Prostate Cancer
Conditions
Keywords
Localised/locally advanced prostate cancer, High-risk biochemical recurrence (BCR), Poly (ADP-ribose) polymerase, Radiation therapy or radiotherapy, Breast cancer gene (BRCA) mutation
Brief summary
The purpose of the study is to demonstrate superiority of Saruparib (AZD5305) relative to placebo added to a standard radiation therapy (RT) + androgen deprivation therapy (ADT) regimen by assessment of metastases-free survival in participants with high-risk and very high-risk localised/locally advanced prostate cancer with a breast cancer gene mutation (BRCAm).
Detailed description
Approximately, 700 adult participants with localised/locally advanced prostate cancer will be randomized in a 1:1 ratio to receive saruparib or placebo with ADT (+ abiraterone) in one of the following two cohorts: Cohort A: 400 adult participants with newly diagnosed high-risk and very high-risk (localised/locally advanced) prostate cancer who have received primary RT and are receiving continuous ADT, and participants with high-risk biochemical recurrence (BCR) \[including prostate-specific antigen (PSA) persistence\] following a radical prostatectomy who have received salvage RT are receiving continuous ADT. Cohort B: 300 adult participants with newly diagnosed very high-risk (locally advanced) prostate cancer who have received primary RT and who are receiving continuous ADT and abiraterone. All participants will be followed for survival until the end of the study. Independent data monitoring committee (DMC) composed of experts will be convened to confirm the safety and efficacy of Saruparib + ADT (+ abiraterone).
Interventions
DRUGSaruparib
Saruparib will be administered orally.
DRUGPlacebo
Matching placebo to saruparib will be administered orally.
DRUGAbiraterone + Prednisolone/Prednisone
Abiraterone will be administered orally in combination with prednisone/prednisolone.
DRUGAndrogen Deprivation Therapy (ADT)
Standard of care ADT will be administered.
Sponsors
AstraZeneca
Parexel
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male participants with a histologically documented diagnosis of prostate adenocarcinoma. * Newly diagnosed high-risk and very high-risk (localised/locally advanced) prostate cancer or a high-risk biochemical recurrence (BCR) following radical prostatectomy. * Provision of a formalin fixed and paraffin embedded (FFPE) tumour tissue sample. * Confirmed BRCA1 or BRCA2 mutation status by central tumour tissue is required for enrolment. * Participants required to have a computed tomography (CT) or magnetic resonance imaging (MRI) and a bone scan following the completion of their planned RT. This screening scan must confirm no evidence of disease or evidence of disease confined to the pelvis (M0). * Participants required to have a prostate-specific membrane antigen-positron emission tomography (PSMA-PET) following the completion of their planned RT. This screening scan must confirm no evidence of disease or evidence of disease confined to the pelvis (M0). * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no deterioration over the 2 weeks prior to randomization. * Minimum life expectancy of 12 months. * Adequate organ and bone marrow function as described in study protocol. * All participants will have received either primary or salvage RT. Participants must be eligible for randomisation within 10 months of initial diagnosis (de novo or BCR). Radiotherapy administered to the prostate (± pelvis) either in the primary or salvage setting must be delivered with curative intent. Use of metastases-directed therapy, as part of the RT radiation plan, is permitted as localised RT treatment for a metastatic lesion(s) outside the pelvis. * All participants will have received a planned regimen of ADT with a gonadotropin releasing hormone (GnRH) analogue. * Participants must not father children or donate sperm from signing informed consent form (ICF), during the study intervention and for 6 months after the last dose of study intervention. * Participants must use a condom (with spermicide - where permitted) from signing ICF, during study intervention, and for 6 months after the last dose of study drug, with all sexual partners.
Exclusion criteria
* Participants with a history of myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML) or with features suggestive of MDS/AML. * Participants with any known predisposition to bleeding \[e.g., active peptic ulceration, recent (within 6 months) hemorrhagic stroke, proliferative diabetic retinopathy\]. * Any history of persisting (\> 2 weeks) severe cytopenia due to any cause. * Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of saruparib and/or abiraterone. * History of another primary malignancy, with exceptions. * Persistent toxicities \[Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 2\] caused by previous anticancer therapy. * Cardiac criteria, including history of arrhythmia and cardiovascular disease. * Evidence of active and uncontrolled hepatitis B and/or hepatitis C. * Evidence of active and uncontrolled human immunodeficiency virus (HIV) infection. * Active tuberculosis infection. * Any prior chemotherapy (i.e., docetaxel) or immunotherapy; any prior treatment with a poly (ADP-ribose) polymerase (PARP) inhibitor. * Prior treatment within 14 days with blood product support or growth factor support. * Concomitant use of strong inducers and inhibitors of CYP3A4 (applies to saruparib and abiraterone) or herbal supplements within 21 days or at least 5 half-lives (whichever is longer), of randomization. * Concomitant use of drugs that are known to prolong QT and have a known risk of Torsades de Pointes (TdP). * Participants with a known hypersensitivity to saruparib or any excipients of these products.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Metastasis-free survival (MFS) | Up to approximately 93 months | MFS is defined as the time from randomisation until the date of first appearance of distant metastases, confirmed by standard clinical imaging \[computed tomography (CT)/ magnetic resonance imaging (MRI) and bone scan, or prostate-specific membrane antigen-positron emission tomography (PSMA-PET)\], as assessed by blinded independent central review (BICR) or death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MFS (CT/MRI and bone scan) | Up to approximately 93 months | MFS is defined as the time from randomisation until the date of distant metastases, confirmed by conventional imaging (CT/MRI and bone scan), or death due to any cause. |
| MFS (PSMA-PET) | Up to approximately 93 months | MFS is defined as the time from randomisation until the date of distant metastases, confirmed by PSMA-PET imaging or death due to any cause. |
| MFS (standard clinical imaging) | Up to approximately 93 months | MFS is defined as the time from randomisation until the date of distant metastases, confirmed by standard clinical imaging (CT/MRI and bone scan or PSMA-PET), histology, or death due to any cause. |
| Time from randomisation to Progression Free Survival 2 (PFS2) | Up to approximately 93 months | Time from randomisation to PFS2 is defined as the time from randomisation to the earliest of progression \[defined as radiographic progression, clinical progression, or prostate-specific antigen (PSA) progression\] after initiation of first subsequent systemic treatment following the initial investigator-assessed progression or death. The date of second progression will be investigator assessed according to local standard clinical practice. |
| Time to biochemical recurrence | Up to approximately 93 months | Time to biochemical recurrence is defined as the time from randomisation to biochemical recurrence per Phoenix criteria. |
| Prostate cancer-specific survival (PCSS) | Up to approximately 11 years | PCSS is defined as the time from randomisation until the date of death due to the underlying prostate cancer. |
| Time to deterioration in urinary symptoms (TTDUS) | Up to approximately 93 months | TTDUS is defined as the time from randomisation to deterioration in EORTC-QLQ-PR25 (US) subscale scores. |
| Time to deterioration in physical function (TTDPF) | Up to approximately 93 months | TTDPF is defined as the time from randomisation to deterioration in EORTC-QLQ-C30 Physical Function subscale scores. |
| Plasma concentrations of saruparib | Day 1 of Cycle 1, Cycle 3 and Cycle 6 (each cycle is of 28 days) | To assess the PK of saruparib in plasma either with or without abiraterone and explore the relationship between the PK concentration/parameters and selected endpoints (which may include pharmacodynamic parameters, efficacy, and/or safety). |
| Area under the curve (AUC) | Day 1 of Cycle 1, Cycle 3 and Cycle 6 (each cycle is of 28 days) | To assess the PK of saruparib in plasma either with or without abiraterone and explore the relationship between the PK concentration/parameters and selected endpoints (which may include pharmacodynamic parameters, efficacy, and/or safety). |
| Maximum observed concentration (Cmax) | Day 1 of Cycle 1, Cycle 3 and Cycle 6 (each cycle is of 28 days) | To assess the PK of saruparib in plasma either with or without abiraterone and explore the relationship between the PK concentration/parameters and selected endpoints (which may include pharmacodynamic parameters, efficacy, and/or safety). |
| Time to Cmax (Tmax) | Day 1 of Cycle 1, Cycle 3 and Cycle 6 (each cycle is of 28 days) | To assess the PK of saruparib in plasma either with or without abiraterone and explore the relationship between the PK concentration/parameters and selected endpoints (which may include pharmacodynamic parameters, efficacy, and/or safety). |
| Overall Survival (OS) | Up to approximately 11 years | OS is defined as the time from randomisation until the date of death due to any cause. |
| Number of participants with adverse events (AEs) | Up to approximately 11 years | To assess the safety and tolerability of saruparib administered in combination with ADT alone (Cohort A) and in combination with ADT + abiraterone (Cohort B). |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, China, Finland, France, Germany, Hungary, India, Israel, Italy, Japan, Malaysia, Netherlands, Peru, Poland, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed