External Beam and Radioligand Radiotherapy for mCRPC

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with Lutetium-177 (¹⁷⁷Lu-PSMA) is an established treatment for metastatic prostate cancer. Administered intravenously, it enables targeted irradiation of PSMA-expressing tumor cells. However, 30-50% of patients derive limited benefit. This variability could be partly explained by heterogeneity in delivered dose across lesions, leading to under-treatment of certain metastases. The addition of targeted external beam radiotherapy (EBRT) may compensate for this underdosing by delivering a precise dose to insufficiently irradiated lesions.

The investigators hypothesize that the addition of adaptive EBRT to ¹⁷⁷Lu-PSMA will reduce the incidence of skeletal-related events (pathologic fracture, spinal cord compression, surgery, or palliative radiotherapy) without increasing toxicity.

Adaptive EBRT and RLT for mCRPC (ARREST) is a pragmatic registry-based phase 2, multi-center randomized controlled trial within the PERa prospective cohort (NCT03378856) planned to activate in 2026. Patients receiving standard-of-care (SOC) ¹⁷⁷Lu-PSMA with targetable metastatic burden identified on imaging and suitable for EBRT will be eligible. One hundred and twenty eligible patients will be randomized 1:1 to receive either SOC ¹⁷⁷Lu-PSMA therapy alone (maximum 6 cycles) or combined ¹⁷⁷Lu-PSMA plus adaptive EBRT. Patients in the experimental arm will undergo FDG-PET at study entry and SPECT-CT after each cycle of radioligand therapy. Lesions selected for EBRT boost will be chosen based on a set of criteria that include estimated suboptimal absorbed dose from ¹⁷⁷Lu-PSMA, lesions demonstrating low PSMA but high FDG uptake, symptomatic lesions, and lesions at high risk for skeletal-related events. Selected lesions will receive single-fraction EBRT. The prescribed dose will range from 6-12 Gy, with the goal of achieving a combined total biological effective dose of ≥50 Gy (α/β = 5), while prioritizing dose limits for organs at risk.

A maximum treatment time of 60 minutes is permitted for each adaptive EBRT treatment. Patients in the experimental arm who achieve a complete response, as measured by ¹⁷⁷Lu-SPECT-CT and PSA, will pause ARREST treatment and resume at disease progression. The primary endpoint is skeletal-related events at 1 year. Secondary objectives include overall survival, ¹⁷⁷Lu-SPECT-CT and PSA response, toxicity, and quality of life. The sample size is designed to detect a 12-month improvement in the rate of skeletal-related events with a hazard ratio of 0.61, a one-sided alpha of 0.1, and 80% power.

ARREST is expected to safely optimize tumor dose, offering a personalized hybrid approach that may lead to improved patient outcomes. In addition, this study will permit further understanding of these two distinct radiation delivery methods and their effects on tissues, thereby refining the relative biological effectiveness model for more precise treatment planning.