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

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

This study is a randomized, open-label, controlled, multicenter phase III clinical trial, which plans to randomly enroll 370 subjects with advanced metastatic castration-resistant prostate cancer (mCRPC). The efficacy of HRS-4357 versus novel androgen receptor pathway inhibitors (ARPI) in the treatment of PSMA-positive advanced metastatic castration-resistant prostate cancer (mCRPC) will be evaluated based on radiographic progression-free survival (rPFS) assessed by the BIRC.

Study Overview

• Status: Recruiting
• Conditions: PSMA-Positive Progressive Metastatic Castration-Resistant Prostate Cancer
• Intervention / Treatment: Drug: HRS-4357 injection; Drug: Enzalutamide；Abiraterone

• Study Type: Interventional
• Enrollment (Estimated): 370
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Yuezheng Ti; Phone Number: +0518-82342973; Email: yuezheng.ti@hengrui.com

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 201321
      • Recruiting
      • Fudan University Shanghai Cancer Center
      • Principal Investigator: Dingwei Ye
      • Principal Investigator: Shaoli Song

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Be willing to participate in this clinical trial, understand the study procedures, and be able to sign the informed consent form in writing;
2. Male, aged ≥ 18 years;
3. ECOG performance status score of 0-1;
4. Expected survival time of no less than 6 months;
5. Prostate adenocarcinoma confirmed by histology and/or cytology, and diagnosed as mCRPC (metastatic castration-resistant prostate cancer) with reference to current clinical guidelines;
6. Presence of at least one metastatic lesion confirmed by imaging examinations (CT/MRI and/or bone scan) within 4 weeks before randomization;
7. Confirmation of at least one PSMA-positive lesion and no PSMA-negative lesions by PSMA PET/CT;
8. 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;
9. 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);
10. 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:

1. Received any of the following treatments before randomization:

   1. Any radionuclide therapy or hemi-body radiotherapy within 6 months.
   2. Any PSMA-targeted radiopharmaceutical therapy.
   3. Surgery, radiotherapy, or any local therapy within 4 weeks.
   4. Any other investigational drug intervention within 4 weeks.
2. Known hypersensitivity to the components of the study drug or its analogs.
3. 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.
4. Occurrence of severe infection (CTCAE > Grade 2) within 4 weeks before randomization.
5. Failure to recover from adverse events of previous treatments (NCI-CTCAE Version 5.0 Grade > 1) before randomization, as judged by the investigator.
6. Presence of poorly controlled clinical cardiac symptoms or cardiac diseases.
7. History of physical or psychiatric illnesses/conditions that may interfere with the study objectives and assessments (including epilepsy and dementia).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HRS-4357 injection	Drug: HRS-4357 injection; HRS-4357 injection are administered each time, with dosing for 4 to 6 cycles
Active Comparator: Enzalutamide Soft Capsules / Abiraterone Acetate Tablets+ Prednisone Acetate Tablets	Drug: Enzalutamide；Abiraterone; ARPI (investigator's choice of any of the following agents, with the requirement that the agent has not been used previously): Enzalutamide 160 mg orally once daily (qd); Abiraterone 1000 mg orally once daily (qd) + Prednisone 5 mg orally twice daily (bid)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
radiographic progression-free survival (rPFS) assessed by the BIRC.	From Baseline to primary completion date, about 24 months

Secondary Outcome Measures

Outcome Measure	Time Frame
OS	From Baseline to primary completion date, about 24 months
rPFS（Investigator-Assessed）	From Baseline to primary completion date, about 24 months
ORR （Investigator-Assessed and BIRC-Assessed）	From Baseline to primary completion date, about 24 months
DCR（Investigator-Assessed and BIRC-Assessed）	From Baseline to primary completion date, about 24 months
DOR（Investigator-Assessed and BIRC-Assessed）	From Baseline to primary completion date, about 24 months
PSA50 Response Rate	From Baseline to primary completion date, about 24 months
Time to PSA Progression	From Baseline to primary completion date, about 24 months
Changes from baseline in scores of the EQ-5D-5L	From Baseline to primary completion date, about 24 months
Changes from baseline in scores of the Functional FACT-P	From Baseline to primary completion date, about 24 months
Changes from baseline in scores of the BPI-SF	From Baseline to primary completion date, about 24 months
Assessment of the incidence and severity of adverse events (AEs) and serious adverse events (SAEs)	From Baseline to primary completion date, about 24 months

Collaborators and Investigators

• Sponsor: Jiangsu HengRui Medicine Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2026
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: December 16, 2025
• First Submitted That Met QC Criteria: December 30, 2025
• First Posted (Actual): December 31, 2025

Study Record Updates

• Last Update Posted (Actual): February 4, 2026
• Last Update Submitted That Met QC Criteria: February 3, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Other Study ID Numbers: HRS-4357-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No