Phase 3 Randomized Open-label Study of Opevesostat Versus Abiraterone Acetate or Enzalutamide in Metastatic Castration-resistant Prostate Cancer

The primary objective of this study is to compare **MK-5684** with alternative treatments, specifically abiraterone acetate or enzalutamide, in participants with metastatic castration-resistant prostate cancer (mCRPC). The comparison focuses on radiographic progression-free survival (rPFS) as assessed by blinded independent central review (BICR) using the Prostate Cancer Working Group (PCWG) Modified RECIST 1.1 criteria. Additionally, the study aims to compare overall survival between the treatment groups. These objectives are clinically relevant as they address the efficacy of MK-5684 in delaying disease progression and improving survival outcomes in mCRPC, a condition with limited treatment options.

Secondary objectives include: - Evaluating the time to initiation of the first subsequent anticancer therapy (TFST) in participants treated with MK-5684 compared to those receiving alternative treatments. - Assessing objective response (OR) and duration of response (DOR) per PCWG Modified RECIST 1.1 as evaluated by BICR. - Evaluating time to pain progression (TTPP) and health-related quality of life (HRQoL) using the FACT-P questionnaire. - Assessing time to prostate-specific antigen (PSA) progression and PSA response rate. - Evaluating the time to first symptomatic skeletal-related event (SSRE). - Assessing the safety and tolerability of MK-5684.

The clinical trial involves a total of **1076 participants** diagnosed with **metastatic castration-resistant prostate cancer**. The study population is exclusively male, with an age range that includes adults and the elderly. Participants were selected based on specific inclusion criteria, such as having histologically or cytologically confirmed adenocarcinoma of the prostate, evidence of metastatic disease, and progression of prostate cancer while on androgen deprivation therapy. The trial excludes female subjects and does not involve a vulnerable population. Participants are required to have an Eastern Clinical Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Lifestyle considerations such as diet and physical activity are not specified, but participants must have adequate organ function and ongoing androgen deprivation with serum testosterone levels below 50 ng/dL. The trial does not include individuals with small cell histology of prostate cancer, and those with a history of hepatitis B or C are eligible if their viral loads are undetectable. The study does not involve participants with uncontrolled HIV, as those infected must have well-controlled HIV on antiretroviral therapy.

The clinical trial is designed as a **randomized**, open-label study to evaluate the efficacy and safety of MK-5684 compared to alternative treatments such as **abiraterone acetate** or **enzalutamide** in participants with metastatic castration-resistant prostate cancer (mCRPC). The trial aims to assess radiographic progression-free survival (rPFS) and overall survival (OS) as primary endpoints, with secondary endpoints including time to initiation of the first subsequent anticancer therapy, objective response rate, and duration of response, among others. The trial is expected to commence recruitment in March 2024 and is estimated to conclude by December 2031.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed adenocarcinoma of the prostate, evidence of metastatic disease, and progression on prior hormonal therapy. Following randomization, participants will receive either MK-5684 or a comparator treatment. The trial includes regular follow-up visits to monitor treatment response, adverse events, and overall health status. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected duration of participant involvement is up to 35 weeks, depending on the treatment arm. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results, contributing valuable data to the understanding and management of mCRPC.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. The primary experimental medication is **Opevesostat**, administered as a film-coated tablet. The active substance is **Opevesostat Tosilate**, with a maximum daily dose of 10 mg and a total dose of 10,675 mg over a 35-day treatment period. The route of administration is oral.

**Abiraterone Acetate** is used as a comparator treatment, provided in tablet form. The maximum daily dose is 1000 mg, with a total dose of 1,067,500 mg over a 35-day period. This medication is also administered orally.

**Enzalutamide** is another comparator, available in capsule form. The maximum daily dose is 160 mg, with a total dose of 170,800 mg over 35 days. The route of administration is oral use.

**Prednisolone** is administered as a tablet, with a maximum daily dose of 10 mg and a total dose of 12,810 mg over a 42-day period. The administration route is oral.

**Hydrocortisone** is provided in various forms, including powder for injection, solution for injection, and tablet. The maximum daily dose for the injectable forms is 100 mg, with a total dose of 100 mg over a single day. The route for injection is intramuscular use. The tablet form also has a maximum daily dose of 100 mg, administered orally.

**Fludrocortisone** is available as a tablet, with a maximum daily dose of 2 mg and a total dose of 2,562 mg over a 42-day period. The administration route is oral.

**Prednisone** and **Prednisone Acetate** are both administered as tablets, with a maximum daily dose of 10 mg and a total dose of 12,810 mg over 42 days. The route of administration is oral.

**Dexamethasone** and **Dexamethasone Acetate** are provided in tablet form, with a maximum daily dose of 2 mg and a total dose of 2,562 mg over a 42-day period. The administration route is oral.

**Fludrocortisone Acetate** is also administered as a tablet, with a maximum daily dose of 2 mg and a total dose of 2,562 mg over 42 days. The route of administration is oral.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to compare the efficacy of the experimental medication, Opevesostat, against the comparator treatments in participants with metastatic castration-resistant prostate cancer (mCRPC).

The efficacy of the clinical trial will be assessed using the primary endpoints of **Radiographic Progression-free Survival (rPFS)** and **Overall Survival (OS)**. These endpoints will be evaluated to compare the investigational product, MK-5684, against alternative treatments such as abiraterone acetate or enzalutamide in participants with metastatic castration-resistant prostate cancer (mCRPC). The assessment of rPFS will be conducted per the Prostate Cancer Working Group (PCWG) Modified RECIST 1.1 criteria, as evaluated by a Blinded Independent Central Review (BICR).

Secondary endpoints include a variety of measures to further evaluate efficacy. These include Time to Initiation of the First Subsequent Anticancer Therapy (TFST), Objective Response Rate (ORR), Duration of Response (DOR), Time to Pain Progression (TTPP), and changes in the FACT-G Total Score, which assesses quality of life. Additionally, Time to Prostate-specific Antigen (PSA) progression, PSA Response Rate, and Time to first symptomatic skeletal-related event (TSSRE) will be measured. Safety will also be monitored by recording the number of participants experiencing adverse events (AEs) and those who discontinue treatment due to AEs.