A Phase 3 Randomized, Open-label Study of Opevesostat Tosylate Versus Abiraterone Acetate or Enzalutamide in Metastatic Castration-Resistant Prostate Cancer
- Trial ID
- 2023-504899-25-00
- Protocol
- MK-5684-003
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare **MK-5684** with alternative treatments, specifically abiraterone acetate or enzalutamide, in terms of overall survival in participants with metastatic castration-resistant prostate cancer (mCRPC). This is clinically relevant as it aims to determine the efficacy of MK-5684 in extending the lifespan of patients with mCRPC, a condition characterized by cancer progression despite hormonal therapy and chemotherapy.
Secondary objectives include:
- Evaluating the time to first symptomatic skeletal-related event (SSRE) of participants treated with MK-5684 compared to those treated with alternative therapies.
- Assessing the time to prostate-specific antigen (PSA) progression in participants receiving MK-5684 versus alternative treatments.
- Comparing the time to pain progression (TTPP) between the two treatment groups.
- Evaluating the objective response (OR) and duration of response (DOR) per Prostate Cancer Working Group (PCWG) Modified RECIST 1.1, as assessed by blinded independent central review (BICR), in participants treated with MK-5684 versus alternative therapies.
- Assessing the time to first SSRE in participants receiving MK-5684 compared to those on alternative treatments.
- Evaluating the safety and tolerability of MK-5684.
Participants
The clinical trial involves a total of **851 participants** diagnosed with **metastatic castration-resistant prostate cancer**. The study population is exclusively male, with an age range corresponding to categories 3 and 4, indicating adult and elderly participants. The selection criteria for the trial included individuals with histologically- or cytologically-confirmed adenocarcinoma of the prostate, excluding those with small cell histology. Participants were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, ensuring a relatively stable general health status. The trial population was selected based on specific inclusion criteria, such as ongoing androgen deprivation therapy and evidence of metastatic disease. Lifestyle considerations include the requirement for participants receiving bone resorptive therapy to have been on stable doses for at least four weeks prior to randomization. The trial does not include female or vulnerable populations, focusing solely on male subjects with the specified medical condition.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label study to evaluate the efficacy and safety of MK-5684 compared to alternative treatments, **abiraterone acetate** or **enzalutamide**, in participants with metastatic castration-resistant prostate cancer (mCRPC). The trial aims to assess overall survival and radiographic progression-free survival (rPFS) as primary endpoints, with secondary endpoints including time to initiation of subsequent anti-cancer therapy, objective response, and duration of response. The study is expected to commence recruitment on March 1, 2024, and conclude by September 5, 2029.
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 therapies. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, with assessments including imaging studies and laboratory tests. The end-of-study visit will occur upon completion of the treatment period or in the event of disease progression or unacceptable toxicity.
The expected duration of participant involvement is up to 42 weeks, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the findings.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. The primary experimental medication is **Opevesostat**, also known as MK-5684 tosylate, which is provided in the form of a film-coated tablet. The maximum daily dose is 10 mg, with a total maximum dose of 10,675 mg over a treatment period of 35 days. The route of administration is oral.
**Abiraterone Acetate** is used as a comparator treatment in the study. It is administered in tablet form with a maximum daily dose of 1000 mg and a total maximum dose of 1,067,500 mg over a 35-day period. The administration route is oral.
**Enzalutamide** is another comparator treatment, provided in capsule form. The maximum daily dose is 160 mg, with a total maximum dose of 170,800 mg over a 35-day treatment period. The route of administration is oral.
**Fludrocortisone** and **Fludrocortisone Acetate** are auxiliary treatments in the study, both administered in tablet form. The maximum daily dose for each is 0.2 mg, with a total maximum dose of 256.2 mg over a 42-day period. The administration route is oral.
**Hydrocortisone** is used in various forms, including powder for injection, solution for injection, and oral use. The maximum daily dose for the injectable forms is 100 mg, with a total maximum dose of 100 mg over a single day. The route of administration for the injectable forms is intramuscular, while the oral form is administered orally.
**Dexamethasone** and **Dexamethasone Acetate** are provided in tablet form, with a maximum daily dose of 2 mg and a total maximum dose of 2562 mg over a 42-day period. The administration route is oral.
**Prednisone** and **Prednisone Acetate** are administered in tablet form, with a maximum daily dose of 10 mg and a total maximum dose of 12,810 mg over a 42-day period. The route of administration is oral.
**Prednisolone** is also administered in tablet form, with a maximum daily dose of 10 mg and a total maximum dose of 12,810 mg over a 42-day period. The administration route is oral.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The study aims to compare the efficacy of MK-5684 against alternative treatments in participants with metastatic castration-resistant prostate cancer (mCRPC) who have previously been treated with next-generation hormonal agents and taxane-based chemotherapy.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Overall Survival (OS)** in both Androgen Receptor Ligand Binding Domain (AR LBD) mutation-positive and mutation-negative participants, as well as **Radiographic Progression-free Survival (rPFS)** per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), assessed by Blinded Independent Central Review (BICR) in both AR LBD mutation-positive and mutation-negative participants.
Secondary endpoints will evaluate additional aspects of efficacy, such as the **Time to Initiation of the First Subsequent Anti-Cancer Therapy or Death (TFST)**, **Objective Response (OR)** per PCWG-modified RECIST 1.1 as assessed by BICR, and **Duration of Response (DOR)**. Other secondary measures include **Time to Pain Progression (TTPP)**, assessed by the Brief Pain Inventory-Short Form (BPI-SF) Item 3 and Opiate Analgesic Use, **Time to Prostate-specific Antigen (PSA) Progression**, and **Time to First Symptomatic Skeletal-related Event (SSRE)**. Additionally, the number of participants experiencing adverse events and those discontinuing study treatment due to adverse events will be recorded.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
- Has prostate cancer progression while on androgen deprivation therapy (or post bilateral orchiectomy) within 6 months before Screening
- If participant received first generation anti-androgen therapy before screening, the participant has evidence of disease progression >4 weeks since the last flutamide treatment and >6 weeks since the last bicalutamide or nilutamide treatment
- Has current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue disease by computed tomography/magnetic resonance imaging (CT/MRI)
- Has disease that progressed during or after treatment with 1 novel hormonal agent (NHA)
- Has received 1 but no more than 2 taxane-based chemotherapy regimens for metastatic castration-resistant prostate cancer (mCRPC) and has had progressive disease (PD) during or after treatment
- Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<1.7 nM)
- Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses for ≥ 4 weeks before the date of randomization
- If capable of producing sperm, participant must agree to the following during the study treatment period and for at least 7 days after the last dose of MK-5684, for at least 30 days after the last dose of abiraterone acetate, and for at least 3 months after the last dose of enzalutamide: EITHER be abstinent OR must agree to use male condom.
- Has provided tumor tissue from a fresh core or excisional biopsy from soft tissue not previously irradiated
- Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART)
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days of randomization
- Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load before randomization.
- Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at Screening.
- Has had prior treatment with poly (ADP-ribose) polymerase inhibitor (PARPi) or were deemed ineligible to receive treatment by the investigator or have refused PARPi treatment
- Has received prior 177Lu-prostate-specific membrane antigen (PSMA)-617 or were deemed ineligible to receive 177Lu-PSMA-617 treatment by the investigator or refused 177Lu-PSMA-617 treatment
- Participants who have not received cabazitaxel can be enrolled if they are ineligible for cabazitaxel treatment as determined by the investigator or have refused treatment
Exclusion Criteria
- Has a gastrointestinal disorder that might affect absorption
- Unable to swallow capsules/tablets
- History of pituitary dysfunction
- Poorly controlled diabetes mellitus
- Clinically significant abnormal serum potassium or sodium level
- Has a history of active or unstable cardio/cerebro-vascular disease, including thromboembolic events
- Has a history of seizure within 6 months of providing documented informed consent or any condition that may predispose to seizures within 12 months before the date of randomization
- Has a history of clinically significant ventricular arrhythmias
- Has received an anticancer monoclonal antibody (mAb) within 4 weeks before the date of randomization, or has not recovered from adverse events (AEs) due to mAbs administered more than 4 weeks before the date of randomization
- Has undergone major surgery, including local prostate intervention (except prostate biopsy), within 28 days before the date of randomization, and has not recovered from the toxicities and/or complications
- Participants who have not adequately recovered from major surgery or have ongoing surgical complications
- Has used herbal or medicinal products that may have hormonal anti-prostate cancer activity and/or are known to decrease prostate-specific Antigen (PSA) (eg, saw palmetto, megesterol acetate) within 4 weeks before the date of randomization
- Has received radium-223 or lutetium-177 within 4 weeks before the date of randomization, or has not recovered to Grade ≤1 or baseline from AEs due to radium-223 or lutetium-177 administered more than 4 weeks before the date of randomization
- Is currently being treated with cytochrome 450-inducing antiepileptic drugs for seizures
- Has received treatment with 5-αreductase inhibitors (eg, finasteride or dutasteride), estrogens, or cyproterone within 4 weeks before the date of randomization
- Use of aldosterone antagonist (eg, spironolactone, eplerenone) and phenytoin within 4 weeks before the start of the study intervention
- Participants on an unstable dose of thyroid hormone therapy within 6 months before the start of the study intervention
- Has received colony-stimulating factors within 28 days before the date of randomization
- Has received a whole blood transfusion in the last 120 days before the date of randomization. Packed red blood cells and platelet transfusions are acceptable if not given within 28 days of the date of randomization.
- Has received prior targeted small molecule therapy or NHA treatment within 4 weeks before the first dose of study intervention as follows: enzalutamide or apalutamide within 3 weeks or abiraterone acetate + prednisone or darolutamide within 2 weeks
- Received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention
- Received prior radiotherapy within 2 weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids
- Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
- Has a “superscan” bone scan
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication
- Known additional malignancy that is progressing or has required active treatment within the past 3 years
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- Has an active autoimmune disease that has required systemic treatment in past 2 years
- Has an active infection requiring systemic therapy
- Has concurrent active HBV or known active HCV infection
- Has a history of long QTc syndrome
- Has any of the following at Screening Visit: hypotension (systolic blood pressure [BP] <110 mm Hg) or uncontrolled hypertension (systolic BP ≥160 mm Hg or diastolic BP ≥90 mm Hg, in 2 out of 3 recordings with optimized antihypertensive therapy)
- Systemic use of the following medications within 2 weeks before the first dose of study intervention: strong CYP3A4 inducers (eg, avasimibe,carbamazepine, lumacaftor, phenobarbital, rifampicin, rifapentine, or St John's Wort); P-gp inhibitors (eg, erythromycin, clarithromycin,rifampicin, ketoconazole, itraconazole, posaconazole, artesunate-pyronaridine, ritonavir, indinavir, nelfi navir, atazanavir, glecaprevir-pibrentasvir,simeprevir, ledipasvir-sofosbuvir, verapamil, diltiazem, dronedarone, propafenone, quinidine, cyclosporine, valspodar, or milk thistle [Silybummarianum])
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 01 Mar 2024 | 18 |
 Czechia | Recruiting | 01 Mar 2024 | 25 |
 Denmark | Recruiting | 01 Mar 2024 | 20 |
 Finland | Recruiting | 01 Mar 2024 | 15 |
 France | Recruiting | 01 Mar 2024 | 55 |
 Germany | Recruiting | 01 Mar 2024 | 35 |
 Hungary | Recruiting | 01 Mar 2024 | 25 |
 Ireland | Recruiting | 01 Mar 2024 | 10 |
 Italy | Recruiting | 01 Mar 2024 | 12 |
 The Netherlands | Recruiting | 01 Mar 2024 | — |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
HYDROCORTISONE | Other | — | INTRAMUSCULAR | 100 | 1 | SUB08065MIG |
PREDNISONE ACETATE | Comparator | — | ORAL USE | 10 | 42 | SUB04024MIG |
ENZALUTAMIDE | Comparator | — | ORAL USE | 160 | 35 | SUB77412 |
DEXAMETHASONE ACETATE | Other | — | ORAL USE | 2 | 42 | SUB01608MIG |
PREDNISONE | Comparator | — | ORAL USE | 10 | 42 | SUB10020MIG |
Opevesostat | Test | FILM-COATED TABLET | ORAL USE | 10 | 35 | PRD10441547 |
ABIRATERONE ACETATE | Comparator | — | ORAL | 1000 | 35 | SUB31647 |
DEXAMETHASONE | Other | — | ORAL USE | 2 | 42 | SUB07017MIG |
HYDROCORTISONE | Other | PHF00099MIG | ORAL USE | 100 | 1 | SCP29190199 |
HYDROCORTISONE | Other | — | INTRAMUSCULAR | 100 | 1 | SUB08065MIG |