localized prostate cancer. These patients will undergo prostate radiotherapy at a dose of 36.25 Gy in 5 fractions, combined with a short course of oral **relugolix**. The primary endpoint will be measured at the 6-month mark following the initiation of treatment.

Secondary endpoints include several parameters: biochemical relapse-free survival (BRFS) at 2 years post-radiotherapy, defined by a PSA increase of 2 ng/mL or more above the nadir, as per the RTOG-ASTRO Phoenix Consensus Conference. Additionally, the rate of patients achieving testosterone recovery at 90 days post-androgen deprivation therapy (ADT) will be assessed, with eugonadal testosterone levels defined as greater than 150 ng/dL. Other secondary endpoints include the rate of non-pathological fractures at 2 years, cardiovascular events at 48 weeks (including myocardial infarction and stroke), erectile dysfunction rate measured by the International Index of Erectile Function (IIEF) at 2 years post-treatment, and quality of life assessed using the EORTC QLQ-C30 and EORTC QLQ-PR25 instruments.