Phase III Randomized, Double-Blind, Placebo-Controlled Study of Saruparib (AZD5305) with New Hormonal Agents in Metastatic Castration-Sensitive Prostate Cancer

The primary objective of this study is to demonstrate the superiority of **AZD5305** in combination with the physician's choice of new hormonal agents (NHA) compared to placebo plus the physician's choice of NHA. This will be assessed by evaluating the **radiographic progression-free survival (rPFS)** in participants with **metastatic castration-sensitive prostate cancer (mCSPC)** within the BRCAm subpopulation, the HRRm cohort, and the non-HRRm cohort. The clinical relevance of this objective lies in its potential to improve treatment outcomes by delaying disease progression in this patient population.

Secondary objectives include demonstrating the superiority of AZD5305 plus physician's choice NHA over placebo plus physician's choice NHA by assessing **overall survival (OS)** in participants with mCSPC in the BRCAm subpopulation within the HRRm cohort, the HRRm cohort, and the non-HRRm cohort. This objective is clinically significant as it aims to extend the lifespan of patients with mCSPC, providing a potential advancement in therapeutic strategies for this condition.

The clinical trial involves a total of **1265 participants** diagnosed with **Metastatic Castration-Sensitive Prostate Cancer (mCSPC)**. The study population is exclusively male, aged 18 years and older, with a confirmed diagnosis of prostate adenocarcinoma that is either de novo or recurrent and castration-sensitive. Participants are required to have metastatic disease with at least one bone or soft tissue lesion suitable for repeated assessment. All participants are receiving androgen deprivation therapy (ADT) with a GnRH analogue or have undergone bilateral orchiectomy. The trial excludes individuals with small cell, neuroendocrine, sarcomatoid, spindle cell, or signet cell histology. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate organ and bone marrow function is necessary, and participants must provide a formalin-fixed paraffin-embedded (FFPE) tumor tissue sample and blood sample for circulating tumor DNA (ctDNA) analysis. The trial does not include female subjects or vulnerable populations. Lifestyle considerations include the requirement for participants to use condoms during the study and for six months after the last dose of the study drug, and they must not father children or donate sperm during this period.

The clinical trial is designed as a **randomized**, double-blind, placebo-controlled, Phase III study to evaluate the efficacy of **Saruparib** (AZD5305) in combination with physician's choice of new hormonal agents in patients with **metastatic castration-sensitive prostate cancer** (mCSPC). The trial aims to demonstrate the superiority of Saruparib plus physician's choice of new hormonal agents over placebo plus physician's choice of new hormonal agents by assessing radiographic progression-free survival in participants with mCSPC. The trial is expected to commence recruitment on March 1, 2024, and conclude by April 30, 2031, with a maximum treatment period of 86 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological documentation of prostate adenocarcinoma, and metastatic disease status. Following randomization, participants will receive either the investigational product or placebo, administered orally in tablet form. The study includes regular follow-up visits to monitor safety, efficacy, and compliance with the treatment regimen. These visits will involve assessments such as imaging studies to evaluate disease progression and laboratory tests to ensure adequate organ and bone marrow function.

The end-of-study visit will occur after the completion of the treatment period or upon early termination from the study. Conditions that may lead to early termination include significant adverse events, disease progression, or withdrawal of consent by the participant. The primary endpoint of the study is radiographic progression-free survival, while secondary endpoints include overall survival, time to second progression or death, and symptomatic skeletal event-free survival, among others. Participants are expected to be involved in the study for the duration of the treatment period and follow-up assessments, with specific timelines determined by individual response and study protocol adherence.

The clinical trial involves the administration of **Saruparib**, an experimental medication, in the form of a tablet. The active substance, saruparib, is chemically synthesized and is identified by the sponsor product code AZD5305. The medication is administered orally. The maximum treatment period for saruparib is 86 days. The specific dosage and frequency of administration are not detailed in the provided data.

**ZYTIGA 250 mg tablets** are used as a comparator treatment in the study. The active substance in ZYTIGA is abiraterone acetate, which is also chemically synthesized. This medication is administered orally in tablet form. The maximum treatment period is 86 days, with the dosage and frequency of administration not specified in the data.

**NUBEQA 300 mg film-coated tablets** contain the active substance darolutamide, which is chemically synthesized. This medication is administered orally. The maximum treatment period is 86 days, with no specific dosage or frequency of administration provided in the data.

**BAY 1841788**, also known as ODM-201 300 mg film-coated tablet, contains the active substance darolutamide. It is chemically synthesized and administered orally. The maximum treatment period is 86 days, with no specific dosage or frequency of administration provided in the data.

**Xtandi - 40 mg film-coated tablets** contain the active substance enzalutamide, which is chemically synthesized. This medication is administered orally. The maximum treatment period is 86 days, with no specific dosage or frequency of administration provided in the data.

**Abiraterone Teva 500 mg film-coated tablets** contain the active substance abiraterone acetate, which is chemically synthesized. This medication is administered orally. The maximum treatment period is 86 days, with no specific dosage or frequency of administration provided in the data.

A **Placebo to match (PTM) tablets** is used in the study as a control. The placebo is designed to match the appearance of the active medications but does not contain any active pharmaceutical ingredients. The administration route and specific details regarding dosage and frequency are not provided in the data.

The efficacy of the clinical trial will be assessed primarily through the measurement of **radiographic progression-free survival (rPFS)**. This endpoint is defined as the time from randomization to radiographic progression, as assessed by the investigator using RECIST 1.1 criteria for soft tissue and/or PCWG3 criteria for bone, or death due to any cause. Secondary endpoints include overall survival, time to second progression or death (PFS2), time to first subsequent therapy or death (TFST), symptomatic skeletal event-free survival, time to castration-resistance (TTCR), and various clinical outcome assessments such as time to pain progression (TTPP), time to deterioration in urinary symptoms (TTDUS), time to deterioration in fatigue (TTDF), time to deterioration in physical functioning (TTDPF), and health-related quality of life (HRQoL).

The trial will involve the administration of Saruparib (AZD5305) in combination with physician's choice of new hormonal agents (NHAs) compared to placebo plus physician's choice of NHAs in patients with metastatic castration-sensitive prostate cancer (mCSPC). The efficacy parameters will be collected and analyzed at specified timepoints throughout the study duration, which is estimated to end by April 2031. The trial will utilize validated scales and criteria to ensure the accuracy and reliability of the efficacy assessments.