A Study of MK-5684 Versus Alternative Next-generation Hormonal Agent (NHA) in Metastatic Castration-resistant Prostate Cancer (mCRPC) Post One NHA (MK-5684-004)

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of MK-5684 plus hormone replacement therapy (HRT) compared to alternative abiraterone acetate or enzalutamide in participants with Metastatic Castration-resistant Prostate Cancer (mCRPC) previously treated with one next-generation hormonal agent (NHA). The primary study hypotheses are that MK-5684 is superior to alternative abiraterone acetate or enzalutamide with respect 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) and overall survival (OS), in androgen receptor ligand binding domain (AR LBD) mutation positive and negative 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) That Progressed On or After Prior Treatment With One Next-generation Hormonal Agent (NHA)

Conditions
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Metastatic Castration-resistant Prostate Cancer (mCRPC), Prostatic Neoplasms

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The main inclusion criteria include but are not limited to the following: Have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell histology Has current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue disease shown by computed tomography scan (CT)/magnetic resonance imaging (MRI) Has prostate cancer progression while receiving androgen deprivation therapy (ADT) (or post bilateral orchiectomy) within 6 months before Screening Has disease that progressed during or after treatment with one next-generation hormonal agent (NHA) for hormone sensitive prostate cancer (HSPC) metastatic hormone sensitive prostate cancer (mHSPC) or non metastatic hormone sensitive prostate cancer (nmHSPC), for at least 8 weeks (at least 14 weeks for participants with bone progression) Note: Participants may have received abiraterone acetate and docetaxel or darolutamide and docetaxel for HSPC. However, participants must have received no more than six cycles of docetaxel and had no radiographic disease progression while receiving docetaxel Has an eastern clinical oncology group (ECOG) performance status of 0 or 1 assessed within 7 days before randomization Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<1.7 nM) Has had prior treatment with Poly polymerase inhibitors (PARPi) or were deemed ineligible to receive treatment by the investigator or have refused PARPi treatment Has adequate organ function Has provided tumor tissue from a fresh core or excisional biopsy from soft tissue not previously irradiated. Samples from tumors progressing at a prior site of radiation are allowed 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 have adverse event (AEs) due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement therapy (HRT) or participants who have ≤Grade 2 neuropathy are eligible Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART) Exclusion Criteria: The main exclusion criteria include but are not limited to the following: Has presence of gastrointestinal condition Is unable to swallow capsules/tablets Has history of pituitary dysfunction Has poorly controlled diabetes mellitus Has active or unstable cardio/cerebro-vascular disease, including thromboembolic events Has clinically significant abnormal serum potassium or sodium level. Has any of the following at Screening Visit: Hypotension: systolic BP <110 mmHg, or Uncontrolled hypertension: systolic BP ≥160mmHg or diastolic BP ≥90 mmHg, in 2 out of 3 recordings with optimized antihypertensive therapy History or family history of long QTc syndrome Has a history of seizure(s) within 6 months prior to signing the IC or has any condition that may predispose to seizure within 12 months prior to the date of enrollment Has a history of clinically significant ventricular arrhythmias or Mobitz II second degree or third-degree heart block without a permanent pacemaker in place Has received a taxane-based chemotherapy and or NHA for metastatic castration-resistant prostate cancer (mCRPC) Has not adequately recovered from major surgery or have ongoing surgical complications Has received prior treatment with radium for prostate cancer Is currently being treated with Cytochrome P450 (CYP450)-inducing antiepileptic drugs for seizures Participants on an unstable dose of thyroid hormone therapy within 6 months before the start of the study intervention Receives prior radiotherapy within 2 weeks before the first dose of study intervention, or radiation-related toxicities, requiring corticosteroids Receives prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention Has systemic use of strong Cytochrome P450 3A4 (CYP3A4) inducers and P-glycoprotein (P-gp) inhibitors within 2 weeks before the first dose of study intervention Has received prior targeted small molecule therapy or NHA treatment within 4 weeks before the first dose of study intervention Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration Has known hypersensitivity to the components or excipients in abiraterone acetate, prednisone or prednisolone, or enzalutamide Has a superscan bone scan defined as an intense symmetric activity in the bones and diminished renal parenchymal activity on baseline bone scan such that the presence of additional metastases in the future could not be evaluated Has known additional malignancy that is progressing or has required active treatment within the past 3 years Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable and have not required steroid treatment for at least 14 days prior to the first dose of study intervention Has active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is allowed Active infection requiring systemic therapy Has concurrent active Hepatitis B virus and Hepatitis C virus infection

Ages Eligible for Study
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Minimum Age: 18 Years

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 + hormone replacement therapy (HRT)<br>Participants receive MK-5684 5 mg by oral tablets twice daily (BID) plus dexamethasone 1.5 mg by oral tablets and fludrocortisone acetate 0.1 mg oral tablet once daily (QD) continuously until disease progression. Hydrocortisone 100 mg (oral or intramuscular [IM]) will also be provided to participants for use as rescue medication. | Drug: MK-5684<br>* Administered orally<br>Drug: Dexamethasone<br>* Administered orally<br>Drug: Fludrocortisone acetate<br>* Administered orally<br>Drug: Hydrocortisone<br>* Administered orally or IM as a rescue drug<br>|
| Active Comparator: Alternative next generation hormonal agent (NHA)<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 until disease progression. | Drug: Abiraterone acetate<br>* Administered orally<br>* Other names: Yonsa;Drug: Prednisone acetate<br>* Administered orally<br>Drug: Enzalutamide<br>* Administered orally<br>* Other names: Xtandi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Progression-free Survival (rPFS) | rPFS is defined as the time from randomization to the first documented disease progression per PCWG-modified RECIST 1.1 by BICR or death due to any cause, whichever occurs first. | Up to approximately 82 months | 
| Overall Survival (OS) | OS is defined as the time from randomization to death due to any cause. | Up to approximately 82 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Initiation of the First Subsequent Anticancer Therapy (TFST) | TFST is defined as the time from randomization to initiation of the first subsequent anti-cancer therapy or death; whichever occurred first. | Up to approximately 82 months | 
| Objective Response Rate (ORR) | ORR is defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented. | Up to approximately 82 months | 
| Duration of Response (DOR) | For participants who demonstrate confirmed CR or PR, duration of response is defined as the time from the first documented evidence of CR or PR until disease progression per PCWG-modified RECIST 1.1 as assessed by BICR or death from any cause, whichever occurs first. | Up to approximately 82 months | 
| Time to Pain Progression (TTPP) | TTPP is defined as the time from randomization to pain progression. TTTP 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 approximately 82 months | 
| Prostrate-specific Antigen (PSA) Response Rate | The Prostate-specific Antigen (PSA) response rate is the percentage of participants who had PSA response defined as a reduction in the PSA level from baseline by ≥50%. The reduction in PSA level was confirmed by an additional PSA evaluation performed ≥3 weeks from the original response. | Up to approximately 82 months | 
| Time to Prostate-specific Antigen (PSA) Progression | The time to PSA progression is the time from randomization to PSA progression. The PSA progression date is defined as the date of: 1) ≥25% increase and ≥2 ng/mL above the nadir, confirmed by a second value ≥3 weeks later if there was PSA decline from baseline; OR 2) ≥25% increase and ≥2 ng/mL increase from baseline. | Up to approximately 82 months | 
| Time to first symptomatic skeletal-related event (TSSRE) | TSSRE is the time from randomization to the first symptomatic skeletal-related event defined as: 1. use of external-beam radiation therapy (EBRT) to prevent or relieve skeletal symptoms 2. occurrence of new symptomatic pathologic bone fracture (vertebral or non-vertebral) 3. occurrence of spinal cord compression 4. tumor-related orthopedic surgical intervention, whichever occurs first. | Up to approximately 82 months | 
| Number of Participants Who Experience an Adverse Event (AE) | An AE is defined as any unfavorable and unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The number of participants who experience one or more AE will be reported. | Up to approximately 82 months | 
| Number of Participants Who Discontinue Study Treatment Due to an AE | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The number of participants who discontinue study treatment due to an AE will be reported. | Up to approximately 82 months |