Rezvilutamide With Radical Prostatectomy and Metastasis-Directed Therapy in Oligometastatic Prostate Cancer

Rezvilutamide Combined With Radical Prostatectomy and Metastasis-Directed Radiotherapy in Oligometastatic Prostate Cancer Patients: A Multicenter, Three-Arm, Open-Label, Randomized Controlled Phase II Clinical Trial

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.

Inclusion Criteria:

1. Voluntary participation with signed informed consent and understanding of study procedures.

2. Age ≥18 years.

3. Histologically or cytologically confirmed prostatic adenocarcinoma without neuroendocrine differentiation, small cell, sarcomatoid, spindle cell, or signet ring cell histology.

4. 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.

5. Planned or ongoing androgen deprivation therapy (ADT) with LHRH agonist/antagonist (medical castration) or prior bilateral orchiectomy (surgical castration) within ≤4 weeks before enrollment.

6. Adequate organ function (without transfusion or hematopoietic growth factor support within 2 weeks prior to screening labs):

   • Absolute neutrophil count (ANC) ≥1.5×10⁹/L
   • Platelet count (PLT) ≥100×10⁹/L
   • Hemoglobin (Hb) ≥90 g/L
   • Serum creatinine (Cr) ≤1.5×ULN or creatinine clearance >50 mL/min
   • Total bilirubin (BIL) ≤1.5×ULN
   • AST/SGOT or ALT/SGPT ≤2.5×ULN
   • International normalized ratio (INR) ≤1.5, PT and APTT ≤1.5×ULN
   • Left ventricular ejection fraction (LVEF) ≥50%

7. Male patients with female partners of childbearing potential must agree to use effective contraception during the study and for 3 months after the last dose, and must not donate sperm during this period.

8. Ability to comply with the study protocol as judged by the investigator.

9. Ability to adhere to scheduled visits, treatment plans, and laboratory assessments.

Exclusion Criteria:

1. 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.

2. Prior radiotherapy to prostate cancer metastases.

3. Known visceral metastases (liver, lung, brain, peritoneum, etc.) or diffuse bone marrow metastases.

4. 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.

5. Other prior or concurrent malignancies, unless basal cell carcinoma of the skin or other cancers cured for >5 years.

6. Active infections, including active hepatitis B (HBV DNA >2×10³ IU/mL), hepatitis C RNA positive with hepatic impairment, HIV infection, or inadequately treated syphilis.

7. Uncontrolled major cardiovascular disease within 6 months prior to screening, including: a) unstable angina or recent myocardial infarction (within 6 months); b) clinically significant arrhythmias (e.g., sustained ventricular tachycardia); c) heart failure (NYHA Class ≥III).

8. Severe hepatic or renal dysfunction or other laboratory abnormalities not meeting the organ function requirements specified in Inclusion Criterion #6.

9. Known hypersensitivity or history of severe adverse reactions to study medications (novel hormonal agents), anesthetics, or contrast agents used in the study.

10. Any medical, psychological, or social factors that may affect patient compliance or interfere with study outcome assessment, including psychiatric disorders, substance abuse, or other conditions deemed unsuitable by the investigator.

11. Concurrent participation in another interventional clinical study, or use of any investigational drug or medical device within 4 weeks prior to randomization.

12. Any other condition that the investigator considers unsuitable for study participation.

    -