PRO-BOOST-LC: Whole-Gland Boost Strategies Versus SBRT Monotherapy in PSMA-Staged Localized and Locally Advanced Prostate Cancer

The PRO-BOOST-LC study is a prospective, multicenter, randomized phase II/III clinical trial designed to evaluate whether biologically intensified whole-gland prostate dose escalation improves clinically meaningful oncologic outcomes compared with contemporary stereotactic body radiotherapy (SBRT) monotherapy in patients with localized and locally advanced prostate cancer staged as cN0/cM0 on mandatory baseline PSMA PET/CT. Scientific Background and Rationale Radiobiological and clinical evidence supports the concept that prostate cancer exhibits a low alpha/beta ratio, suggesting enhanced sensitivity to hypofractionation and dose escalation. Multiple randomized and prospective studies have demonstrated that higher biologically effective doses delivered to the prostate are associated with improved biochemical control and delayed disease progression. Modern dose-escalation techniques-including high-dose-rate (HDR) brachytherapy boost, low-dose-rate (LDR) brachytherapy boost, and stereotactic boost strategies-enable intraprostatic dose intensification beyond what is typically achievable with external beam radiotherapy alone. Brachytherapy boost strategies allow delivery of ablative-equivalent dose levels exceeding 100 Gy EQD2 (α/β=1.5), resulting in durable biochemical control improvements in intermediate- and high-risk populations. HDR boost approaches offer the advantage of optimized dose distribution and rapid dose fall-off, whereas LDR brachytherapy provides continuous low-dose radiation exposure over time. SBRT boost strategies represent a non-invasive alternative capable of delivering highly conformal, ablative single-fraction treatments. Although these modalities have individually demonstrated favorable oncologic outcomes, direct head-to-head comparison using a uniform external beam backbone has not been performed in a prospective randomized setting. Additionally, prior trials were conducted largely in the pre-PSMA staging era, potentially including occult nodal or distant disease. Modern PSMA PET/CT allows improved staging accuracy and may refine the therapeutic benefit of local dose intensification. The PRO-BOOST-LC trial is designed to address this evidence gap by directly comparing three whole-gland boost modalities delivered after a standardized ultrahypofractionated external beam backbone against SBRT monotherapy in a contemporary, PSMA-staged population. Study Hypothesis The central hypothesis is that the addition of a whole-gland ablative boost following a standardized ultrahypofractionated external beam backbone will improve failure-free survival and metastasis-free survival compared with SBRT monotherapy, without unacceptable increases in clinically significant toxicity or deterioration in quality of life. Overall Study Design This is a prospective, multicenter, randomized, controlled, multi-arm, multi-stage phase II/III trial employing a seamless adaptive design. Eligible patients are randomized to one of four treatment strategies: SBRT monotherapy (control arm), or Ultrahypofractionated external beam radiotherapy backbone followed by HDR brachytherapy boost, Ultrahypofractionated external beam radiotherapy backbone followed by LDR brachytherapy boost, or Ultrahypofractionated external beam radiotherapy backbone followed by single-fraction SBRT boost. Randomization is centralized and stratified to ensure balance of major prognostic factors across arms. Seamless Phase II/III Structure The trial incorporates an initial safety and feasibility stage (phase II component) across all experimental boost arms. During this stage, treatment delivery compliance, acute toxicity, and technical feasibility are prospectively monitored. Predefined safety thresholds and feasibility criteria are applied. If an experimental arm demonstrates unacceptable toxicity, inadequate compliance, or operational infeasibility, that arm may be discontinued upon recommendation of the Data Safety Monitoring Board. Arms meeting predefined criteria proceed seamlessly into the confirmatory phase III stage without interruption of accrual. This adaptive structure preserves statistical integrity while allowing early optimization of the investigational platform. Treatment Principles All treatments are delivered with curative intent using contemporary image-guided radiotherapy techniques. Multiparametric MRI-based planning is mandatory for all patients. Baseline PSMA PET/CT is mandatory for staging confirmation of node-negative, non-metastatic disease. The ultrahypofractionated external beam backbone consists of five high-dose fractions delivered using intensity-modulated arc therapy (VMAT) with daily image guidance. This backbone serves as a standardized platform across experimental arms. Whole-gland boost delivery differs by modality: HDR brachytherapy boost consists of a single high-dose fraction delivered via temporary transperineal catheter implantation under image guidance. LDR brachytherapy boost consists of permanent seed implantation delivering continuous low-dose radiation. SBRT boost consists of a single ablative stereotactic fraction delivered with dedicated immobilization and high-precision image guidance. The control arm consists of SBRT monotherapy delivered in five fractions using stereotactic technique. Androgen deprivation therapy is administered according to contemporary guideline-based risk stratification. The protocol allows incorporation of androgen receptor pathway inhibitors in selected very high-risk patients, provided declaration prior to randomization and appropriate stratification. Imaging Integration Baseline staging requires PSMA PET/CT and multiparametric MRI within protocol-defined timeframes prior to randomization. Imaging ensures accurate classification of cN0 and cM0 status. Follow-up imaging for disease assessment prioritizes PSMA PET/CT for confirmation of distant metastasis. Local recurrence requires radiologic progression confirmation and cannot be defined solely by PSA kinetics or isolated biopsy findings. Primary Endpoint Strategy The primary analysis follows a hierarchical confirmatory framework: Failure-Free Survival (FFS) Metastasis-Free Survival (MFS) Failure-Free Survival includes biochemical recurrence, radiologic progression (local, regional, or distant), initiation of salvage therapy, or death from any cause. Metastasis-Free Survival includes confirmed distant metastasis or death from any cause and is tested only if superiority in FFS is demonstrated. This hierarchical approach preserves type I error control while enabling earlier readout in a heterogeneous NCCN risk population. Secondary Objectives Secondary analyses evaluate: Intraprostatic local control Regional pelvic nodal control Acute and late genitourinary and gastrointestinal toxicity Patient-reported quality of life outcomes PSA kinetics parameters Time to salvage therapy Cancer-specific survival Overall survival Patient-reported outcomes are assessed using validated prostate cancer-specific and general health-related quality of life instruments. Toxicity Monitoring Adverse events are graded using CTCAE version 5.0. Acute toxicity is defined as events occurring within 90 days following completion of radiotherapy. Late toxicity includes events occurring beyond 90 days. The Data Safety Monitoring Board periodically reviews safety data and may recommend protocol modifications if necessary. Statistical Considerations The study is powered to detect clinically meaningful improvements in failure-free survival between pooled boost strategies and SBRT monotherapy. Secondary exploratory comparisons between individual boost modalities will also be conducted. Time-to-event analyses will use Kaplan-Meier and Cox proportional hazards modeling. Hierarchical testing preserves overall alpha allocation. Interim safety analyses are prespecified during the phase II stage. Clinical Significance By integrating PSMA-based staging, contemporary ultrahypofractionation, and direct comparison of three ablative boost strategies within a unified platform, PRO-BOOST-LC represents a next-generation dose-escalation trial. The study aims to determine which prostate dose-intensification strategy provides the optimal balance between durable oncologic control and long-term functional preservation in the modern era.