| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10071119 |
| E.1.2 | Term | Hormone-dependent prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. To compare pembrolizumab (MK-3475) plus enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus enzalutamide plus ADT with respect to radiographic progression-free survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR) where soft tissue will be assessed per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and bone disease will be assessed per PCWG criteria.
2. To compare pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT with respect to overall survival (OS).
|
|
| E.2.2 | Secondary objectives of the trial |
1. To compare pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT with respect to TFST.
2. To compare pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT with respect to TTSSRE.
3. To assess pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT with respect to the: time to PSA progression; time to radiographic soft tissue progression per soft tissue rules of PCWG-modified RECIST 1.1, as assessed by BICR; TTPP; and PFS2.
4. To assess pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT with respect to the: PSA response rate; PSA undetectable rate; and ORR and DOR per PCWG-modified RECIST 1.1 as assessed by BICR.
5. To assess the safety and tolerability of pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has histologically- or cytologically-confirmed (if acceptable according to local health authority regulations) adenocarcinoma of the prostate without small cell histology. Diagnosis must be stated in a pathology report and confirmed by the investigator.
2. Has metastatic disease as assessed by investigator and verified by BICR (prior to randomization) by either ≥2 bone lesions on bone scan and/or visceral disease (eg, lung or liver) by CT/MRI. Participants whose metastatic disease is limited to lymph nodes are not eligible.
3. Once randomized, participant must be willing to maintain continuous ADT with a LHRH agonists or antagonists during study treatment or have a history of bilateral orchiectomy.
4. Has an 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 for ≥4 weeks prior to randomization.
6. Demonstrates adequate organ function; all screening labs should be performed in central laboratory within 10 days of the first dose of study intervention.
7. Is male, ≥18 years of age at the time of signing the informed consent.
8. Male participants are eligible to participate if they 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 as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent OR
• Must agree to use contraception, unless confirmed to be azoospermic (vasectomized or secondary to medical cause), as detailed below:
- Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
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.
10. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study.
11. 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; other exceptions may be considered after Sponsor consultation). Participants with bone only or bone predominant disease may provide a bone biopsy sample (decalcification not allowed). However, if obtaining a new biopsy is not feasible, then participants may provide an archival tumor tissue sample after Sponsor consultation (SCF). FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archive tissue. Adequacy of these specimens for PD-L1 biomarker analysis will be required by a central laboratory prior to randomization. |
|
| E.4 | Principal exclusion criteria |
1. Has a known additional malignancy that is progressing or has required active treatment in the last 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that have undergone potentially curative therapy are not excluded.
2. Has an active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is not considered a form of systemic treatment.
3. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention.
4. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
5. 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.
6. Has a gastrointestinal disorder affecting absorption.
7. Is unable to swallow tablets/capsules.
8. Has an active infection (including tuberculosis) requiring systemic therapy.
9. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
10. Has known active HIV, hepatitis B virus or HCV. Testing for Hepatitis B and Hepatitis C is not required unless mandated by local regulation.
11. Has known or suspected CNS metastases and/or carcinomatous meningitis.
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
13. Has a history of seizure or any condition that may predispose to seizure (including, but not limited to prior cerebrovascular accident, transient ischemic attack, or brain arteriovenous malformation; or intracranial masses such as a schwannoma or meningioma that is causing edema or mass effect).
14. Has a history of loss of consciousness within 12 months of the Screening Visit.
15. Has had myocardial infarction or uncontrolled angina within 6 months prior to randomization.
16. 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 unless a screening echocardiogram or multigated acquisition scan performed within 3 months prior to randomization date demonstrates a left ventricular ejection fraction >45%.
17. Has a history of clinically significant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, torsades de pointes).
18. Has a history of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.
19. Has hypotension as indicated by systolic blood pressure <86 millimeters of mercury (mmHg) at the Screening Visit.
20. Has bradycardia as indicated by a heart rate of <50 beats per minute on the Screening ECG.
21. Has uncontrolled hypertension as indicated by systolic blood pressure >170 mm Hg or diastolic blood pressure >105 mm Hg at the Screening visit.
22. Has severe hypersensitivity (Grade ≥3) to pembrolizumab and/or any of its excipients.
23. Has hypersensitivity reaction to enzalutamide or any of its capsule components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene.
24. Has received any prior pharmacotherapy, radiation therapy or surgery for metastatic prostate cancer with some exceptions
25. 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.
26. Has had prior treatment with a next generation hormonal agent (eg, abiraterone, enzalutamide, apalutamide, darolutamide).
27. Has received prior therapy 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 (eg, CTLA-4, OX-40, CD137).
28. Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (eg, saw palmetto) within 4 weeks prior to randomization.
29. Has received treatment with 5-α reductase inhibitors (eg, finasteride, dutasteride), estrogens, cyproterone acetate and/or androgens within 4 weeks prior to randomization.
30. Has received a live vaccine within 30 days prior to randomization.
31. 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 randomization.
32. Has a “superscan” bone scan.
33. Has had an allogenic tissue/solid organ transplant |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. 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
2. Overall Survival (OS)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 32 months
2. Up to approximately 32 months
|
|
| E.5.2 | Secondary end point(s) |
1. Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST)
2. Time to Symptomatic Skeletal-Related Event (TTSSRE)
3. Time to Prostate-specific Antigen (PSA) Progression
4. 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
5. 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
6. 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)
7. Prostate-specific Antigen (PSA) Response Rate
8. Prostate-specific antigen (PSA) Undetectable Rate
9. 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
10. 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
11. Number of Participants Who Experience an Adverse Event (AE)
12. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 32 months
2. Up to approximately 32 months
3. Up to approximately 32 months
4. Up to approximately 32 months
5. Up to approximately 32 months
6. Up to approximately 32 months
7. Up to approximately 32 months
8. Up to approximately 32 months
9. Up to approximately 32 months
10. Up to approximately 32 months
11. Up to approximately 41 months
12. Up to approximately 38 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
To identify molecular (genomic, metabolic, and/or proteomic) biomarkers that may be indicative of clinical response/resistance, safety, and/or the mechanism of action, between the experimental and comparator arms, using blood and/or tumor tissue. To compare the experimental and comparator arm with respect to the change from baseline disease-related symptoms and health-related quality of life questionnaires.
|
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 110 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Chile |
| Colombia |
| New Zealand |
| Peru |
| Switzerland |
| Ireland |
| Taiwan |
| Australia |
| Austria |
| Brazil |
| Canada |
| China |
| Denmark |
| Finland |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The overall study ends when the last participant completes the last study-related telephone-call or visit, withdraws
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the last laboratory test result or at the time of final contact with the last participant, whichever comes last. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
