| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration resistant Prostate Cancer (mCRPC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Castration-Resistant Prostate Cancer |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
-To compare pembrolizumab plus olaparib to abiraterone acetate or enzalutamide with respect to overall survival (OS)
-To compare pembrolizumab plus olaparib to abiraterone acetate or enzalutamide 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 (BICR)
|
|
| E.2.2 | Secondary objectives of the trial |
-To compare pembrolizumab + olaparib to abiraterone acetate or enzalutamide with respect to time to initiation of the first subsequent anticancer therapy or death
-To evaluate pembrolizumab + olaparib vs abiraterone acetate or enzalutamide with respect to the objective response rate and duration of response per Prostate Cancer Working Group-modified Response Evaluation Criteria in Solid Tumors Version 1.1 as assessed by blinded independent central review
-To compare pembrolizumab + olaparib to abiraterone acetate or enzalutamide with respect to time to PSA progression; time to first symptomatic skeletal related event; time to radiographic soft tissue progression per soft tissue rules of PCWG- RECIST 1.1 as assessed by BICR and time to pain progression as determined by Item 3 of the Brief Pain Inventory-Short Form and by the Analgesic Quantification Algorithm score
-To evaluate the safety and tolerability of pembrolizumab + olaparib vs abiraterone acetate or enzalutamide
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Exploratory Biomarker Research, Genetic (DNA) analyses from tumor, Tumor and blood RNA analyses, Proteomics and immunohistochemistry (IHC) using blood or tumor, Other biomarkers, Future Biomedical Research. |
|
| E.3 | Principal inclusion criteria |
1.Have histologically or cytologically confirmed (if acceptable according to local health authority regulations) adenocarcinoma of the prostate without small cell histology. The diagnosis must be stated in a pathology report and confirmed by the investigator
2. Have prostate cancer progression while receiving androgen deprivation therapy (or post bilateral orchiectomy) within 6 months prior to screening, as determined by the investigator through 1 of the following:
-PSA progression shown by local laboratory values, as defined by a minimum of 2 consecutive rising PSA levels with an interval of ≥1 week between each assessment, where PSA at screening should be ≥1 ng/mL.
-Radiographic disease progression in soft tissue based on RECIST 1.1, with or without PSA progression.
-Radiographic disease progression in bone per PCWG, defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression
3.Have disease progression under the following conditions if the participant received anti-androgen therapy prior to enrollment:
-Evidence of progression >4 weeks since the last flutamide treatment.
-Evidence of progression >6 weeks since the last bicalutamide or nilutamide treatment.
4.Have current evidence of metastatic disease documented by bone lesions on bone scan and/or soft tissue disease shown by CT/MRI.
5.Have received prior treatment with abiraterone acetate OR enzalutamide, but not both
-Have disease that progressed through treatment with abiraterone acetate or
enzalutamide for mCRPC for at least 8 weeks (at least 14 weeks for participants with bone progression).
6.Have received no more than 1 previous chemotherapy regimen for mCRPC and have had PD during treatment. If docetaxel chemotherapy has been used more than once, it will be considered as 1 therapy. Prior docetaxel for mCRPC is allowed if ≥4 weeks have elapsed from the last dose of docetaxel prior to Day 1 of Cycle 1.
7.Have ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM). If the participant is currently being treated with luteinizing hormone-releasing hormone agonists or antagonists (in participants who have not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to the date of randomization, and treatment must be continued hroughout the study.
8.If receiving bone resorptive therapy, including but not limited to bisphosphonates or denosumab, have been receiving stable doses for ≥4 weeks prior to the date of randomization.
9.Have adequate organ function; all screening laboratory tests should be performed by the central laboratory within 10 days of the first dose of study intervention
10.Be male
11.Be ≥18 years of age on the day of signing the informed consent.Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
12.Agree to the following during the intervention period and for at least 180 days,corresponding to the time needed to eliminate 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:
-Agree to use contraception unless confirmed to be azoospermic
or
-Secondary to medical cause as detailed: Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penilevaginal intercourse or use a male condom during each episode of penilevaginal penetration.
13.Also agree to use a male condom when engaging in any activity that allows passage of ejaculate to another person of any sex.
14.The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research.
15.Have provided tumor tissue from a fresh core or excisional biopsy (obtained within 12 months of screening) from soft tissue not previously irradiated. Samples from tumors progressing at 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. However, if obtaining a fresh biopsy is not feasible, participants may provide an archival tumor tissue sample after Sponsor consultation. Formalin-fixed, paraffin embedded tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
16.Have an Eastern Cooperative Oncology Group performance status of 0 or 1, assessed within 7 days of randomization. |
|
| E.4 | Principal 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 the past 2 years
- Has a history of (noninfectious) pneumonitis requiring steroids, or has current pneumonitis
- Has known active human immunodeficiency virus (HIV), hepatitis B virus (e.g., hepatitis B surface antigen reactive) or hepatitis C virus (HCV) infection (e.g., HCV RNA [qualitative] is detected)
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- Has a history of seizure or any condition that may predispose to seizure
- Has a history of loss of consciousness within 12 months of screening
- Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or has features suggestive of MDS/AML
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
- Has severe (Grade >3) hypersensitivity to pembrolizumab and/or any of its excipients
- Has known hypersensitivity to the components or excipients in olaparib, abiraterone acetate, prednisone or prednisolone, or enzalutamide
- Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease)
- Has received an anticancer monoclonal antibody (mAb) prior to randomization
- Has received prior treatment with olaparib or any other PARP inhibitor
- Has received prior treatment with apalutamide or darolutamide
- Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA (e.g., saw palmetto) prior to the date of randomization
- Has received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer
- Has received prior treatment 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(e.g., CTLA-4, OX-40, or CD137)
- Is currently receiving either strong or moderate inhibitors of cytochrome P450
[CYP] (CYP3A4) that cannot be discontinued for the duration of the study
- Has received a previous allogenic bone marrow transplant or double umbilical cord transplantation (dUCBT)
- Has received a live vaccine within 30 days prior to the date of randomization
- 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 date of randomization
- Has a bone “superscan”
- Is expecting to father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study intervention
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Overall survival (OS)
2. 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) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 29 months
1. Up to approximately 29 months |
|
| E.5.2 | Secondary end point(s) |
1.Time to initiation of the first subsequent anticancer therapy or death (TFST)
2.Objective response 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)
3.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)
4.Time to prostate-specific antigen (PSA)progression
5.Time to first symptomatic skeletal-related event (SSRE)
6.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)
7.Time to pain progression (TTPP)
8.Number of Participants with One or More Adverse Events (AEs)
9.Number of Participants with Study Discontinuations Due to Adverse Events (AEs) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Up to approximately 29 months
2.Up to approximately 29 months
3.Up to approximately 29 months
4.Up to approximately 29 months
5.Up to approximately 29 months
6.Up to approximately 29 months
7.Up to approximately 29 months
8.Up to approximately 29 months
9.Up to approximately 29 months
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 19 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 83 |
| 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 |
| Argentina |
| Australia |
| Austria |
| Brazil |
| Canada |
| Chile |
| Colombia |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| New Zealand |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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