PSMA PET/CT-Guided SBRT Plus Darolutamide in mHSPC

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.