A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) Plus Enzalutamide Versus Placebo Plus Enzalutamide in Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC) (KEYNOTE-641)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,244
- 试验地点
- 518
- 主要终点
- 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
研究概览
简要总结
The purpose of this study is to assess the efficacy and safety of the combination of pembrolizumab (MK-3475) and enzalutamide in the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy for mCRPC, are abiraterone-naïve, or are intolerant to or progressed on abiraterone acetate. There are two primary study hypotheses.
Hypothesis 1: The combination of pembrolizumab plus enzalutamide is superior to placebo plus enzalutamide with respect to Overall Survival (OS).
Hypothesis 2: The combination of pembrolizumab plus enzalutamide is superior to placebo plus enzalutamide with respect to 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Study became unblinded in February 2023.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •The main inclusion and
排除标准
- •include but are not limited to the following:
- •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 prior to randomization
- •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 met one of the following criteria with regard to abiraterone acetate exposure: (1) is abiraterone-naïve; (2) received prior abiraterone acetate for the treatment of mHSPC or mCRPC, for a minimum of 4 weeks and not progressed while on treatment; or (3) received prior abiraterone acetate for the treatment of mHSPC or mCRPC and progressed on treatment after a minimum of 8 weeks treatment (minimum 14 weeks for those with bone progression)
- •Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM)
- •Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses prior to randomization
- •Participants must agree to the following during the study treatment period and for at least 90 days after the last dose of enzalutamide: Refrain from donating sperm, plus EITHER be abstinent OR must agree to use male condom
- •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
- •Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days of randomization
- •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 (noninfectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease
- •Has known active human immunodeficiency virus (HIV), concurrent active hepatitis B virus (HBV) or known active hepatitis C virus (HCV) infection
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- •Has hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their excipients
- •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 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 bradycardia (heart rate of <50 beats per minute) on the screening electrocardiogram (ECG)
- •Has history of prostate cancer progression on ketoconazole
- •Has had prior treatment with enzalutamide, apalutamide, darolutamide or cytochrome P450 (CYP) 17 inhibitor other than abiraterone acetate
- •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-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor
- •Has received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer
- •Has received prior treatment with docetaxel or another chemotherapy agent for mCRPC
- •Has had a prior anti-cancer monoclonal antibody (mAb) prior to randomization
- •Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (eg, saw palmetto) prior to randomization
- •Has received a live or live attenuated vaccine within 30 days prior to randomization
- •Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
- •Has a "superscan" bone scan
- •Is expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 90 days after the last dose of enzalutamide
- •Has had an allogenic tissue/solid organ transplant
研究组 & 干预措施
Placebo + Enzalutamide
Participants receive placebo by IV infusion administered on Day 1 Q3W for up to 35 cycles (approximately 2 years) PLUS enzalutamide 160 mg administered PO QD continuously until progression.
干预措施: Placebo (Drug)
Pembrolizumab + Enzalutamide
Participants receive 200 mg pembrolizumab by intravenous (IV) infusion administered on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 2 years) PLUS enzalutamide 160 mg administered orally (PO) once a day (QD) continuously until progression.
干预措施: Pembrolizumab (Biological)
Pembrolizumab + Enzalutamide
Participants receive 200 mg pembrolizumab by intravenous (IV) infusion administered on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 2 years) PLUS enzalutamide 160 mg administered orally (PO) once a day (QD) continuously until progression.
干预措施: Enzalutamide (Drug)
Placebo + Enzalutamide
Participants receive placebo by IV infusion administered on Day 1 Q3W for up to 35 cycles (approximately 2 years) PLUS enzalutamide 160 mg administered PO QD continuously until progression.
干预措施: Enzalutamide (Drug)
结局指标
主要结局
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
时间窗: Up to 40 months (through database cut-off date of 12-Dec-2022)
rPFS was defined as the time from randomization to the first documented progressive disease (PD) per PCWG-modified RECIST 1.1 based on blinded independent central review or death due to any cause, whichever occurred first. The rPFS per PCWG-modified RECIST for all participants is presented.
Overall Survival (OS)
时间窗: Up to 40 months (through database cut-off date of 12-Dec-2022)
OS was defined as the time from randomization to death due to any cause. The OS for all participants is presented.
次要结局
- Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST)(Up to 40 months (through database cut-off date of 12-Dec-2022))
- Time to Prostate-specific Antigen (PSA) Progression(Up to 40 months (through database cut-off date of 12-Dec-2022))
- Prostate-specific Antigen (PSA) Response Rate(Up to 40 months (through database cut-off date of 12-Dec-2022))
- Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of Prostate Cancer Working Group (PCWG)-Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by as Assessed by Blinded Independent Central Review(Up to 40 months (through database cut-off date of 12-Dec-2022))
- Time to First Symptomatic Skeletal-related Event (SSRE)(Up to 40 months (through database cut-off date of 12-Dec-2022))
- Objective Response (OR) Per Prostate Cancer Working Group (PCWG)-Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by as Assessed by Blinded Independent Central Review(Up to 40 months (through database cut-off date of 12-Dec-2022))
- Prostate-specific Antigen (PSA) Undetectable Rate(Up to 40 months (through database cut-off date of 12-Dec-2022))
- Duration of Response (DOR) Per Prostate Cancer Working Group (PCWG)-Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by as Assessed by Blinded Independent Central Review(Up to 40 months (through database cut-off date of 12-Dec-2022))
- Time to Pain Progression (TTPP) as 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 40 months (through database cut-off date of 12-Dec-2022))
- Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)(Up to 40 months (through database cut-off date of 12-Dec-2022))
- Number of Participants Who Experience an Adverse Event (AE)(Up to 40 months (through database cut-off date of 12-Dec-2022))