Phase III Randomized Study of Saruparib and Camizestrant Versus CDK4/6 Inhibitor and Endocrine Therapy in BRCA1/2 or PALB2 Mutated HR+/HER2- Advanced Breast Cancer

The primary objective of this study is to demonstrate the superiority of **saruparib** (AZD5305) combined with **camizestrant** compared to the physician's choice of CDK4/6 inhibitor plus endocrine therapy (ET) in terms of progression-free survival (PFS) in participants with advanced breast cancer. This objective is clinically relevant as it aims to establish a more effective first-line treatment option for patients with BRCA1, BRCA2, or PALB2 mutations and hormone receptor-positive, HER2-negative advanced breast cancer, potentially improving patient outcomes by delaying disease progression.

Secondary objectives include:

• To demonstrate the superiority of saruparib (AZD5305) plus camizestrant relative to the physician’s choice of CDK4/6 inhibitor plus ET by assessment of overall survival (OS).

The clinical trial involves a total of **364 participants** diagnosed with **Advanced Breast Cancer**. The study population includes adult females, both pre/peri-menopausal and postmenopausal, as well as adult males. Participants are required to have a histologically or cytologically documented diagnosis of HR-positive, HER2-negative breast cancer, with either locally advanced disease not amenable to curative treatment or metastatic disease. The age range of participants falls within categories 3 and 4, indicating a broad adult age spectrum. Both genders are included in the study, and the trial population selection considers individuals with an **ECOG performance status** of 0 or 1, ensuring no deterioration over the previous two weeks. Participants must have adequate organ and marrow function and provide FFPE tissue with a documented loss of function mutation in BRCA1, BRCA2, or PALB2. The trial also includes a vulnerable population, although specific lifestyle considerations such as diet or physical activity are not detailed in the available data.

The clinical trial is designed as a **randomized**, open-label, Phase III study to evaluate the efficacy and safety of **saruparib** (AZD5305) in combination with **camizestrant** compared to a physician's choice of CDK4/6 inhibitor plus endocrine therapy or camizestrant alone in patients with **advanced breast cancer**. The primary objective is to assess progression-free survival, with secondary endpoints including overall survival, time to chemotherapy, and objective response rate. The trial is expected to commence recruitment on September 30, 2024, and conclude by July 18, 2030.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as documented **BRCA1**, **BRCA2**, or **PALB2** mutations, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, with assessments conducted per RECIST v1.1 guidelines. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected duration of participant involvement is up to 88 weeks, contingent on individual response and tolerability. Conditions that may lead to early termination include disease progression, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the findings, contributing valuable insights into the treatment of advanced breast cancer.

The clinical trial involves the administration of **Camizestrant**, a film-coated tablet developed by AstraZeneca AB. The active substance, camizestrant, is chemically synthesized and administered orally. The dosage and frequency of administration are determined based on the study protocol, with a maximum treatment period of 88 days. Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule.

**Saruparib** is another experimental medication used in the trial, also developed by AstraZeneca AB. It is provided in tablet form and contains the active substance saruparib, which is chemically derived. The administration route is oral, and the treatment duration is capped at 88 days. The dosing schedule is strictly followed, with compliance checks in place to monitor participant adherence.

**Verzenios**, containing the active substance **Abemaciclib**, is used as a comparator treatment. Manufactured by Eli Lilly Nederland B.V., it is available in film-coated tablet form and administered orally. The trial includes different dosages: 50 mg, 100 mg, and 150 mg tablets. The treatment period is limited to 88 days, with participant compliance closely monitored.

**Fulvestrant** is utilized as a comparator treatment in the form of a solution for injection. The active substance, fulvestrant, is chemically synthesized and administered intramuscularly. The treatment duration is set at 88 days, with adherence to the dosing schedule being a critical component of the trial.

**Ribociclib** is another comparator treatment, provided as a film-coated tablet. The active substance, ribociclib, is chemically derived and administered orally. The trial protocol specifies a maximum treatment period of 88 days, with participant compliance being a key focus.

**Exemestane** is included as a comparator treatment in the form of a film-coated tablet. The active substance, exemestane, is chemically synthesized and administered orally. The treatment duration is limited to 88 days, with compliance monitoring in place to ensure adherence to the dosing schedule.

**Ibrance**, containing the active substance **Palbociclib**, is used as a comparator treatment. Manufactured by Pfizer Europe MA EEIG, it is available in film-coated tablet form with dosages of 75 mg, 100 mg, and 125 mg. The administration route is oral, and the treatment period is capped at 88 days, with participant compliance being closely monitored.

**Letrozole** is utilized as a comparator treatment in the form of a film-coated tablet. The active substance, letrozole, is chemically synthesized and administered orally. The trial protocol specifies a maximum treatment period of 88 days, with adherence to the dosing schedule being a critical component of the trial.

**Anastrozole** is included as a comparator treatment in the form of a film-coated tablet. The active substance, anastrozole, is chemically derived and administered orally. The treatment duration is set at 88 days, with compliance monitoring in place to ensure adherence to the dosing schedule.

Efficacy in this clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**. PFS is defined as the time from randomization until disease progression, as determined by RECIST version 1.1 criteria and assessed by Blinded Independent Central Review (BICR), or death from any cause. Secondary endpoints include **Overall Survival (OS)**, which is the time from randomization until death from any cause, and **Progression-Free Survival 2 (PFS2)**, which measures the time from randomization to the earliest progression event following initial progression, subsequent therapy, or death.

Additional secondary endpoints involve the **Objective Response Rate (ORR)**, defined as the proportion of participants achieving complete or partial response per RECIST v1.1, and the **Duration of Response (DoR)**, which is the time from first documented response to progression or death. Patient-reported outcomes will be evaluated using the EORTC quality of life questionnaire (QLQ), focusing on global health status and quality of life changes from baseline. Tolerability will be assessed by the proportion of participants reporting severity levels of diarrhea and abdominal pain using specific EORTC items.

Plasma concentrations of the investigational drugs, **saruparib (AZD5305)** and **camizestrant**, will be measured to support pharmacokinetic analyses. The trial will also explore the development of companion diagnostics by analyzing their performance characteristics and consistency with clinical trial assays. These assessments will be conducted at various time points throughout the study, ensuring comprehensive data collection and analysis to evaluate the efficacy of the treatment regimens under investigation.