PSMA PET/CT-Guided SBRT Plus Darolutamide in mHSPC

A Multicenter, Prospective, Randomized Controlled Phase II Trial of PSMA PET/CT-Guided Stereotactic Body Radiotherapy Combined With Darolutamide and Androgen Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer

This is a multicenter, randomized, open-label phase 2 study for men with metastatic hormone-sensitive prostate cancer. About 254 participants will first receive 6 months of darolutamide plus androgen deprivation therapy. Participants whose cancer has not progressed and who still have active tumor lesions on prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) will then be randomly assigned to one of two groups. One group will continue darolutamide plus androgen deprivation therapy. The other group will receive stereotactic body radiotherapy (SBRT) to all active tumor lesions identified by PSMA PET/CT, while continuing darolutamide plus androgen deprivation therapy. The main purpose of this study is to find out whether adding PSMA PET/CT-guided SBRT can help participants live longer without tumor growth seen on scans or death. The study will also evaluate prostate-specific antigen (PSA) changes, time to castration-resistant prostate cancer, overall survival, side effects, and quality of life.

Metastatic hormone-sensitive prostate cancer is usually treated with systemic therapy, including androgen deprivation therapy and androgen receptor pathway inhibitors such as darolutamide. However, some patients still have active tumor lesions after initial systemic treatment, and these residual lesions may contribute to later disease progression.

This study is designed to test whether adding targeted radiotherapy to residual active tumor lesions can improve disease control. All enrolled participants will first receive 6 months of darolutamide plus androgen deprivation therapy. After this initial treatment period, participants will undergo clinical and imaging assessment, including prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT), to evaluate whether active tumor lesions remain.

Participants who have no disease progression and still have PSMA PET/CT-positive active tumor lesions will be randomly assigned in a 1:1 ratio to one of two groups. Participants in the control group will continue darolutamide plus androgen deprivation therapy. Participants in the experimental group will continue darolutamide plus androgen deprivation therapy and will also receive stereotactic body radiotherapy (SBRT) to all active tumor lesions identified by PSMA PET/CT, including active lesions in the prostate or prostate bed and metastatic sites when appropriate.

This is a multicenter, prospective, randomized, open-label phase 2 study. The study plans to enroll about 254 men with metastatic hormone-sensitive prostate cancer. The main question is whether PSMA PET/CT-guided SBRT, when added to darolutamide and androgen deprivation therapy after 6 months of initial systemic treatment, can increase the proportion of participants who are alive without radiographic disease progression at 3 years after randomization.

Participants will be followed regularly with physical examinations, blood tests including prostate-specific antigen (PSA), testosterone monitoring when required, imaging examinations, assessment of adverse events, and quality-of-life questionnaires. Imaging-based disease progression will be assessed using standard criteria for soft tissue and bone lesions. Safety will be monitored throughout the study, including side effects related to darolutamide, androgen deprivation therapy, and radiotherapy.

The study will also explore whether PSMA PET/CT imaging features, PSA changes, circulating tumor DNA, and molecular features of tumor or blood samples are associated with treatment response, disease progression, or survival outcomes. These exploratory analyses may help identify future biomarkers for selecting patients who are more likely to benefit from combined systemic therapy and PSMA PET/CT-guided radiotherapy.

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 or pathological evidence.
• PSMA PET/CT and FDG PET/CT show ≤20 metastatic lesions.
• PSMA PET/CT and FDG PET/CT show concordant tracer uptake activity.
• No prior systemic or local anti-tumor treatment for prostate cancer.
• No prior androgen deprivation therapy.
• No prior first-generation antiandrogen therapy.
• No prior androgen receptor signaling inhibitor therapy, including abiraterone, enzalutamide, apalutamide, rezvilutamide, or darolutamide.
• No prior chemotherapy for prostate cancer.
• No prior radical prostatectomy.
• No prior radiotherapy for prostate cancer.
• 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.