Study of Pembrolizumab (MK-3475) Plus Docetaxel Versus Placebo Plus Docetaxel in Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-3475-921/KEYNOTE-921)

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 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
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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).

Official Title
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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)

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Docetaxel
* Drug: Prednisone
* Drug: Placebo
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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The main inclusion and exclusion criteria 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab+Docetaxel<br>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 Q3W for a maximum of 10 cycles (approximately 7 months). Participants also 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 docetaxel cycle. | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Docetaxel<br>* IV infusion<br>* Other names: TAXOTERE®;Drug: Prednisone<br>* Oral tablets<br>Drug: Dexamethasone<br>* Oral tablets<br>* Other names: DECADRON®;|
| Placebo Comparator: Placebo+Docetaxel<br>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 Q3W for a maximum of 10 cycles (approximately 7 months). Participants also 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 docetaxel cycle. | Drug: Docetaxel<br>* IV infusion<br>* Other names: TAXOTERE®;Drug: Prednisone<br>* Oral tablets<br>Drug: Placebo<br>* IV infusion<br>* Other names: Normal saline or dextrose infusion;Drug: Dexamethasone<br>* Oral tablets<br>* Other names: DECADRON®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from randomization to death due to any cause. The OS was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. | Up to 36.5 months | 
| 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) | 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. 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 (Kaplan-Meier) method for censored data. Participants without a rPFS event were censored at the date of last disease assessment. | Up to approximately 28 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Initiation of the First Subsequent Anti-cancer Therapy (TFST) | TFST was defined as the time from randomization to initiation of the first subsequent anti-cancer therapy or death; whichever occurred first. The TFST was calculated using the product-limit (Kaplan-Meier) method for censored data. Any participant not known to have further subsequent therapy or death was censored at the last known time that no subsequent new anti-cancer therapy was received. | Up to approximately 28 months | 
| Prostate-specific Antigen (PSA) Response Rate | The Prostate-specific Antigen (PSA) response rate was 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. The analysis was performed on participants who had baseline PSA measurements. | 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 | ORR was defined as the percentage of participants with complete response (CR: disappearance of all target lesions per RECIST 1.1; and no evidence of disease (NED) on bone scan per PCWG) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions per RECIST 1.1; and non-progressive disease, non-evaluable [NE], or NED on bone scan or CR with non-progressive disease or NE bone scan per PCWG). | Up to 36.5 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 | DOR was defined as the time from first documented evidence of complete response (CR) or partial response (PR) per PCWG and RECIST 1.1 criteria until progressive disease (PD) or death. PD per RECIST 1.1 was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PD per PCWG was the appearance of ≥2 new bone lesions on bone scan, that have been confirmed to not represent tumor flare, and were persistent for ≥6 weeks. The DOR was calculated using the product-limit (Kaplan-Meier) method for censored data. If a participant had not progressed, the participant was censored at the date of last disease assessment. | Up to 36.5 months | 
| 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 | TTPP was defined as the time from randomization to pain progression as determined by Item 3 of the BPI-SF and by the AQA score. Pain progression was defined as: For participants asymptomatic at baseline: a ≥2-point change from baseline in the average (4-7 days) BPI-SF item 3 score at 2 consecutive visits OR initiation of opioid use for pain For participants symptomatic at baseline (average BPI-SF Item 3 score >0 and/or currently taking opioids:, a ≥2-point change from baseline in the average BPI-SF Item 3 score and an average worst pain score ≥4 and no decrease in average opioid use (≥1-point decrease in AQA score from a starting value of 2 or higher) OR any increase in opioid use at 2 consecutive follow-up visits. TTPP was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants who had > 2 consecutive visits that were not evaluable for pain progression were censored at the last evaluable assessment. | Up to 36.5 months | 
| Time to First Symptomatic Skeletal-related Event (SSRE) | SSRE was the time from randomization to the first symptomatic skeletal-related event defined as: Use of external-beam radiation therapy (EBRT) to prevent or relieve skeletal symptoms Occurrence of new symptomatic pathologic bone fracture (vertebral or non-vertebral) Occurrence of spinal cord compression Tumor-related orthopedic surgical intervention, whichever occurs first. The SSRE was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants without symptomatic skeletal-related events were censored at the last evaluable assessment. | Up to 36.5 months | 
| Time to Prostate-specific Antigen (PSA) Progression | The time to PSA progression was the time from randomization to PSA progression. The PSA progression date was defined as the date of: ≥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 ≥25% increase and ≥2 ng/mL increase from baseline beyond 12 weeks if there was no PSA decline from baseline Time to PSA progression was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants without PSA progression were censored at the last evaluable assessment. | 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) | The time to radiographic soft tissue progression was defined as the time from randomization to radiographic soft tissue progression per soft tissue rules of PCWG-modified RECIST 1.1 as assessed by BICR. Progression was 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 was also considered progression. Time to radiographic soft tissue progression was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants without radiographic soft tissue progression were censored at the last evaluable assessment. | Up to 36.5 months | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experienced an AE is presented. | Up to approximately 30 months | 
| Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE) | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued study treatment due to an AE is presented. | Up to approximately 27 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death 1 (PD 1, PD-1), Programmed Cell Death 1 Ligand 1 (PDL 1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL 2, PD-L2)