An International, Randomized, Double-Blind, Phase III Study of Fuzuloparib Combined with Abiraterone Acetate and Prednisone (AA-P) versus Placebo Combined with AA-P as First-Line Treatment in Patients with Metastatic Castration-Resistant Prostate Cancer

Prior treatment

• Prior treatment with any PARP inhibitor.
• Presence of dysphagia, chronic diarrhea, intestinal obstruction, or other factors affecting drug intake and absorption.
• Have received any systemic anti-tumor treatment during the mCRPC stage or non-metastatic CRPC (nmCRPC) stage, including chemotherapy, immunotherapy, abiraterone acetate or other CYP17 inhibitors, novel AR antagonists (such as enzalutamide, apalutamide, darolutamide, SHR3680, and proxalutamide) and other molecular targeted therapies. See protocol for the allowed exceptions.
• Confirmed SARS-CoV-2 (COVID-19) infection (validated test positive), or suspected COVID-19 infection (clinical symptoms without documented test results), or close contact with a person with known or suspected COVID-19 infection, within 4 weeks before the first dose. The subject may be included with a documented negative result for a validated COVID-19 test.
• Presence of concomitant diseases (such as severe diabetes mellitus, psychiatric disorders, and pneumonitis or interstitial lung disease) or any other situation that may pose serious risks to the safety of the subjects or may affect their ability to complete the study as judged by the investigator.
• Prior treatment with abiraterone acetate, other CYP17 inhibitors, novel AR antagonists, or chemotherapy during HSPC stage, with PSA elevation, radiographic progression or other clinical progressions during the treatment and 6 months after the end of this treatment (as determined by the investigator).
• With severe bone injury caused by bone metastasis of prostate cancer as judged by the investigator, including poorly controlled severe bone pain, and pathological fractures and spinal cord compressions that have occurred in the last 6 months before the first dose or are expected to occur soon.
• Radiotherapy or major surgery within 4 weeks before the first dose, or participation in other drug clinical trials within 4 weeks or 5 half-lives, whichever is longer, prior to start of this study drug at day 1 (C1D1).
• Have used any strong/moderate CYP3A4 inducers or inhibitors within 14 days prior to the first dose.
• The use of drugs that may affect P-gp cannot be interrupted during the study.

Other illness

• Contraindications to the use of prednisone (corticosteroids), such as active infections or other medical conditions.
• Any chronic medical conditions that require a dose of corticosteroid ≥ 5 mg prednisone BID.
• History of uncontrolled pituitary or adrenal dysfunction.
• Uncontrolled hypertension (persistent systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg). Subjects with a history of hypertension are allowed to participate in the study if their blood pressure can be effectively controlled by antihypertensive therapy.
• History of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), or a history of other malignant tumors within 5 years prior to the first dose (except carcinoma in situ that has been completely relieved and the malignant tumor that is judged by investigators as slowly progressive).
• Active HBV or HCV infection (HBsAg positive with virus copy ≥ 500 IU/mL, HCV antibody positive with HCV RNA higher than the lower limit of detection of the analytical method).
• With known allergy or intolerance to fuzuloparib, abiraterone acetate, prednisone, or their excipients.

Lab values

• Presence of active heart diseases (including severe/unstable angina pectoris, symptomatic congestive heart failure of NYHA Class III or IV, left ventricular ejection fraction < 50%, and ventricular arrhythmia requiring drug therapy) or a history of arterial or venous thrombosis (including pulmonary embolism and cerebrovascular accident) within 6 months, or myocardial infarction within 12 months prior to the first dose.
• Human immunodeficiency virus-positive subjects with 1 or more of the following: - Not receiving highly active antiretroviral therapy. - Had a change in antiretroviral therapy within 6 months of the start of screening. - Receiving antiretroviral therapy that may interfere with study drug (consult sponsor for review of medication prior to enrollment). - CD4 count < 350/mm3 or CD4/CD8 ratio value lower than the minimum of the normal range at screening. - AIDS-defining opportunistic infection within 12 months of start of screening.

Other

• Plan to receive any other anti-tumor treatment during the study treatment of this study.
• Presence of radiologically confirmed tumor lesions in the brain.

• Age of ≥ 18 years old.
• The functional level of the organs must meet the requirements (no blood transfusion or treatment with hematopoietic growth factor within 2 weeks prior to routine blood screening) as detailed in the protocol.
• For patients who are judged by the investigator as having the ability to ejaculate and who are sexually active must agree to take effective contraceptive measures and not to donate sperm from the first dose to 3 months after the last dose of study treatment.
• Participate in this clinical trial voluntarily, understand and have signed the informed consent.
• A score of 0 to 1 for ECOG performance status.
• Expected survival of ≥ 6 months.
• Prostate adenocarcinoma confirmed by histology or cytology examinations, with no indication of neuroendocrine differentiation or small cell characteristics.
• Metastatic lesions with imaging evidence.
• Disease progression of metastatic prostate cancer while the subject was on androgen deprivation therapy. See the disease progression at study entry definition in the protocol.
• Continuous treatment with luteinizing hormone-releasing hormone analogue (LHRHa) (drug-induced castration) or previous bilateral orchidectomy (surgical castration); subjects who have not undergone bilateral orchidectomy must plan to maintain effective LHRHa treatment within 4 weeks prior to the randomization of this study and throughout the entire study.
• Testosterone is at the castration level (≤ 50 ng/dL or 1.73 nmol/L) during screening.
• Blood and tumor tissue samples (tumor sample is optional) are provided during screening to determine the DRD status; subjects in Cohort 2 must be DRD positive.