臨床研究等提出・公開システム

A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) Plus Enzalutamide Plus ADT Versus Placebo Plus Enzalutamide Plus ADT in Participants With Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) (KEYNOTE-991)

Phase 3 Study of Pembrolizumab/Placebo plus Enzalutamide plus ADT in mHSPC

1251

Pembrolizumab + Enzalutamide + ADT group -Mean Age: 67.6 years -Sex: Male 100.0% -Race: White 71.4%, Asian 15.8% -Prior Docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC) at baseline: Yes 10.2%, No 89.8% Placebo + Enzalutamide + ADT group -Mean Age: 67.6 years -Sex: Male 100.0% -Race: White 70.4%, Asian 18.9% -Prior Docetaxel for mHSPC at baseline: Yes 9.8%, No 90.2%

As of data cutoff date (Oct-31-2022) Pembrolizumab + Enzalutamide + ADT group -Randomized: 626 participants -Received study treatment: 625 participants -Completed the study: 0 participants -Discontinued the study: 108 participants (Reason for discontinued the study: Death 102 participants, Withdrawal by subject 5 participants, lost to follow up 1 participant) -Ongoing the study: 518 participants Placebo + Enzalutamide + ADT group -Randomized: 625 participants -Received study treatment: 625 participants -Completed the study: 0 participants -Discontinued the study: 95 participants (Reason for discontinued the study: Death 89 participants, Withdrawal by subject 5 participants, lost to follow up 1 participant) -Ongoing the study: 530 participants

Percentage of all-cause mortality -Pembrolizumab + Enzalutamide + ADT group: 16.77% (105/626 participants) -Placebo + Enzalutamide + ADT group: 14.88% (93/625 participants) Percentage of participants with serious adverse events -Pembrolizumab + Enzalutamide + ADT group: 40.32% (252/625 participants) -Placebo + Enzalutamide + ADT group: 23.20% (145/625 participants) Serious adverse events with an incidence of >= 1% -Pembrolizumab + Enzalutamide + ADT group: Urinary tract infection (1.76%), Rash and Rash maculo-papular (1.60% each), Pneumonia (1.44%), Colitis, Myocardial infarction and Pneumonitis (1.12% each) -Placebo + Enzalutamide + ADT group: Urinary tract infection, Pneumonia and Myocardial infarction (1.12% each) Percentage of participants with non-serious adverse events with an incidence of > 5% in one or more treatment groups -Pembrolizumab + Enzalutamide + ADT group: 94.08% (588/625 participants) -Placebo + Enzalutamide + ADT group: 88.16% (551/625 participants) Non-serious adverse events with an incidence of >= 20% -Pembrolizumab + Enzalutamide + ADT group: Fatigue (31.04%), Arthralgia (28.96%), Rash (23.68%), and Diarrhoea (20.32%) -Placebo + Enzalutamide + ADT group: Fatigue (28.48%), Arthralgia (25.76%), Hot flush (23.04%), and Hypertension (20.80%)

Primarily Outcome Radiographic progression-free survival (rPFS) per PCWG-modified RECIST 1.1 as assessed by BICR -Analysis population: All randomized participants -Pembrolizumab + Enzalutamide + ADT group: NA (95% CI: NA, NA) -Placebo + Enzalutamide + ADT group: NA (95% CI: NA, NA) -HR: 1.20 (95% CI: 0.96, 1.49), P-Value: 0.9467 Overall Survival (OS) -Analysis population: All randomized participants -Pembrolizumab + Enzalutamide + ADT group: NA (95% CI: NA, NA) -Placebo + Enzalutamide + ADT group: NA (95% CI: NA, NA) -HR: 1.16 (95% CI: 0.88, 1.53), P-Value: 0.85122

Time to Initiation of the First Subsequent Anticancer Therapy (TFST) -Analysis population: All randomized participants -Pembrolizumab + Enzalutamide + ADT group: NA (95% CI: 29.0, NA) -Placebo + Enzalutamide + ADT group: NA (95% CI: NA, NA) -HR: 1.24 (95% CI: 1.01, 1.54), P-Value: 0.97907 Time to Symptomatic Skeletal-Related Event (TTSSRE) -Analysis population: All randomized participants -Pembrolizumab + Enzalutamide + ADT group: NA (95% CI: NA, NA) -Placebo + Enzalutamide + ADT group: NA (95% CI: NA, NA) -HR: 0.89 (95% CI: 0.61, 1.30), P-Value: 0.27202 Time to prostate-specific antigen (PSA) progression -Analysis population: All randomized participants -Pembrolizumab + Enzalutamide + ADT group: NA (95% CI: NA, NA) -Placebo + Enzalutamide + ADT group: NA (95% CI: NA, NA) -HR: 0.92 (95% CI: 0.69, 1.23), P-Value: 0.2972 Time to radiographic soft tissue progression per PCWG-modified RECIST 1.1 as assessed by BICR -Analysis population: All randomized participants -Pembrolizumab + Enzalutamide + ADT group: NA (95% CI: NA, NA) -Placebo + Enzalutamide + ADT group: NA (95% CI: NA, NA) -HR: 1.07 (95% CI: 0.81, 1.41), P-Value: 0.6863 Time to Pain Progression (TTPP) as assessed by Brief Pain Inventory-Short Form (BPI-SF) Item #3 (Worst Pain in 24 Hours) and Opiate use -Analysis population: All randomized participants who received at least one dose of study treatment, and who had at least 1 BPI-SF assessment -Pembrolizumab + Enzalutamide + ADT group: NA (95% CI: 25.4, NA) -Placebo + Enzalutamide + ADT group: NA (95% CI: NA, NA) -HR: 1.15 (95% CI: 0.95, 1.39), P-Value: 0.9235 Time from randomization to disease progression as determined by investigator assessment of radiological or clinical progression after next-line of therapy or death from any cause, whichever occurs first (PFS2) -Analysis population: All randomized participants -Pembrolizumab + Enzalutamide + ADT group: NA (95% CI: 29.0, NA) -Placebo + Enzalutamide + ADT group: NA (95% CI: NA, NA) -HR:1.16 (95% CI: 0.90, 1.50), p-Value: 0.8801 PSA response rate -Analysis population: All randomized participants who had a baseline PSA measurement and had data available for analysis -Pembrolizumab + Enzalutamide + ADT group: 90.3% (95% CI: 87.7, 92.5) -Placebo + Enzalutamide + ADT group: 93.0% (95% CI: 90.7, 94.9) -Percent Difference -2.7 (95% CI: -5.8, 0.4), P-Value: 0.9576 PSA undetectable rate -Analysis population: All randomized participants with detectable PSA at baseline and had data available for analysis -Pembrolizumab + Enzalutamide + ADT group: 63.4% (95% CI: 59.3, 67.3) -Placebo + Enzalutamide + ADT group: 64.1% (95% CI: 60.1, 68.0) -Percent Difference -0.8 (95% CI: -6.3, 4.8), P-Value: 0.6053 ORR per PCWG-modified RECIST 1.1 as assessed by BICR -Analysis population: All randomized participants with measurable disease at baseline and had data available for analysis -Pembrolizumab + Enzalutamide + ADT group: 65.7% (95% CI: 59.5, 71.6) -Placebo + Enzalutamide + ADT group: 71.8% (95% CI: 65.8, 77.4) -Percent Difference -5.6 (95% CI: -13.7, 2.6), P-Value: 0.9105 DOR per PCWG-modified RECIST 1.1 as assessed by BICR -Analysis population: All randomized participants who demonstrated a CR or PR, and had data available for analysis -Pembrolizumab + Enzalutamide + ADT group: NA (95% CI: 22.2, NA) -Placebo + Enzalutamide + ADT group: NA (95% CI: NA, NA)

Efficacy KEYNOTE-991 did not meet the predefined success criteria for superiority of the dual primary endpoints of rPFS and OS. Safety Pembrolizumab in combination with enzalutamide + ADT demonstrated a manageable safety profile in participants with mHSPC.

Yes

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

Fujita Tomoko

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

April. 30, 2020

Interventional

randomized controlled trial,placebo control,parallel assignment,Multicenter clinical study,double blind

treatment purpose

3

1) Male participants with histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
2) Has metastatic disease assessed by investigator and verified by BICR by either >=2 bone lesions on bone scan and/or visceral disease by computed tomography/magnetic resonance imaging (CT/MRI)
3) Willing to maintain continuous Androgen Deprivation Therapy (ADT) with a luteinizing-hormone releasing hormone (LHRH) agonists or antagonists during study treatment or have a history of bilateral orchiectomy
4) Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 10 days of randomization
5) Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses prior to randomization
6) Has adequate organ function
7) 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
8) Male participants must agree to the following during the intervention period and for at least 120 days after the last dose of study intervention: Refrain from donating sperm PLUS either be abstinent from heterosexual intercourse and agree to remain abstinent OR agree to use contraception, unless confirmed to be azoospermic
9) Male participants must agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex

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 (non-infectious) pneumonitis that required steroids or has current pneumonitis
8) Has known active human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
9) Has known or suspected central nervous system (CNS) metastases and/or carcinomatous meningitis
10) Has a history of seizure or any condition that may predispose to seizure
11) Has a history of loss of consciousness within 12 months of screening
12) Has had myocardial infarction or uncontrolled angina within 6 months prior to randomization, or has New York Heart Association class III or IV congestive heart failure or a history of New York Heart Association class III or IV congestive heart failure
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 a history of clinically significant ventricular arrhythmias
15) Has hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their excipients
16) Has received prior ADT as neoadjuvant/adjuvant therapy for non-metastatic prostate cancer for >39 months in duration or within 9 months prior to randomization or with evidence of disease progression while receiving ADT
17) Has had prior treatment with a next generation hormonal agent (eg, abiraterone, enzalutamide, apalutamide, darolutamide)
18) 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-programmed cell death-ligand 2 (anti PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor
19) Has received a live vaccine within 30 days prior to randomization
20) Has a "superscan" bone scan
21) Has had an allogenic tissue/solid organ transplant
22) 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
23) Has received any prior pharmacotherapy, radiation therapy or surgery for metastatic prostate cancer with the following exceptions:
a) Up to 3 months of ADT or orchiectomy with or without concurrent first-generation antiandrogens, if patient was not treated with docetaxel
b) May have 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 4 weeks prior to randomization
c) For participants with low volume metastatic disease, may have 1 course of definitive radiotherapy if it was administered at least 4 weeks prior to randomization
d) Up to 6 cycles of docetaxel therapy with final treatment administration completed within 2 months of randomization and no evidence of disease progression. In these participants up to 6 months of ADT permitted

Male

Metastatic Hormone-Sensitive Prostate Cancer

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 : Starting on Day 1 of each 21-day cycle, participants receive 200 mg pembrolizumab IV every 3 weeks (Q3W) for up to 35 cycles (approximately 2 years), plus 160 mg enzalutamide taken orally once daily. Participants will continue to receive enzalutamide and ADT until criteria for discontinuation are met.

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 : Starting on Day 1 of each 21-day cycle, participants receive placebo IV Q3W for up to 35 cycles (approximately 2 years), plus 160 mg enzalutamide taken orally once daily. Participants will continue to receive enzalutamide and ADT until criteria for discontinuation are met.

efficacy
- 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)
- Overall Survival (OS)

safety
efficacy
- Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST)
- Time to First Symptomatic Skeletal-related Event (TTSSRE)
- Time to Prostate-specific Antigen (PSA) Progression
- Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of PCWG-Modified RECIST 1.1 as Assessed by BICR
- Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item #3 ("Worst Pain in 24 Hours") and Opiate Use
- Time From Randomization to Disease Progression as Determined by Investigator Assessment After Next-line of Therapy or Death From Any Cause, Whichever Occurs First (PFS2)
- Prostate-specific Antigen (PSA) Response Rate
- Prostate-specific Antigen (PSA) Undetectable
- Objective Response Rate (ORR) Per PCWG-Modified RECIST 1.1 as Assessed by BICR
- Duration of Response (DOR) Per PCWG- Modified RECIST 1.1 as Assessed by BICR
- Number of Participants Who Experience an Adverse Event (AE)
- Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)

April. 03, 2020