HRS-4357 versus novel androgen receptor pathway inhibitors for 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 trial will test whether HRS-4357 works better than newer androgen receptor pathway drugs (like enzalutamide or abiraterone) for men with PSMA-positive metastatic castration-resistant prostate cancer.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 370 (estimated)
• Ages: 18 Years and up
• Sex: Male
• Sponsor: Jiangsu HengRui Medicine Co., Ltd. (Industry-sponsored)
• Locations: 1 site (Shanghai, Shanghai Municipality)
• Trial ID: NCT07311694 on ClinicalTrials.gov

What this trial studies

This randomized, open-label, multicenter Phase III trial plans to enroll about 370 men with PSMA-positive metastatic castration-resistant prostate cancer and randomly assign them to receive HRS-4357 or a novel androgen receptor pathway inhibitor (enzalutamide or abiraterone). The primary outcome is radiographic progression-free survival (rPFS) as determined by a blinded independent review committee (BIRC). Eligible participants must have castration-level testosterone, ECOG performance status 0-1, at least one metastatic lesion on conventional imaging, and at least one PSMA-positive lesion on PSMA PET/CT without PSMA-negative lesions. Safety, secondary efficacy endpoints, and survival will be monitored during and after treatment across participating centers.

Who should consider this trial

Good fit: Men aged 18 or older with histologically confirmed mCRPC, castration-level testosterone, ECOG 0-1, at least one metastatic lesion on imaging, and at least one PSMA-positive lesion on PSMA PET/CT are appropriate candidates.

Not a fit: Patients without PSMA-positive disease, with ECOG >1, expected survival under six months, or who cannot maintain medical or surgical castration are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, HRS-4357 could extend the time before radiographic disease progression compared with current AR pathway inhibitors, potentially prolonging disease control and delaying more toxic treatments.

How similar studies have performed: PSMA-targeted approaches and newer therapies compared against AR pathway inhibitors have shown clinical benefit in prior mCRPC trials, but HRS-4357 itself represents a novel agent that has not yet been proven in large Phase III comparisons.

Eligibility criteria

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).

Where this trial is running

Shanghai, Shanghai Municipality

• Fudan University Shanghai Cancer Center — Shanghai, Shanghai Municipality, China (Recruiting)

Study contacts

• Study coordinator: Yuezheng Ti

Conditions PSMA-Positive Progressive Metastatic Castration-Resistant Prostate Cancer