A Phase 3, Randomized Open-label Study of Pembrolizumab (MK-3475) Plus Olaparib Versus Abiraterone Acetate or Enzalutamide in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) Who Are Unselected for Homologous Recombination Repair Defects and Have Failed Prior Treatment With One Next-generation Hormonal Agent (NHA) and Chemotherapy (KEYLYNK-010)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 793
- 试验地点
- 193
- 主要终点
- Overall Survival (OS)
研究概览
简要总结
The purpose of this study is to assess the efficacy and safety of the combination of the polyadenosine 5'-diphosphoribose poly (ADP-ribose) polymerase (PARP) inhibitor olaparib and pembrolizumab in the treatment of participants with mCRPC who have failed to respond to either abiraterone acetate or enzalutamide (but not both) and to chemotherapy.
The primary study hypotheses are that the combination of pembrolizumab plus olaparib is superior to abiraterone acetate or enzalutamide with respect to:
- Overall Survival (OS) and
- Radiographic progression-free survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 as assessed by blinded independent central review (BICR)
As of Amendment 06, the Data Monitoring Committee (DMC) is no longer applicable. Participants still on treatment may have the option to continue receiving study intervention or SOC if they are deriving clinical benefit, until criteria for discontinuation are met. Participants who are still on study treatment and deriving clinical benefit will no longer have tumor response assessments by BICR. However, local tumor imaging assessments should continue per standard of care (SOC) schedule. In addition, electronic patient-reported outcome (ePRO) assessments will no longer be performed and biomarker samples will no longer be collected.
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
- None
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
- •Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
- •Has prostate cancer progression while receiving androgen deprivation therapy (or post bilateral orchiectomy) within 6 months before screening
- •Has current evidence of metastatic disease documented by bone lesions on bone scan and/or soft tissue disease shown by computed tomography/magnetic resonance imaging (CT/MRI)
- •Has received prior treatment with abiraterone acetate OR enzalutamide, but not both
- •Have disease that progressed during or after treatment with abiraterone acetate for either metastatic hormone-sensitive prostate cancer (mHSPC) or mCRP or enzalutamide for mCRPC for at least 8 weeks (at least 14 weeks for participants with bone progression)
- •Participants that received abiraterone acetate for mHSPC may not have received abiraterone acetate or enzalutamide for mCRPC
- •Have received docetaxel chemotherapy regimen for metastatic castration-resistant prostate cancer (mCRPC) and have had progressive disease during or after treatment with docetaxel
- •Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM)
- •If receiving bone resorptive therapy, including but not limited to bisphosphonates or denosumab, must have been receiving stable doses before randomization
- •Must agree to refrain from donating sperm during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention PLUS be abstinent from heterosexual intercourse OR must agree to use contraception unless confirmed to be azoospermic
- •Contraception use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirement above, the local label requirements are to be followed.
- •Has provided tumor tissue from a fresh core or excisional biopsy (obtained within 12 months of screening) from soft tissue not previously irradiated. Samples from tumors progressing at 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
排除标准
- •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 the past 2 years
- •Has a history of (noninfectious) pneumonitis requiring steroids, or has current pneumonitis
- •Has known active human immunodeficiency virus (HIV), hepatitis B virus (e.g., hepatitis B surface antigen reactive) or hepatitis C virus (HCV) infection (e.g., HCV RNA [qualitative] is detected)
- •Has known active 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 myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or has features suggestive of MDS/AML
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
- •Has (≥Grade 3) hypersensitivity to pembrolizumab and/or any of its excipients
- •Has known hypersensitivity to the components or excipients in olaparib, abiraterone acetate, prednisone or prednisolone, or enzalutamide
- •Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease)
- •Has received an anticancer monoclonal antibody (mAb) before randomization
- •Has received prior treatment with olaparib or any other PARP inhibitor
- •Has received prior treatment with apalutamide or darolutamide
- •Has received prior treatment with enzalutamide or apalutamide for metastatic hormone-sensitive prostate cancer
- •Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA (e.g., saw palmetto) before the date of randomization
- •Has received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer
- •Has received prior treatment with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, or CD137)
- •Is currently receiving either strong or moderate inhibitors of cytochrome P450 [CYP] (CYP3A4) that cannot be discontinued for the duration of the study
- •Has received a previous allogenic bone marrow transplant or double umbilical cord transplantation (dUCBT) or a solid organ transplant
- •Has received a live vaccine within 30 days prior to the date of randomization
- •Is currently participating in or has participated in a study of an investigational agent, or has used an investigational device, within 4 weeks before the date of randomization
- •Has a bone "superscan"
- •Is expecting to father children within the projected duration of the study, starting with the screening visit through 90 days after the last dose of study intervention
研究组 & 干预措施
Pembrolizumab + Olaparib
Participants will receive olaparib 600 mg as two 150 mg oral tablets twice daily (BID) continuously until progression PLUS on Day 1 of each 21-day cycle, pembrolizumab 200 mg by intravenous (IV) infusion for up to 35 cycles (approximately 2 years).
干预措施: Pembrolizumab (Biological)
Pembrolizumab + Olaparib
Participants will receive olaparib 600 mg as two 150 mg oral tablets twice daily (BID) continuously until progression PLUS on Day 1 of each 21-day cycle, pembrolizumab 200 mg by intravenous (IV) infusion for up to 35 cycles (approximately 2 years).
干预措施: Olaparib (Drug)
Next-generation Hormonal Agent Monotherapy (NHA)
Participants will receive a single NHA, which will be either abiraterone acetate (participants previously treated with enzalutamide) 1000 mg as two 500 mg or four 250 mg oral tablets once daily (QD) PLUS prednisone or prednisolone 10 mg as one 5 mg tablet BID until progression OR enzalutamide (participants previously treated with abiraterone acetate) 160 mg as four 40 mg oral tablets or capsules OR two 80 mg tablets QD until progression.
干预措施: Abiraterone acetate (Drug)
Next-generation Hormonal Agent Monotherapy (NHA)
Participants will receive a single NHA, which will be either abiraterone acetate (participants previously treated with enzalutamide) 1000 mg as two 500 mg or four 250 mg oral tablets once daily (QD) PLUS prednisone or prednisolone 10 mg as one 5 mg tablet BID until progression OR enzalutamide (participants previously treated with abiraterone acetate) 160 mg as four 40 mg oral tablets or capsules OR two 80 mg tablets QD until progression.
干预措施: Prednisone (Drug)
Next-generation Hormonal Agent Monotherapy (NHA)
Participants will receive a single NHA, which will be either abiraterone acetate (participants previously treated with enzalutamide) 1000 mg as two 500 mg or four 250 mg oral tablets once daily (QD) PLUS prednisone or prednisolone 10 mg as one 5 mg tablet BID until progression OR enzalutamide (participants previously treated with abiraterone acetate) 160 mg as four 40 mg oral tablets or capsules OR two 80 mg tablets QD until progression.
干预措施: Enzalutamide (Drug)
Next-generation Hormonal Agent Monotherapy (NHA)
Participants will receive a single NHA, which will be either abiraterone acetate (participants previously treated with enzalutamide) 1000 mg as two 500 mg or four 250 mg oral tablets once daily (QD) PLUS prednisone or prednisolone 10 mg as one 5 mg tablet BID until progression OR enzalutamide (participants previously treated with abiraterone acetate) 160 mg as four 40 mg oral tablets or capsules OR two 80 mg tablets QD until progression.
干预措施: Prednisolone (Drug)
结局指标
主要结局
Overall Survival (OS)
时间窗: Up to ~31 months
Overall survival (OS) is defined as the time from randomization to death due to any cause. The nonparametric Kaplan-Meier method was used to estimate the survival curves.
Radiographic Progression-Free Survival (rPFS)
时间窗: Up to ~26 months
rPFS is defined as the time from randomization to the first documented progressive disease (PD) per PCWG-modified RECIST 1.1 based on BICR or death due to any cause, whichever occurred first. Per PCWG-modified RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions or ≥2 new bone lesions was also considered PD. PCWG-modified RECIST is similar to RECIST 1.1 with the exception that a confirmation assessment of PD (\>4 weeks after the initial PD) is required for participants who remain on treatment following a documented PD per RECIST 1.1 and PCWG rules include new bone lesions. The rPFS per PCWG-modified RECIST as assessed by BICR for all participants is presented. The nonparametric Kaplan-Meier method was used to estimate the survival curves.
次要结局
- Objective Response Rate (ORR)(Up to ~31 months)
- Time to Initiation of the First Subsequent Anticancer Therapy (TFST)(Up to ~26 months)
- Duration of Response (DOR)(Up to ~26 months)
- Time to Prostate-Specific Antigen (PSA) Progression(Up to ~31 months)
- Time to First Symptomatic Skeletal-Related Event (SSRE)(Up to ~31 months)
- Time to Radiographic Soft Tissue Progression(Up to ~31 months)
- Time to Pain Progression (TTPP)(Up to ~31 months)
- Number of Participants Who Experience an Adverse Event (AE)(Up to ~55 months)
- Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)(Up to ~1461 Days)