Phase 3 Randomized, Double-Blind Trial of Talazoparib and Enzalutamide Versus Placebo and Enzalutamide in DDR Gene Mutated Metastatic Castration-Sensitive Prostate Cancer

The primary objective of this study is to demonstrate that **talazoparib** in combination with **enzalutamide** is superior to placebo in combination with enzalutamide in prolonging investigator-assessed Radiographic Progression-free Survival (rPFS) in participants with metastatic castration-sensitive prostate cancer (mCSPC) harboring DNA damage repair (DDR) deficiencies. This is clinically relevant as it aims to improve the management and outcomes of mCSPC, a condition where effective treatment options are crucial for delaying disease progression.

Secondary objectives include demonstrating that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging overall survival (OS) in participants with mCSPC harboring DDR deficiencies. This objective is significant as it seeks to extend the lifespan of patients with this specific genetic profile, potentially offering a more effective therapeutic strategy.

The clinical trial involves a total of **344 male participants** diagnosed with **Metastatic Castration-sensitive Prostate Cancer**. The study population is composed exclusively of males, as female subjects are not included. Participants are within the age range corresponding to categories 3 and 4, which typically include adults and older adults. The selection criteria for the trial population require histologically or cytologically confirmed adenocarcinoma of the prostate, with specific genetic mutations confirmed by approved testing methods. Participants must be undergoing androgen deprivation therapy (ADT) and have documented metastatic prostate cancer, excluding those with disease limited to regional pelvic lymph nodes. The trial does not include vulnerable populations, and participants are expected to 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. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy of **talazoparib** in combination with **enzalutamide** compared to a placebo with enzalutamide in men with **metastatic castration-sensitive prostate cancer** (mCSPC) harboring DDR gene mutations. The primary objective is to assess the superiority of the talazoparib combination in prolonging investigator-assessed radiographic progression-free survival (rPFS). The trial is expected to commence recruitment on April 22, 2024, and conclude by August 7, 2027, with a maximum treatment period of 24 months 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 histologically confirmed adenocarcinoma of the prostate, DDR gene mutation status, and ongoing androgen deprivation therapy (ADT). Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of rPFS per RECIST 1.1 and PCWG3 criteria. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected length of participant involvement is up to 24 months, contingent upon individual response and tolerance to the treatment regimen. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of **Talazoparib**, an experimental medication, in the form of a hard capsule. The active substance, **Talazoparib**, is a chemical entity administered orally. The maximum daily dose is 0.5 mg, with a total dose not exceeding 0.5 mg per day. The treatment period is set for a maximum of 24 months. The medication is subject to packaging and labeling modifications, and participant compliance is monitored throughout the trial.

A placebo, referred to as "Talazoparib placebo," is also utilized in the study. The placebo is designed to mimic the experimental medication in appearance but contains no active substance. It serves as a comparator to evaluate the efficacy of Talazoparib in combination with other treatments.

**Enzalutamide**, marketed as Xtandi, is used as a standard-of-care therapy in this trial. It is provided in the form of soft capsules, each containing 40 mg of the active substance, **Enzalutamide**. The maximum daily dose is 160 mg, with a total dose not exceeding 160 mg per day. The administration route is oral, and the treatment duration is up to 24 months. Enzalutamide is a chemical entity, and its administration is also subject to packaging and labeling changes. Compliance with the dosing schedule is monitored to ensure adherence to the treatment regimen.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint of investigator-assessed **Radiographic Progression-free Survival (rPFS)**. This will be measured according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for soft tissue disease and the Prostate Cancer Working Group 3 (PCWG3) criteria for bone disease. The trial involves participants with metastatic castration-sensitive prostate cancer (mCSPC) harboring DNA damage repair (DDR) deficiencies. The secondary endpoint includes overall survival (OS) in the same participant group, with alpha protection applied.

Measurements will be conducted at specified intervals throughout the trial, with the maximum treatment period set at 24 months. The trial is designed to compare the efficacy of talazoparib in combination with enzalutamide versus placebo with enzalutamide. The study is randomized and double-blind, ensuring that neither the participants nor the investigators know which treatment the participants are receiving, thereby reducing bias in the assessment of efficacy.