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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)

Phase 3 Study of Pembrolizumab/Placebo plus Enzalutamide in mCRPC

1244

Pembrolizumab + Enzalutamide group -Mean Age: 70.6 years -Sex: Male 100.0% -Race: White 81.3%, Asian 12.9% Placebo + Enzalutamide group -Mean Age: 69.9 years -Sex: Male 100.0% -Race: White 79.3%, Asian 13.8%

Pembrolizumab + Enzalutamide group -Randomized: 621 participants -Received study treatment: 615 participants -Completed the study: 0 participants -Discontinued the study: 310 participants (Reason not completed: Death 289 participants, Withdrawal by Subject 20 participants, Physician Decision 1 participant) -Ongoing 311 participants Placebo + Enzalutamide group -Randomized: 623 participants -Received study treatment: 620 participants -Completed the study: 0 participants -Discontinued the study: 299 participants (Reason not completed: Death 282 participants, Withdrawal by Subject 17 participants) - Ongoing 324 participants

Percentage of all-cause mortality -Pembrolizumab + Enzalutamide group: 47.50% (295/621 participants) -Placebo + Enzalutamide group: 46.71% (291/623 participants) Percentage of participants with serious adverse events -Pembrolizumab + Enzalutamide group: 38.70% (238/615 participants) -Placebo + Enzalutamide group: 26.61% (165/620 participants) Serious adverse events with an incidence of >= 1% -Pembrolizumab + Enzalutamide group: Pneumonia (2.60%), Urinary tract infection (1.95%), Pyrexia and Spinal cord compression (1.46%, each), Urosepsis (1.30%), Anaemia, COVID-19 pneumonia and Pneumonitis (1.14%, each) -Placebo + Enzalutamide group: Spinal cord compression (1.77%), Urinary tract infection, Pneumonia and Haematuria (1.61%, each) Percentage of participants with non-serious adverse events with an incidence of > 5% in one or more treatment groups -Pembrolizumab + Enzalutamide group: 91.54% (563/615 participants) -Placebo + Enzalutamide group: 88.87% (551/620 participants) Non-serious adverse events with an incidence of >= 20% -Pembrolizumab + Enzalutamide group: Fatigue (30.89%), Arthralgia (24.23%), Decreased appetite (23.74%), Anaemia (22.93%), Rash (22.60%), Nausea (20.49%) -Placebo + Enzalutamide group: Fatigue (27.42%), Arthralgia (20.65%) and Decreased appetite (20.00%)

Primarily Outcome Efficacy Overall Survival (OS) -Analysis population: all randomized participants -Pembrolizumab + Enzalutamide group: 24.7 months (95% CI: 22.0, 26.8) -Placebo + Enzalutamide group: 27.3 months (95% CI: 24.5, 30.1) -HR: 1.04 (95% CI: 0.88, 1.22), P-Value: 0.6621 Radiographic Progression-free Survival (rPFS) Per Prostate Cancer Working Group (PCWF)-Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) -Analysis population: all randomized participants -Pembrolizumab + Enzalutamide group: 10.4 months (95% CI: 8.4, 12.5) - Placebo + Enzalutamide group: 9.0 months (95% CI: 8.3, 11.5) -HR: 0.98 (95% CI: 0.84, 1.14), P-Value: 0.4073

Secondary Outcome Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST) -Analysis population: all randomized participants -Pembrolizumab + Enzalutamide group: 13.2 months (95% CI: 11.7, 15.7) -Placebo + Enzalutamide group: 12.6 months (95% CI: 11.3, 14.2) -HR: 0.95 (95% CI: 0.83, 1.09) Prostate-specific Antigen (PSA) response rate -Analysis population: all randomized participants with PSA measurement at baseline, who had data available for analysis -Pembrolizumab + Enzalutamide group: 49.0% (95% CI: 44.9, 53.1) -Placebo + Enzalutamide group: 45.1% (95% CI: 41.1, 49.2) - Percent Difference: 3.4 (95% CI: -1.5, 8.3) PSA Undetectable Rate -Analysis population: all randomized participants with PSA measurement at baseline, who had data available for analysis -Pembrolizumab + Enzalutamide group: 13.1% (95% CI: 10.5, 16.1) -Placebo + Enzalutamide group: 12.6% (95% CI: 10.0, 15.5) - Percent Difference: 0.3 (95% CI: -3.4, 4.1) Objective Response Per PCWG-Modified RECIST 1.1 by as Assessed by BICR -Analysis population: all randomized participants - Pembrolizumab + Enzalutamide group: 12.2% (95% CI: 9.8, 15.1) -Placebo + Enzalutamide group: 9.3% (95% CI: 7.1, 11.9) -Percent Difference: 2.9 (95% CI:-0.2, 6.1) Duration of Response (DOR) Per PCWG-Modified RECIST 1.1 by as Assessed by BICR -Analysis population: all randomized participants -Pembrolizumab + Enzalutamide group: 16.1 months (95% CI: 1.4, 35.3) -Placebo + Enzalutamide group: 21.5 months (95% CI: 0.0, 35.3) Time to PSA Progression -Analysis population: all randomized participants -Pembrolizumab + Enzalutamide group: 6.4 months (95% CI: 5.5, 7.1) -Placebo + Enzalutamide group: 5.6 months (95% CI: 4.9, 6.9) -HR: 0.99 (95% CI:0.86, 1.15) Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of PCWG-modified RECIST 1.1 by as Assessed by BICR -Analysis population: all randomized participants -Pembrolizumab + Enzalutamide group: 20.7 months (95% CI: 18.0, 30.1) -Placebo + Enzalutamide group: 26.3 months (95% CI: 17.8, NA) -HR: 0.90 (95% CI: 0.74, 1.09) Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item 3 and Opiate Analgesic Use (Analgesic Quantification Algorithm [AQA] score) -Analysis population: all participants who received at least 1 dose of study treatment and who had at least 1 PRO assessment available. -Pembrolizumab + Enzalutamide group: NA (95% CI: 23.3, NA) -Placebo + Enzalutamide group: NA (95% CI: NA, NA) -HR: 1.05 (95% CI:0.82, 1.35) Time to First Symptomatic Skeletal-related Event (SSRE) -Analysis population: all randomized participants -Pembrolizumab + Enzalutamide group: NA (95% CI: NA, NA) -Placebo + Enzalutamide group: NA (95% CI: NA, NA) -HR: 1.13 (95% CI:0.85, 1.51) Percentage of Participants Who Experienced an Adverse Event (AE) -Analysis population: all randomized participants who received at least 1 dose of study treatment. -Pembrolizumab + Enzalutamide group: 96.6% (594/615 participant) -Placebo + Enzalutamide group: 96.1% (596/620 participant) Percentage of Participants Who Discontinued Study Treatment Due to an AE -Pembrolizumab + Enzalutamide group: 18.7% (115/615 participant) -Placebo + Enzalutamide group: 8.1% (50/620 participant)

Efficacy KEYNOTE-641 did not meet the predefined success criteria for superiority of the dual primary endpoints of OS and rPFS. The observed OS HR crossed the prespecified OS futility HR boundary. Safety Pembrolizumab in combination with enzalutamide demonstrated a manageable safety profile in participants with mCRPC that was generally consistent with the safety profile anticipated for the component drugs when administered as monotherapy.

May. 28, 2021

https://pubmed.ncbi.nlm.nih.gov/34044584/

Yes

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Tanaka Yoshiyuki

MSD K.K.

KITANOMARU SQUARE,1-13-12,Kudan-kita,Chiyoda-ku,Tokyo 102-8667,Japan

JPCT@msd.com

MSDJRCT inquiry mailbox

MSD K.K.

KITANOMARU SQUARE,1-13-12,Kudan-kita,Chiyoda-ku,Tokyo 102-8667,Japan

+81-3-6272-1957

JPCT@msd.com

completed

Dec. 11, 2019

Interventional

randomized controlled trial,double blind,placebo control

treatment purpose

3

1) Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
2) Has prostate cancer progression while on androgen deprivation therapy (or post bilateral orchiectomy) within 6 months prior to randomization
3) 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)
4) Has met one of the following criteria with regard to abiraterone acetate exposure: (1) is abiraterone-naive; (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)
5) Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM)
6) Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses prior to randomization
7) 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
8) 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
9) Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days of randomization

1) Has a known additional malignancy that is progressing or has required active treatment in the last 3 years
2) Has an active autoimmune disease that has required systemic treatment in past 2 years
3) Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
4) 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
5) Has a gastrointestinal disorder affecting absorption or is unable to swallow tablets/capsules
6) Has an active infection (including tuberculosis) requiring systemic therapy
7) Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease
8) Has known active human immunodeficiency virus (HIV), concurrent active hepatitis B virus (HBV) or known active hepatitis C virus (HCV) infection
9) Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
10) Has hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their excipients
11) Has a history of seizure or any condition that may predispose to seizure
12) Has a history of loss of consciousness within 12 months of screening
13) 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
14) Has bradycardia (heart rate of <50 beats per minute) on the screening electrocardiogram (ECG)
15) Has history of prostate cancer progression on ketoconazole
16) Has had prior treatment with enzalutamide, apalutamide, darolutamide or cytochrome P450 (CYP) 17 inhibitor other than abiraterone acetate
17) 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
18) Has received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer
19) Has received prior treatment with docetaxel or another chemotherapy agent for mCRPC
20) Has had a prior anti-cancer monoclonal antibody (mAb) prior to randomization
21) 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
22) Has received a live or live attenuated vaccine within 30 days prior to randomization
23) 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
24) Has a "superscan" bone scan
25) 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
26) Has had an allogenic tissue/solid organ transplant

Male

Prostatic Neoplasms

investigational material(s)
Generic name etc : Pembrolizumab + Enzalutamide
INN of investigational material : pembrolizumab, enzalutamide
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : 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.

control material(s)
Generic name etc : Placebo + Enzalutamide
INN of investigational material : -, enzalutamide
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : 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.

efficacy
- Overall Survival (OS): OS was defined as the time from randomization to death due to any cause.
- 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: 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.

safety
efficacy
- Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST)
- Prostate-specific Antigen (PSA) Response Rate
- 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
- 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
- Time to Prostate-specific Antigen (PSA) Progression
- 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
- 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)
- Time to First Symptomatic Skeletal-related Event (SSRE)
- Number of Participants Who Experience an Adverse Event (AE)
- Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)

June. 18, 2019