A Phase 3, Randomized, Double-blind Study of Pembrolizumab (MK-3475) Plus Docetaxel Plus Prednisone Versus Placebo Plus Docetaxel Plus Prednisone in Participants With Chemotherapy-naïve Metastatic Castration-Resistant Prostate Cancer (mCRPC) Who Have Progressed on a Next Generation Hormonal Agent (NHA) (KEYNOTE-921)
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 1,030
- Locations
- 215
- Primary Endpoint
- Overall Survival (OS)
Study Overview
Brief Summary
The purpose of this study is to assess the efficacy and safety of the combination of pembrolizumab (MK-3475) and docetaxel in the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy for mCRPC but have progressed on or are intolerant to Next Generation Hormonal Agent (NHA).
There are two primary study hypotheses.
Hypothesis 1: The combination of pembrolizumab plus docetaxel plus prednisone is superior to placebo plus docetaxel plus prednisone with respect to Overall Survival (OS).
Hypothesis 2: The combination of pembrolizumab plus docetaxel plus prednisone is superior to placebo plus docetaxel plus prednisone 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.
Detailed Description
With Amendment 6 (effective date: 29-Sep-2022), all participants will be unblinded and placebo treatment will be stopping. Participants who are deemed to be deriving clinical benefit from treatment may continue at the discretion of the investigator.
The global study for MK-3475-921 enrolled 1030 participants. Of the 1030 total participants enrolled in the global study, 21 were also enrolled in the China extension study for MK-3475-921 (NCT04907227).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- No
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 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 received prior treatment with one (but not more than one) NHA (eg, abiraterone acetate, enzalutamide, apalutamide, or darolutamide) for metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC) and either a) progressed through treatment OR b) has become intolerant of the drug
- •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 120 days after the last dose of pembrolizumab or for at least 180 days after the last dose of docetaxel (whichever is longer): Refrain from donating sperm PLUS Use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause)
- •Participants must agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex
- •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 (non-infectious) pneumonitis that required steroids or current pneumonitis
- •Has known active human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- •Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
- •Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease)
- •Has had a prior anti-cancer monoclonal antibody (mAb) prior to randomization or who has not recovered (i.e., Grade ≤1 or at baseline) from AEs due to mAbs
- •Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g. saw palmetto) prior to randomization
- •Has received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer
- •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 co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137)
- •Has received prior treatment with docetaxel or another chemotherapy agent for mCRPC
- •Has hypersensitivity to docetaxel or polysorbate 80
- •Is currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study
- •Has received prior targeted small molecule therapy or abiraterone acetate, enzalutamide, apalutamide, or darolutamide within 4 weeks prior to the first dose of study treatment, or has not recovered (i.e., Grade ≤1 or at baseline) from AEs due to a previously administered agent
- •Has received prior radiotherapy to within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis
- •Has received a live vaccine within 30 days prior to randomization
- •Has received treatment with 5α reductase inhibitors (eg, finasteride or dutasteride), estrogens, and/or cyproterone within 4 weeks prior to randomization
- •Has received prior treatment with ketoconazole for prostate cancer
- •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 120 days after the last dose of study treatment
- •Has had an allogenic tissue/solid organ transplant
Arms & Interventions
Pembrolizumab+Docetaxel
Participants receive pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly receive dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.
Intervention: Pembrolizumab (Biological)
Pembrolizumab+Docetaxel
Participants receive pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly receive dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.
Intervention: Docetaxel (Drug)
Pembrolizumab+Docetaxel
Participants receive pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly receive dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.
Intervention: Prednisone (Drug)
Pembrolizumab+Docetaxel
Participants receive pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly receive dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.
Intervention: Dexamethasone (Drug)
Placebo+Docetaxel
Participants receive placebo by IV infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly receive dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.
Intervention: Docetaxel (Drug)
Placebo+Docetaxel
Participants receive placebo by IV infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly receive dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.
Intervention: Prednisone (Drug)
Placebo+Docetaxel
Participants receive placebo by IV infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly receive dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.
Intervention: Placebo (Drug)
Placebo+Docetaxel
Participants receive placebo by IV infusion on Day 1 of each 21-day cycle (Q3W) for up to a maximum of 35 cycles (approximately 2 years) PLUS docetaxel 75 mg/m^2 by IV infusion on Day 1 of each 21-day cycle (Q3W) for a maximum of 10 cycles (approximately 7 months). Participants also concomitantly receive dexamethasone 8 mg by oral tablets at 12 hours, 3 hours, and 1 hour prior to docetaxel administration and prednisone 5 mg by oral tablets twice daily during each 21-day docetaxel cycle.
Intervention: Dexamethasone (Drug)
Outcomes
Primary Outcomes
Overall Survival (OS)
Time Frame: Up to 36.5 months
OS was defined as the time from randomization to death due to any cause. The OS was calculated using the product-limit Kaplan-Meier (K-M) method for censored data. Participants without documented death at the time of the analysis were censored at the date of the last follow-up.
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)
Time Frame: Up to approximately 28 months
rPFS was defined as the time from randomization to occurrence of: radiological tumor progression using RECIST 1.1 as assessed by BICR; progression of bone lesions using PCWG criteria; or death due to any cause. Radiological progression as per RECIST 1.1 was ≥20% increase in sum of diameters of target lesions and progression of existing non-target lesions. Progression of bone lesions by PCWG criteria was the appearance of ≥2 new bone lesions on bone scan, that have been confirmed to not represent tumor flare, and was persistent for ≥6 weeks. The rPFS was calculated using the product-limit K-M method for censored data. Participants without a rPFS event were censored at the date of last disease assessment.
Secondary Outcomes
- 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 Assessed by the Analgesic Quantification Algorithm (AQA) Score(Up to 36.5 months)
- Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE)(Up to approximately 27 months)
- Prostate-specific Antigen (PSA) Response Rate(Up to 36.5 months)
- Time to Prostate-specific Antigen (PSA) Progression(Up to 36.5 months)
- Number of Participants Who Experienced an Adverse Event (AE)(Up to approximately 30 months)
- Time to Initiation of the First Subsequent Anti-cancer Therapy (TFST)(Up to approximately 28 months)
- Duration of Response (DOR) 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)(Up to 36.5 months)
- Time to First Symptomatic Skeletal-related Event (SSRE)(Up to 36.5 months)
- Objective Response Rate (ORR) 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)(Up to 36.5 months)
- 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) as Assessed by Blinded Independent Central Review (BICR)(Up to 36.5 months)