Prostate cancer represents the second most common malignancy in men worldwide. Oligometastatic prostate cancer (OMPC), defined as a transitional state between localized and widespread metastatic disease (≤10 metastatic lesions without visceral metastases), exhibits relatively indolent biological behavior, offering a window for curative-intent multimodal therapy. While standard systemic therapy with androgen deprivation therapy (ADT) plus novel hormonal agents (NHA) remains the backbone for metastatic hormone-sensitive prostate cancer (mHSPC), emerging evidence suggests that maximal cytoreductive therapy-combining systemic treatment with local interventions (Radical prostatectomy（RP） and Metastasis-directed radiotherapy（MDT）)-may improve survival outcomes. Rezvilutamide (SHR3680), a novel androgen receptor inhibitor independently developed by a Chinese pharmaceutical company, has demonstrated superior radiographic progression-free survival (rPFS) and overall survival (OS) compared to bicalutamide in high-volume mHSPC (CHART study). However, the value of adding metastasis-directed radiotherapy (MDRT) to rezvilutamide and radical prostatectomy in OMPC remains unproven. This trial hypothesizes that maximal cytoreductive therapy (systemic therapy + surgery + MDRT) will significantly prolong progression-free survival (PFS) compared to systemic therapy alone.
This is a multicenter, three-arm, open-label, randomized controlled phase II clinical trial (Protocol No.: MA-PCa-II-023; Lead Investigator: Prof. Bo Dai, Fudan University Shanghai Cancer Center). The study will enroll 300 patients randomized in a 2:2:1 ratio to:
Arm A (Experimental): Rezvilutamide (240 mg QD) + ADT → radical prostatectomy at month 3 (if PSA decline ≥50%, castrate testosterone level, and resectable disease) → MDT (SBRT 30-40 Gy/3-5 fractions) to all evaluable metastases at month 6 （ 3 month post-surgery）
Arm B (Control): Rezvilutamide (240 mg QD) + ADT alone
Arm C (Factorial): Rezvilutamide (240 mg QD) + ADT → radical prostatectomy at month 3 (without MDT)
Eligible patients are males ≥18 years with histologically confirmed prostate adenocarcinoma (no neuroendocrine differentiation), newly diagnosed mHSPC with oligometastatic disease (≤10 bone/lymph node metastases on conventional imaging; no visceral metastases), and planned ADT. Key exclusion criteria include prior radical prostatectomy, pelvic radiotherapy, systemic therapy for prostate cancer (except ≤4 weeks of ADT), or contraindications to surgery/radiotherapy.
The primary endpoint is PFS, defined as time from randomization to first biochemical progression (PSA rise ≥25% and ≥1 ng/mL above nadir confirmed after ≥3 weeks), radiographic progression (RECIST 1.1/PCWG4), clinical progression (new symptoms from local/metastatic disease), or death. Secondary endpoints include rPFS, OS, PSA response rates (PSA50/PSA90), local therapy completion rate, time to CRPC, quality of life (FACT-P and EPIC-26 questionnaires), and safety profiles. Exploratory endpoints evaluate the role of baseline PSMA PET/CT in staging and the development of artificial intelligence models using multimodal data (clinical, imaging, pathology, molecular) to predict prognosis.
Voluntary participation with signed informed consent and understanding of study procedures.
Age ≥18 years.
Histologically or cytologically confirmed prostatic adenocarcinoma without neuroendocrine differentiation, small cell, sarcomatoid, spindle cell, or signet ring cell histology.
Metastatic hormone-sensitive prostate cancer (mHSPC) with oligometastatic disease defined as: a) ≤10 metastatic lesions combined (bone lesions on Tc-99m bone scan plus extra-pelvic lymph nodes on CT/MRI); and b) No visceral metastases on CT/MRI.
Prior radical prostatectomy, pelvic radiotherapy, prostatic ablation, or any systemic anti-prostate cancer therapy (including novel hormonal therapy, chemotherapy, radionuclide therapy, cancer vaccines, or immune checkpoint inhibitors), except ADT initiated ≤4 weeks prior to randomization that meets inclusion criteria.
Prior radiotherapy to prostate cancer metastases.
Known visceral metastases (liver, lung, brain, peritoneum, etc.) or diffuse bone marrow metastases.
Severe contraindications to surgery or radiotherapy, including major cardiovascular disease (e.g., NYHA Class III-IV heart failure, recent myocardial infarction), pulmonary insufficiency unable to tolerate anesthesia, severe bleeding tendency, or bone marrow suppression.
Parallel
Metastasis-directed radiotherapy
RadiationMetastasis-directed radiotherapy (MDRT; SBRT 30-40 Gy/3-5 fractions to all evaluable metastases) at 3 months post-surgery
Rezvilutamide + ADT
DrugRezvilutamide (240 mg daily) plus ADT alone until progression or unacceptable toxicity.
Radical prostatectomy
Procedure/SurgeryRadical prostatectomy with extended pelvic lymph node dissection (ePLND), including removal of the prostate gland, seminal vesicles, and bilateral pelvic lymph node groups (obturator, internal iliac, external iliac, and common iliac nodes), performed in patients with oligometastatic prostate cancer
Progression-free survival (PFS)
Time from randomization to the first occurrence of biochemical progression, radiographic progression, clinical progression, or death. Biochemical progression: (1) For patients with PSA decline from baseline: PSA increase ≥25% and ≥1 ng/mL above nadir, confirmed by repeat testing ≥3 weeks later; or (2) For patients without PSA decline: PSA increase ≥25% and ≥1 ng/mL above baseline after ≥12 weeks of treatment. Radiographic progression: Disease progression per RECIST 1.1 (soft tissue) and PCWG4 (bone) criteria. Clinical progression: New symptoms due to local disease progression, lymph node involvement, or systemic metastases (e.g., pathologic fracture, spinal cord compression, worsening pain unresponsive to symptomatic treatment).
Radiographic PFS (rPFS)
Time from randomization to first radiographic disease progression (RECIST 1.1 for soft tissue; PCWG3 for bone) or death.
Overall Survival (OS)
Time from randomization to death from any cause.
PSA Response Rates
Proportion of patients achieving PSA50 (≥50% decline), PSA90 (≥90% decline), or undetectable PSA (\<0.2 ng/mL).
Local Therapy Completion Rate
Proportion of patients in experimental arms completing all planned local therapies (surgery ± radiotherapy).
PSMA PET/CT-based rPFS (rPFS-PSMA).
Time from randomization to the first documented radiographic disease progression as assessed by PSMA PET/CT (per PCWG4 criteria) or death from any cause. This endpoint evaluates the utility of molecular imaging compared to conventional imaging for detecting progression.
Artificial Intelligence (AI) Predictive Model Development
Development and validation of machine learning/deep learning models integrating multimodal data-including clinical-pathological variables (age, Gleason score, baseline PSA), imaging features (radiomics from PSMA PET/CT, CT/MRI), pathological features (surgical specimen characteristics), and molecular biomarkers-to predict patient prognosis (PFS, OS) and treatment response. This explores personalized risk stratification and treatment optimization through advanced data analytics.
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Fudan University
Lead sponsor
Jiangsu Hengrui Pharmaceutical Co., Ltd.
Collaborator
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