A Phase III Study Comparing HRS-4357 With Novel Androgen Receptor Pathway Inhibitors in Patients With Progressive, PSMA-Positive Metastatic Castration-Resistant Prostate Cancer

Inclusion criteria

• Be willing to participate in this clinical trial, understand the study procedures, and be able to sign the informed consent form in writing;
• Male, aged ≥ 18 years;
• ECOG performance status score of 0-1;
• Expected survival time of no less than 6 months;
• Prostate adenocarcinoma confirmed by histology and/or cytology, and diagnosed as mCRPC (metastatic castration-resistant prostate cancer) with reference to current clinical guidelines;
• Presence of at least one metastatic lesion confirmed by imaging examinations (CT/MRI and/or bone scan) within 4 weeks before randomization;
• Confirmation of at least one PSMA-positive lesion and no PSMA-negative lesions by PSMA PET/CT;
• Serum testosterone at castration level (< 50 ng/dl or < 1.7 nmol/L) at the screening visit; continuous luteinizing hormone-releasing hormone analog (LHRHA) therapy (medical castration) or previous bilateral orchiectomy (surgical castration); subjects who have not undergone bilateral orchiectomy must plan to maintain effective LHRHA therapy throughout the study period;
• Previous treatment with second-generation ARPIs, with only one episode of disease progression during treatment; and assessed by the investigator as suitable for switching to another ARPI (suitable for receiving abiraterone or enzalutamide);
• Disease progression at the time of enrollment. Disease progression is defined as the occurrence of at least one of the following while the subject's serum testosterone is at a stable castration level: ① PSA progression: PSA value > 1 ng/mL, with two consecutive increases in PSA at intervals of at least 1 week; ② Radiographic progression: occurrence of clearly new lesions; appearance of 2 or more new bone lesions on bone scan; lesion progression indicated by CT or MRI (per RECIST v1.1);

Exclusion criteria

• Received any of the following treatments before randomization:

• Any radionuclide therapy or hemi-body radiotherapy within 6 months.
• Any PSMA-targeted radiopharmaceutical therapy.
• Surgery, radiotherapy, or any local therapy within 4 weeks.
• Any other investigational drug intervention within 4 weeks.
• Known hypersensitivity to the components of the study drug or its analogs.
• History of malignancy (other than prostate cancer) within 5 years before randomization that is expected to alter life expectancy or may interfere with disease assessment, excluding cured malignancies with low risk of metastasis and mortality (5-year survival rate > 90%), such as non-metastatic basal cell carcinoma of the skin, superficial squamous cell carcinoma of the skin, and low-grade superficial bladder cancer.
• Occurrence of severe infection (CTCAE > Grade 2) within 4 weeks before randomization.
• Failure to recover from adverse events of previous treatments (NCI-CTCAE Version 5.0 Grade > 1) before randomization, as judged by the investigator.
• Presence of poorly controlled clinical cardiac symptoms or cardiac diseases.
• History of physical or psychiatric illnesses/conditions that may interfere with the study objectives and assessments (including epilepsy and dementia).