Study of Opevesostat (MK-5684) Versus Alternative NHA in mCRPC (MK-5684-003)

Prostate Cancer Metastatic Clinical Trial

Official title:

A Phase 3 Randomized, Open-label Study of MK-5684 Versus Alternative Abiraterone Acetate or Enzalutamide in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) Previously Treated With Next-generation Hormonal Agent (NHA) and Taxane-based Chemotherapy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06136624
• Other study ID #: 5684-003
• Secondary ID: 2023-504899-25MK
• Status: Recruiting
• Phase: Phase 3
• Start date: December 31, 2023
• Est. completion date: August 2, 2028

Study information

• Verified date: May 2024
• Source: Merck Sharp & Dohme LLC
• Contact: Toll Free Number
• Phone: 1-888-577-8839
• Email: Trialsites[@]merck.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a phase 3, randomized, open-label study of opevesostat compared to alternative abiraterone acetate or enzalutamide in participants with metastatic castration-resistant prostate cancer (mCRPC) with respect to overall survival (OS) and to radiographic progression-free survival (rPFS) per Prostate Cancer Working Group (PCWG) Modified Response Evaluation Criteria In Solid Tumors (RECIST 1.1) as assessed by blinded independent central review (BICR) in participants with mCRPC previously treated with next-generation hormonal agent (NHA) and taxane-based chemotherapy. It is hypothesized that opevesostat is superior with respect to OS and rPFS per PCWG Modified RECIST 1.1 as assessed by BICR in androgen receptor ligand binding domain (AR LBD) mutation-negative and -positive participants.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1200
• Est. completion date: August 2, 2028
• Est. primary completion date: August 2, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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
• 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)
• Has provided tumor tissue from a fresh core or excisional biopsy from soft tissue not previously irradiated
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days of randomization
• Has had prior treatment with PARPi or were deemed ineligible to receive treatment by the investigator or have refused PARPi treatment
• Has received prior 177Lu-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
• 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
• 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
• Participants with human immunodeficiency virus (HIV) infection must have well controlled HIV on antiretroviral therapy (ART)
• 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.
• Participants who can produce sperm must agree to the following during the study treatment period and for at least 7 days after the last dose of opevesostat, 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

Exclusion Criteria:

• Has a gastrointestinal disorder that might affect absorption
• Has a history of pituitary dysfunction
• Has poorly controlled diabetes mellitus
• Has 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
• Has received treatment with 5-areductase inhibitors (eg, finasteride or dutasteride), estrogens, or cyproterone within 4 weeks before the date of randomization
• 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
• 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
• Has a 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 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)
• Is unable to swallow capsules/tablets
• Is currently being treated with cytochrome 450-inducing antiepileptic drugs for seizures
• Participants on an unstable dose of thyroid hormone therapy within 6 months before the start of the study intervention
• 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
• 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, nelfinavir, atazanavir, glecaprevir-pibrentasvir, simeprevir, ledipasvir-sofosbuvir, verapamil, diltiazem, dronedarone, propafenone, quinidine, cyclosporine, valspodar, or milk thistle [Silybum marianum])
• Use of aldosterone antagonist (eg, spironolactone, eplerenone) and phenytoin within 4 weeks before the start of the study intervention

Related Conditions & MeSH terms

• Prostate Cancer Metastatic
• Prostatic Neoplasms

Intervention

Drug:
• Opevesostat
Administered orally
• Abiraterone acetate
Administered orally
• Enzalutamide
Administered orally
• Hydrocortisone
Administered orally or IM as a rescue medication
• Fludrocortisone acetate
Administered orally
• Prednisone
Administered orally
• Dexamethasone
Administered orally as rescue medication

Locations

Country	Name	City	State
Australia	Dubbo Hospital ( Site 0235)	Dubbo	New South Wales
Australia	Macquarie University-MQ Health Clinical Trials Unit ( Site 0234)	Macquarie University	New South Wales
Australia	Peter MacCallum Cancer Centre-Parkville Cancer Clinical Trials Unit (PCCTU) ( Site 0230)	Melbourne	Victoria
Australia	Westmead Hospital-Department of Medical Oncology ( Site 0232)	Westmead	New South Wales
Canada	Centre Hospitalier de l'Université de Montréal ( Site 0326)	Montréal	Quebec
Canada	Centre intégré de cancérologie du CHU de Québec Université Laval, Hôpital de l'Enfant-Jésus ( Site 0	Quebec City	Quebec
Canada	Centre intégré universitaire de santé et de services sociaux de l'Estrie - Centre Hospitalier Univer	Sherbrooke	Quebec
Chile	Bradford Hill Norte ( Site 0357)	Antofagasta
Chile	IC La Serena Research ( Site 0356)	La Serena	Coquimbo
Chile	Bradfordhill-Clinical Area ( Site 0351)	Santiago	Region M. De Santiago
Chile	FALP ( Site 0353)	Santiago	Region M. De Santiago
Chile	Pontificia Universidad Catolica de Chile-Hemato-Oncology ( Site 0354)	Santiago	Region M. De Santiago
Chile	Clinica Universidad Catolica del Maule-Oncology ( Site 0355)	Talca	Maule
Chile	Clinical Research Chile SpA ( Site 0358)	Valdivia	Los Rios
China	Zhejiang Provincial People's Hospital-Urology ( Site 0378)	Hangzhou	Zhejiang
China	The First Hospital of Jiaxing-urology ( Site 0380)	Jiaxing	Zhejiang
China	Nanchong Central Hospital-urology ( Site 0422)	Nanchong	Sichuan
China	Ningbo First Hospital-Urology ( Site 0383)	Ningbo	Zhejiang
China	Fudan University Shanghai Cancer Center-Urology department ( Site 0376)	Shanghai	Shanghai
China	Xinjiang Medical University Cancer Hospital - Urumqi-Urology ( Site 0419)	Urumqi	Xinjiang
China	Hubei Cancer Hospital-Urinary surgery ( Site 0406)	Wuhan	Hubei
Czechia	Masarykuv onkologicky ustav-Klinika komplexni onkologicke pece ( Site 0553)	Brno	Brno-mesto
Czechia	Fakultni nemocnice Olomouc-Onkologicka klinika ( Site 0555)	Olomouc	Olomoucky Kraj
Czechia	Fakultni nemocnice Ostrava-Klinika onkologicka ( Site 0554)	Ostrava	Moravskoslezsky Kraj
Czechia	Fakultni nemocnice v Motole-Onkologicka klinika 2. LF UK a FN Motol ( Site 0551)	Praha	Praha 5
Denmark	Rigshospitalet ( Site 0576)	Copenhagen	Hovedstaden
Denmark	Odense Universitetshospital-Department of oncology ( Site 0579)	Odense	Syddanmark
Finland	Kuopion Yliopistollinen Sairaala ( Site 0603)	Kuopio	Pohjois-Savo
Finland	Tampereen yliopistollinen sairaala ( Site 0604)	Tampere	Pirkanmaa
Finland	Turku University Hospital-Department of Oncology ( Site 0601)	Turku	Varsinais-Suomi
France	Centre Hospitalier de la Côte Basque ( Site 0633)	Bayonne	Pyrenees-Atlantiques
France	Institut de cancérologie Strasbourg Europe (ICANS) ( Site 0627)	Strasbourg	Alsace
Germany	Charité Universitaetsmedizin Berlin - Campus Mitte ( Site 0679)	Berlin
Germany	klinikum rechts der isar der technischen universität münchen-Urologische Klinik und Poliklinik ( Sit	Munich	Bayern
Hong Kong	Queen Mary Hospital ( Site 0727)	Hksar
Hungary	Országos Onkológiai Intézet-Urogenitális Tumorok és Klinikai Farmakológiai Osztály ( Site 0756)	Budapest	Pest
Israel	Emek Medical Center ( Site 0830)	Afula
Israel	Rambam Health Care Campus-Oncology Division ( Site 0826)	Haifa
Israel	Hadassah Medical Center ( Site 0833)	Jerusalem
Israel	Rabin Medical Center ( Site 0828)	Petah Tikva
Israel	Sheba Medical Center ( Site 0827)	Ramat Gan
Italy	IRCCS - Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori"-Oncologia Medica ( Site 08	Meldola	Emilia-Romagna
Korea, Republic of	Samsung Medical Center ( Site 1405)	Seoul
Korea, Republic of	Seoul National University Hospital-Oncology ( Site 1401)	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System-Medical oncology ( Site 1404)	Seoul
Korea, Republic of	Asan Medical Center-Oncology ( Site 1402)	Songpagu	Seoul
Netherlands	Meander Medisch Centrum ( Site 1157)	Amersfoort	Utrecht
Netherlands	Radboudumc-Medical Oncology ( Site 1152)	Nijmegen	Gelderland
Norway	Akershus Universitetssykehus-Onkologisk avdeling ( Site 1227)	Lørenskog	Akershus
Norway	Sykehuset Østfold Kalnes ( Site 1228)	Sarpsborg	Ostfold
Norway	St. Olavs Hospital-Kreftklinikken ( Site 1231)	Trondheim	Sor-Trondelag
Poland	Mazowiecki Szpital Wojewódzki w Siedlcach-Siedleckie Centrum Onkologii ( Site 1310)	Siedlce	Mazowieckie
Puerto Rico	Ad-Vance Medical Research-Research ( Site 1353)	Ponce
Puerto Rico	Pan American Center for Oncology Trials - Ciudadela ( Site 1351)	San Juan
Spain	Hospital Lucus Augusti-Oncology ( Site 1432)	Lugo
Spain	Hospital Universitario 12 de Octubre-Medical Oncology ( Site 1433)	Madrid	Madrid, Comunidad De
Spain	Hospital Universitario Ramón y Cajal-Medical Oncology ( Site 1431)	Madrid	Madrid, Comunidad De
Spain	Complexo Hospitalario Universitario de Ourense ( Site 1426)	Ourense	Orense
Spain	HOSPITAL UNIVERSITARIO VIRGEN DEL ROCIO-Medical Oncology ( Site 1428)	Sevilla
Sweden	Sahlgrenska Universitetssjukhuset ( Site 1479)	Gothenburg	Vastra Gotalands Lan
Sweden	Karolinska Universitetssjukhuset Solna ( Site 1478)	Stockholm	Stockholms Lan
Sweden	Akademiska sjukhuset-Blod- och tumörsjukdomar ( Site 1477)	Uppsala	Uppsala Lan
Taiwan	China Medical University Hospital-Department of Urology ( Site 1503)	Taichung
Taiwan	National Taiwan University Hospital-Urology ( Site 1506)	Taipei
Taiwan	Taipei Veterans General Hospital ( Site 1505)	Taipei
Taiwan	Chang Gung Medical Foundation-Linkou Branch-Medical Oncology ( Site 1504)	Taoyuan
Turkey	Gulhane Egitim Arastirma Hastanesi ( Site 1558)	Ankara
Turkey	Hacettepe Universite Hastaneleri-oncology hospital ( Site 1551)	Ankara
Turkey	Memorial Ankara Hastanesi-Medical Oncology ( Site 1557)	Ankara
United Kingdom	The Royal Cornwall Hospital ( Site 1610)	Truro	England
United States	Baltimore Veterans Affairs Medical Center ( Site 0069)	Baltimore	Maryland
United States	University of Virginia Health System ( Site 0054)	Charlottesville	Virginia
United States	University Hospitals Cleveland Medical Center ( Site 0043)	Cleveland	Ohio
United States	Colorado Clinical Research ( Site 0067)	Lakewood	Colorado
United States	Comprehensive Cancer Centers of Nevada ( Site 0010)	Las Vegas	Nevada
United States	Blue Ridge Cancer Care ( Site 0004)	Roanoke	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC	Orion Corporation, Orion Pharma

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Chile,  China,  Czechia,  Denmark,  Finland,  France,  Germany,  Hong Kong,  Hungary,  Israel,  Italy,  Korea, Republic of,  Netherlands,  Norway,  Poland,  Puerto Rico,  Spain,  Sweden,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS) in Androgen Receptor Ligand Binding Domain (AR LBD) Mutation-Positive Participants	OS is defined as time from randomization to death due to any cause. OS in AR LBD mutation-positive participants will be reported for each study arm.	Up to ~54 months
Primary	OS in AR LBD Mutation-Negative Participants	OS is defined as time from randomization to death due to any cause. OS in AR LBD mutation-negative participants will be reported for each study arm.	Up to ~54 months
Primary	Radiographic Progression-free Survival (rPFS) Per Prostate Cancer Working Group-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review in AR LBD Mutation-Positive Participant	rPFS is defined as the time from randomization to the first documented disease progression per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR) or death due to any cause, whichever occurs first. rPFS in AR LBD mutation-positive participants will be reported for each study arm.	Up to ~36 months
Primary	rPFS Per Prostate Cancer Working Group-modified RECIST 1.1 as Assessed by Blinded Independent Central Review in AR LBD Mutation-Negative Participants	rPFS is defined as the time from randomization to the first documented disease progression per PCWG-modified RECIST 1.1 as assessed by BICR or death due to any cause, whichever occurs first. rPFS in AR LBD mutation-negative participants will be reported for each study arm.	Up to ~36 months
Secondary	Time to Initiation of the First Subsequent Anti-Cancer Therapy or Death (TFST)	TFST is defined as the time from randomization to initiation of the first subsequent anticancer therapy or death, whichever occurs first.	Up to ~54 months
Secondary	Objective Response (OR)	OR is determined by PCWG-modified RECIST 1.1 as assessed by BICR.	Up to ~54 months
Secondary	Duration of Response (DOR)	DOR is determined by PCWG-modified RECIST 1.1 as assessed by BICR.	Up to ~54 months
Secondary	Time to Pain Progression (TTPP)	TTPP is assessed by Brief Pain Inventory-Short Form (BPI-SF) Item 3 ("Worst Pain in 24 Hours") and opiate analgesic use (Analgesic Quantification Algorithm [AQA] Score).	Up to ~54 months
Secondary	Time to Prostate-specific Antigen (PSA) Progression	The time from randomization to PSA progression. The PSA progression date is defined as the date of either: 1) =25% increase and =2 ng/mL above the nadir, confirmed by a second value =3 weeks later if there is PSA decline from baseline 2) =25% increase and =2 ng/mL increase from baseline beyond 12 weeks if there is no PSA decline from baseline.	Up to ~54 months
Secondary	Time to First Symptomatic Skeletal-related Event (SSRE)	The time from randomization to the first occurrence of any of the following symptomatic skeletal-related events: 1) Use of EBRT to prevent or relieve skeletal symptoms; 2) new symptomatic pathologic bone fracture (vertebral or nonvertebral); 3) spinal cord compression; or 4) tumor-related orthopedic surgical intervention.	Up to ~54 months
Secondary	Number of Participants Who Experience an Adverse Event	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.	Up to ~54 months
Secondary	Number of Participants Who Discontinue Study Treatment Due to an Adverse Event	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.	Up to ~54 months

External Links

•   Merck Clinical Trials Information