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

Study Overview
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Brief Summary
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This is a phase 3, randomized, open-label study of MK-5684 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 MK-5684 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.

Official Title
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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

Conditions
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Prostate Cancer Metastatic

Intervention / Treatment
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* Drug: MK-5684
* Drug: Abiraterone acetate
* Drug: Enzalutamide
* Drug: Hydrocortisone
* Drug: Fludrocortisone acetate
* Drug: Prednisone
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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 MK-5684, for at least 30 days after the last dose of abiraterone acetate, and for at least 30 days 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 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-αreductase 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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-5684<br>Participants receive MK-5684 5 mg by oral tablets twice daily (bid) plus dexamethasone 1.5 mg by oral tablets once daily (qd) and 0.1 mg fludrocortisone acetate by oral tablet qd until progression. Hydrocortisone 100 mg (oral or intramuscular [IM]) dose will also be provided to participants for use as rescue medication. | Drug: MK-5684<br>* Administered orally<br>Drug: Hydrocortisone<br>* Administered orally or IM as a rescue medication<br>Drug: Fludrocortisone acetate<br>* Administered orally<br>Drug: Dexamethasone<br>* Administered orally as rescue medication<br>|
| Active Comparator: Abiraterone Acetate or Enzalutamide<br>Participants receive abiraterone 1000 mg qd by oral tablets plus prednisone 5 mg bid by oral tablets or enzalutamide 160 mg qd by oral tablets. | Drug: Abiraterone acetate<br>* Administered orally<br>* Other names: YONSA;Drug: Enzalutamide<br>* Administered orally<br>* Other names: XTANDI;Drug: Prednisone<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as time from randomization to death due to any cause. | Up to  54 months | 
| Radiographic Progression-free Survival (rPFS) | rPFS is determined by 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). | Up to  54 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Objective Response (OR) | OR is determined by PCWG-modified RECIST 1.1 as assessed by BICR. | Up to  54 months | 
| Duration of Response (DOR) | DOR is determined by PCWG-modified RECIST 1.1 as assessed by BICR. | Up to  54 months | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 |