PSMA PET/CT-Guided SBRT Plus Darolutamide in mHSPC (PSMA-DaroRT)

Inclusion Criteria:

• Male participants aged ≥18 years and <85 years.
• Histologically confirmed prostate adenocarcinoma.
• No neuroendocrine carcinoma, ductal adenocarcinoma, small-cell carcinoma, signet-ring cell carcinoma, or sarcomatoid carcinoma component.
• Metastatic prostate cancer confirmed by imaging and/or pathological evidence.
• Baseline PSMA PET/CT assessment demonstrates a total of ≤20 metastatic lesions.
• No prior radical prostatectomy or radiotherapy for prostate cancer.
• No prior systemic anti-tumor therapy that may affect the efficacy assessment of this study, including androgen receptor signaling inhibitors (ARSIs; e.g., abiraterone, enzalutamide, apalutamide, rezvilutamide, or darolutamide), chemotherapy, PARP inhibitors, radionuclide therapy, or other such treatments.
• Short-term androgen deprivation therapy (ADT) and/or first-generation antiandrogen therapy prior to enrollment is permitted, provided that the interval from the first initiation of any such treatment to the date of enrollment does not exceed 3 months (≤12 weeks).
• Expected survival >12 months.
• Able to understand the study and voluntarily sign written informed consent.
• Able and willing to comply with study visits and protocol procedures.
• Willing to provide tumor tissue, blood, and other biological samples as required by the study protocol.
• Absolute neutrophil count ≥1.5 × 10^9/L.
• Platelet count ≥100 × 10^9/L.
• Hemoglobin ≥90 g/L.
• Total bilirubin ≤1.5 × upper limit of normal.
• Alanine aminotransferase and aspartate aminotransferase ≤2.5 × upper limit of normal.
• Serum albumin ≥20 g/L.
• Serum creatinine ≤1.5 × upper limit of normal or creatinine clearance ≥50 mL/min.
• Eastern Cooperative Oncology Group performance status ≤2.

Exclusion Criteria:

• Current or prior history of another primary malignancy.
• History of another malignancy within 3 years that differs from the study cancer in primary site or histology.
• History of papillary thyroid carcinoma is allowed if it is well controlled.
• History of basal cell carcinoma of the skin is allowed if it is well controlled.
• History of squamous cell carcinoma of the skin is allowed if it is well controlled.
• History of cervical carcinoma in situ is allowed if it is well controlled.
• Prior radical prostatectomy.
• Prior external beam radiotherapy.
• Prior radical or ablative local therapy for prostate cancer.
• Prior treatment with an androgen receptor signaling inhibitor, including abiraterone, enzalutamide, apalutamide, rezvilutamide, or darolutamide.
• Prior chemotherapy for prostate cancer.
• Major surgery within 4 weeks before enrollment.
• Serious trauma within 4 weeks before enrollment.
• Contraindication to radiotherapy.
• Spinal cord compression.
• Active enteritis.
• Severe pelvic infection.
• Inability to maintain the required body position for radiotherapy.
• History of allergy to PET/CT tracer.
• Nuclear medicine assessment showing super bone imaging.
• Marked discordance between PSMA PET/CT and FDG PET/CT findings.
• Disease progression during the 6-month run-in period of androgen deprivation therapy plus darolutamide before randomization.
• Unacceptable toxicity during the 6-month run-in period of androgen deprivation therapy plus darolutamide before randomization.
• No active tumor lesion on PSMA PET/CT after the 6-month run-in period.
• Allergy to any component of the study treatment.
• Active or poorly controlled serious infection.
• Human immunodeficiency virus infection.
• Acute or chronic active hepatitis B infection, defined as positive hepatitis B surface antigen with hepatitis B virus DNA >1 × 10^3/mL.
• Acute or chronic active hepatitis C infection, defined as positive hepatitis C virus antibody with hepatitis C virus RNA >15 IU/mL.
• Active pulmonary tuberculosis.
• Other serious infectious disease.
• New York Heart Association class III or IV congestive heart failure.
• Persistent symptomatic arrhythmia.
• Uncontrolled atrial fibrillation.
• Left ventricular ejection fraction below the lower limit of normal on repeated echocardiographic assessments.
• Uncontrolled hypertension, defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg.
• Arterial thrombotic, embolic, or ischemic event within 6 months before enrollment.
• Myocardial infarction within 6 months before enrollment.
• Unstable angina within 6 months before enrollment.
• Cerebrovascular accident within 6 months before enrollment.
• Transient ischemic attack within 6 months before enrollment.
• Medical condition requiring warfarin or coumarin anticoagulation therapy.
• Uncontrolled hypercalcemia, defined as ionized calcium >1.5 mmol/L, total calcium >12 mg/dL, or corrected serum calcium above the upper limit of normal.
• Symptomatic hypercalcemia requiring continuous bisphosphonate therapy.
• Uncontrolled adrenal insufficiency.
• History of abdominal fistula within 6 months before enrollment.
• History of gastrointestinal perforation within 6 months before enrollment.
• History of intra-abdominal abscess within 6 months before enrollment.
• Severe non-healing wound.
• Severe non-healing ulcer.
• Gastrointestinal disease that may impair absorption.
• Active peptic ulcer disease.
• Uncontrolled nausea.
• Uncontrolled vomiting.
• Uncontrolled diarrhea.
• History of small bowel resection that may impair drug absorption.
• Other acute or chronic disease, psychiatric disorder, or laboratory abnormality that may increase the risk associated with study participation or study treatment.
• Other acute or chronic disease, psychiatric disorder, or laboratory abnormality that may interfere with interpretation of study results.
• Any other medical or psychological condition that, in the investigator's judgment, may affect participant safety, compliance, or study integrity.
• Any condition that, in the investigator's judgment, makes the participant unsuitable for this study.