Phase III Randomized, Double-Blind, Placebo-Controlled Study of Saruparib (AZD5305) with Radiotherapy and Androgen Deprivation Therapy in BRCAm High-Risk Prostate Cancer

The primary objective is to evaluate the superiority of saruparib compared to a placebo when added to a standard regimen of radiotherapy and androgen deprivation therapy. This assessment is conducted by measuring metastases-free survival in patients presenting with high-risk or very high-risk localized or locally advanced prostate cancer harboring a BRCA mutation. Scope: 3.

This study involves 447 male participants diagnosed with prostate cancer. The population consists of individuals with high-risk or very high-risk localized or locally advanced disease, or those experiencing high-risk biochemical recurrence following radical prostatectomy. Inclusion requires a histologically documented diagnosis of prostate adenocarcinoma and a confirmed BRCA1 or BRCA2 mutation. Eligible participants must have undergone radiotherapy with curative intent and a planned regimen of androgen deprivation therapy utilizing a gonadotropin releasing hormone analogue. Clinical assessment via computed tomography, magnetic resonance imaging, bone scan, or prostate-specific membrane antigen-positron emission tomography must confirm the absence of distant disease. Participants are required to maintain an Eastern Cooperative Oncology Group performance status of 0 or 1 and possess a minimum life expectancy of 12 months. Stringent contraception requirements are mandated for all participants. Selection is contingent upon the provision of a formalin fixed and paraffin embedded tumor tissue sample and adequate organ and bone marrow function.

This is a Phase III, randomised, double-blind, placebo-controlled interventional study designed to evaluate the impact of saruparib added to a standard radiotherapy and androgen deprivation therapy regimen compared to a placebo. The primary objective is to demonstrate superiority in metastases-free survival in patients with high-risk or very high-risk localised or locally advanced prostate cancer harboring a BRCA mutation. The study includes a screening phase to confirm histologically documented prostate adenocarcinoma, BRCA1 or BRCA2 mutation status via tumor tissue analysis, and the absence of distant disease through computed tomography, magnetic resonance imaging, bone scan, or prostate-specific membrane antigen-positron emission tomography. Following randomisation, participants will receive either saruparib or a matching placebo in addition to their standard treatment. Secondary endpoints include overall survival, progression-free survival, and biochemical recurrence. The estimated study duration extends through April 2036. Participant involvement may be subject to early termination based on clinical progression or specific protocol requirements.

Saruparib (AZD5305) is administered as an oral tablet.

Abiraterone acetate is provided as 250 mg tablets or 500 mg film-coated tablets for oral administration.

A placebo to match (PTM) AZD5305 film-coated tablets is utilized as a comparator treatment.

The primary efficacy endpoint is metastases-free survival (MFS), defined as the interval from randomization to the first occurrence of distant metastases or death from any cause. Metastases are confirmed via standard clinical imaging, including computed tomography (CT), magnetic resonance imaging (MRI), bone scan, or prostate-specific membrane antigen-positron emission tomography (PSMA-PET), and are assessed by blinded independent central review (BICR).

Secondary efficacy endpoints include:

• Overall survival (OS), measured from randomization to death due to any cause.
• Additional MFS assessments categorized by specific imaging modalities, including conventional imaging, PSMA-PET, or histological confirmation.
• Time to progression-free survival 2 (PFS2), defined as the time from randomization to the earliest instance of radiographic progression, clinical progression, or prostate-specific antigen (PSA) progression following the initiation of the first subsequent systemic treatment.
• Time to biochemical recurrence as determined by Phoenix criteria.
• Prostate cancer-specific survival (PCSS), measured from randomization to death due to underlying prostate cancer.
• Time to deterioration in EORTC-QLQ-PR25 (US) subscale scores.
• Time to deterioration in EORTC-QLQ-C30 Physical Function subscale scores.
• Evaluation of the pharmacokinetics (PK) of saruparib in plasma to explore the relationship between concentration parameters and efficacy endpoints.