Clinical trial NCT04934722: Efficacy and Safety of Pembrolizumab (MK-3475) Plus Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus Enzalutamide Plus ADT in Participants With Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) (MK-3475-991/KEYNOTE-991)-China Extension
Official title: A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) Plus Enzalutamide Plus ADT Versus Placebo Plus Enzalutamide Plus ADT in Participants With Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) (KEYNOTE-991)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Metastatic Hormone-Sensitive Prostate Cancer
Keywords: Programmed Cell Death-1 (PD1, PD-1),
Programmed Death-Ligand 1 (PDL1, PD-L1)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2021-06-22
Enrollment: 186
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will assess the efficacy and safety of pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT in Chinese participants with mHSPC. The primary hypothesis is that in participants with mHSPC, the combination of pembrolizumab plus enzalutamide plus ADT is superior to placebo plus enzalutamide plus ADT with respect to 1) 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 2) overall survival (OS). As of Amendment 4, the study is being stopped for futility. All the prespecified interim analysis after interim analysis (IA1) and final analysis of the study described the statistical analysis plan (SAP) will not be performed. Safety analysis will be performed at the end of the study; there will be no further analyses for efficacy and electronic patient-reported outcome (ePRO) endpoints collected from participants beyond the IA1 cutoff date. All study participants will stop ongoing treatment with pembrolizumab/placebo. Exceptions may be requested for study participants who, in the assessment of their study physician, are benefitting from the combination of enzalutamide and pembrolizumab, after consulting with the Sponsor. All other study participants should be discontinued from study and be offered standard of care (SOC) treatment as deemed necessary by the Investigator. If enzalutamide as SOC is not accessible off study to the participant, central sourcing may continue. As of Amendment 04, disease progression will no longer be centrally verified, participants will only be assessed locally. As of Amendment 4, Second Course treatment is not an option for participants. There are currently no participants in the Second Course Phase.

Detailed description: The China extension study will include participants previously enrolled in China in the global study for MK-3475-991 (NCT04191096) plus those enrolled during the China extension enrollment period. A total of approximately 186 Chinese participants will be enrolled.

Eligibility criteria: Inclusion Criteria:

* Male participants with histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
* Has metastatic disease assessed by investigator and verified by BICR by either ≥2 bone lesions on bone scan and/or visceral disease by computed tomography/magnetic resonance imaging (CT/MRI)
* Willing to maintain continuous Androgen Deprivation Therapy (ADT) with a luteinizing-hormone releasing hormone (LHRH) agonists or antagonists during study treatment or have a history of bilateral orchiectomy
* Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 10 days of randomization
* Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses prior to randomization
* Has adequate organ function
* Has provided newly obtained core or excisional biopsy (obtained within 12 months of screening) from soft tissue not previously irradiated (samples from tumors progressing in a prior site of radiation are allowed). Participants with bone only or bone predominant disease may provide a bone biopsy sample
* Male participants must agree to the following during the intervention period and for at least 120 days after the last dose of study intervention: Refrain from donating sperm PLUS either be abstinent from heterosexual intercourse and agree to remain abstinent OR agree to use contraception, unless confirmed to be azoospermic
* Male participants must agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex

Exclusion Criteria:

* Has a known additional malignancy that is progressing or has required active treatment in the last 3 years
* Has an active autoimmune disease that has required systemic treatment in past 2 years
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
* Has undergone major surgery including local prostate intervention (excluding prostate biopsy) within 28 days prior to randomization and not recovered adequately from the toxicities and/or complications
* Has a gastrointestinal disorder affecting absorption or is unable to swallow tablets/capsules
* Has an active infection (including tuberculosis) requiring systemic therapy
* Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
* Has known active human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
* Has known or suspected central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has a history of seizure or any condition that may predispose to seizure
* Has a history of loss of consciousness within 12 months of screening
* Has had myocardial infarction or uncontrolled angina within 6 months prior to randomization, or has New York Heart Association class III or IV congestive heart failure or a history of New York Heart Association class III or IV congestive heart failure
* Has hypotension (systolic blood pressure \<86 millimeters of mercury \[mmHg\]) or uncontrolled hypertension (systolic blood pressure \>170 mmHg or diastolic blood pressure \>105 mmHg) at the screening visit
* Has a history of clinically significant ventricular arrhythmias
* Has hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their excipients
* Has received prior ADT as neoadjuvant/adjuvant therapy for non-metastatic prostate cancer for \>39 months in duration or within 9 months prior to randomization or with evidence of disease progression while receiving ADT
* Has had prior treatment with a next generation hormonal agent (eg, abiraterone, enzalutamide, apalutamide, darolutamide)
* Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-programmed cell death-ligand 2 (anti PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor
* Has received a live vaccine within 30 days prior to randomization
* Has a "superscan" bone scan
* Has had an allogenic tissue/solid organ transplant
* Is expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
* Has received any prior pharmacotherapy, radiation therapy or surgery for metastatic prostate cancer with the following exceptions:

  1. Up to 3 months of ADT or orchiectomy with or without concurrent first-generation antiandrogens, if patient was not treated with docetaxel
  2. May have 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 4 weeks prior to randomization
  3. For participants with low volume metastatic disease, may have 1 course of definitive radiotherapy if it was administered at least 4 weeks prior to randomization
  4. Up to 6 cycles of docetaxel therapy with final treatment administration completed within 2 months of randomization and no evidence of disease progression. In these participants up to 6 months of ADT permitted

Primary outcomes:
measure: Radiographic Progression-free Survival (rPFS) 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)
timeFrame: Up to approximately 17 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 17 months
Secondary outcomes:
measure: Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST)
timeFrame: Up to Approximately 17 months
measure: Time to First Symptomatic Skeletal-related Event (TTSSRE)
timeFrame: Up to Approximately 17 months
measure: Time to Prostate-specific Antigen (PSA) Progression
timeFrame: Up to Approximately 17 months
measure: Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of PCWG-Modified RECIST 1.1 as Assessed by BICR
timeFrame: Up to Approximately 17 months
measure: Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item #3 ("Worst Pain in 24 Hours") and Opiate Use
timeFrame: Up to Approximately 17 months
measure: Time From Randomization to Disease Progression as Determined by Investigator Assessment After Next-line of Therapy or Death From Any Cause, Whichever Occurs First (PFS2)
timeFrame: Up to Approximately 17 months
measure: Prostate-specific Antigen (PSA) Response Rate
timeFrame: Up to Approximately 17 Months
measure: Prostate-specific Antigen (PSA) Undetectable
timeFrame: Up to Approximately 17 Months
measure: Objective Response Rate (ORR) Per PCWG-Modified RECIST 1.1 as Assessed by BICR
timeFrame: Up to Approximately 17 Months
measure: Duration of Response (DOR) Per PCWG- Modified RECIST 1.1 as Assessed by BICR
timeFrame: Up to Approximately 17 Months
measure: Number of Participants Who Experience an Adverse Event (AE)
timeFrame: Up to Approximately 17 Months
measure: Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
timeFrame: Up to Approximately 17 Months
Other outcomes:
Locations:
city: Beijing
country: China
facility: Peking University First Hospital ( Site 0800)
state: Beijing
city: Beijing
country: China
facility: Beijing Cancer Hospital ( Site 0802)
state: Beijing
city: Chongqing
country: China
facility: Chongqing Cancer Hospital ( Site 0815)
state: Chongqing
city: Xiamen
country: China
facility: The First Affiliated Hospital of Xiamen University (Site 0816)
state: Fujian
city: Guangzhou
country: China
facility: Sun Yat-Sen University Cancer Center ( Site 0825)
state: Guangdong
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou Medical University-Urology ( Site 0638)
state: Guangdong
city: Guangzhou
country: China
facility: Sun Yat Sen Memorial Hospital (Site # 0819)
state: Guangdong
city: Guangzhou
country: China
facility: Southern Medical University Nanfang Hospital ( Site 0838)
state: Guangdong
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital ( Site 0822)
state: Heilongjiang
city: Zhengzhou
country: China
facility: Henan Cancer Hospital ( Site 0818)
state: Henan
city: Wuhan
country: China
facility: Union Hospital Tongji Medical College Huazhong University of Science and Technology ( Site 0829)
state: Hubei
city: Wuhan
country: China
facility: Hubei Cancer Hospital ( Site 0833)
state: Hubei
city: Changsha
country: China
facility: Hunan Cancer Hospital ( Site 0817)
state: Hunan
city: Nanjing
country: China
facility: Nanjing Drum Tower Hospital ( Site 0811)
state: Jiangsu
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University ( Site 0821)
state: Jiangxi
city: XI An
country: China
facility: The Second Affiliated Hosp of Xi'an Jiaotong Univ College of Medicine ( Site 0831)
state: Shaanxi
city: Shanghai
country: China
facility: Renji Hospital Shanghai Jiaotong University School of Medicine ( Site 0807 )
state: Shanghai
city: XI An
country: China
facility: The first affiliated Hospital of Xi an Jiaotong University ( Site # 0812)
state: Shanxi
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute & Hospital ( Site 0804 )
state: Tianjin
city: Hangzhou
country: China
facility: 2nd Affil Hosp of Zhejiang University College of Medicine ( Site 0808)
state: Zhejiang
city: Hangzhou
country: China
facility: The 1st Affil Hosp of College of Medicine, Zhejiang Univ ( Site 0830)
state: Zhejiang
city: Hangzhou
country: China
facility: Zhejiang Provincial People's Hospital ( Site 0809)
state: Zhejiang
city: Ningbo
country: China
facility: Ningbo First Hospital-Urology (0835)
state: Zhejiang
city: Wenzhou
country: China
facility: The First Affiliated Hospital of Wenzhou Medical University ( Site 0834)
state: Zhejiang
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: