PRO-BOOST-N: Prostate-First Versus Combined Prostate and Nodal Dose Escalation in PSMA PET-Staged Node-Positive Prostate Cancer

PRO-BOOST-N: A Randomized Phase II/III Trial Evaluating Prostate-First Versus Combined Prostate and Nodal Dose Escalation in PSMA PET-Staged Node-Positive Prostate Cancer Using an Ultrahypofractionated Whole-Pelvis Radiotherapy Platform

PRO-BOOST-N is a prospective, multicenter, randomized phase II/III clinical trial for patients with prostate cancer and pelvic lymph node involvement (cN1M0) confirmed by PSMA PET/CT, without distant metastatic disease.

Patients with PSMA PET-staged node-positive prostate cancer are potentially curable, but remain at substantial risk of distant progression despite contemporary treatment with radiotherapy, long-term androgen deprivation therapy, and, when appropriate, androgen receptor pathway inhibitors. The optimal way to intensify radiotherapy to the prostate and PSMA PET-positive pelvic lymph nodes remains uncertain in the era of modern molecular imaging.

All participants receive a standardized ultrahypofractionated whole-pelvis radiotherapy backbone delivered in five fractions, combined with long-term systemic therapy according to contemporary clinical practice. The study uses a 2 x 2 factorial randomized design to evaluate two treatment questions.

The primary comparison evaluates whether prostate dose escalation improves metastasis-free survival compared with no additional prostate boost. Patients assigned to prostate boost receive one of three protocol-defined boost techniques: high-dose-rate brachytherapy, low-dose-rate brachytherapy, or single-fraction SBRT. If more than one prostate boost technique is available at the treating center and technically suitable for the patient, the boost technique is assigned by embedded subrandomization.

The key secondary, hierarchically tested comparison evaluates nodal dose escalation by comparing two predefined dose levels to PSMA PET-positive pelvic lymph nodes. Organ-at-risk-driven nodal dose de-escalation is permitted within the higher-dose arm when required for patient safety and protocol compliance.

The primary endpoint is metastasis-free survival (MFS) . Secondary endpoints include overall survival (OS), radiographic progression-free survival (rPFS), intraprostatic and regional nodal control, time to castration-resistant prostate cancer, time to next systemic therapy, treatment-related adverse events graded according to CTCAE version 6.0, and patient-reported quality of life, including urinary, bowel, sexual, and global health domains.

PRO-BOOST-N aims to determine the optimal radiotherapy intensification strategy for patients with PSMA PET-staged node-positive prostate cancer by prospectively evaluating prostate-directed and nodal-directed dose escalation within a modern, standardized radiotherapy platform.

Disease Background and Unmet Clinical Need Prostate cancer with pelvic lymph node involvement (cN1M0) represents a clinically challenging disease state characterized by a substantial risk of subsequent metastatic progression and prostate cancer-specific mortality. Historically, patients with node-positive disease were frequently considered to harbor occult systemic spread and were often managed with androgen deprivation therapy (ADT) alone. This treatment paradigm was largely driven by limitations in imaging sensitivity and by the perception that regional nodal involvement inevitably reflected disseminated disease.

Over the past two decades, accumulating clinical evidence has fundamentally altered this view. Multiple retrospective analyses, population-based studies, and prospective randomized trials have demonstrated that definitive local-regional radiotherapy combined with long-term ADT can achieve durable disease control and improve survival outcomes in selected patients with node-positive prostate cancer. These findings have established combined radiotherapy and systemic therapy as a contemporary standard of care for cN1 disease treated with curative intent.

Despite these advances, outcomes remain heterogeneous. Even with modern multimodality treatment, a substantial proportion of patients experience disease progression, most commonly manifesting as distant metastatic spread. This persistent failure pattern highlights an unmet clinical need to optimize local-regional treatment strategies and to better define the relative contributions of prostate-directed and nodal-directed radiotherapy dose escalation to long-term disease control.

Transformation of Staging in the PSMA PET Era The widespread clinical adoption of prostate-specific membrane antigen positron emission tomography (PSMA PET) has transformed staging and risk stratification in prostate cancer. PSMA PET offers superior sensitivity and specificity compared with conventional imaging for the detection of nodal and distant metastatic disease. This has led to stage migration, particularly among patients previously classified as node-negative on conventional imaging who are now identified as having limited pelvic nodal involvement.

As a result, the contemporary population of patients classified as cN1M0 based on PSMA PET represents a biologically and clinically distinct cohort compared with historical node-positive populations. Many of these patients harbor small-volume nodal disease that would previously have remained undetected. Consequently, existing evidence guiding radiotherapy dose prescription and target volume selection, largely derived from the pre-PSMA era, may not be directly applicable to current clinical practice.

Importantly, while PSMA PET improves detection of nodal disease, it does not define the optimal therapeutic response. The identification of pelvic nodal metastases raises critical questions regarding treatment intensification: whether improved outcomes are best achieved through more aggressive treatment of the primary prostate tumor, through escalation of dose to involved lymph nodes, or through a combined strategy addressing both compartments.

Biological Rationale for Local-Regional Disease Control From a biological perspective, prostate cancer progression is increasingly understood as a dynamic process in which the primary tumor and regional nodal metastases may serve as sources of further metastatic dissemination. In this context, effective control of both intraprostatic disease and regional nodal deposits may reduce subsequent disease spread and delay or prevent the emergence of castration-resistant disease.

Durable intraprostatic disease control has consistently been associated with improved long-term outcomes across multiple prostate cancer risk groups. Dose escalation to the prostate has been shown to improve biochemical control, local control, and, in selected analyses, metastasis-free and overall survival. These benefits have been demonstrated using a variety of techniques, including conventionally fractionated radiotherapy, moderate and ultrahypofractionation, stereotactic body radiotherapy (SBRT), and brachytherapy boost approaches.

In node-positive prostate cancer specifically, emerging real-world and propensity score-matched analyses suggest that intensified prostate-directed radiotherapy may exert an important influence on systemic disease control. Patients receiving high biologically effective doses to the prostate, particularly through brachytherapy boost techniques, may experience improved metastasis-free survival even in the presence of pelvic nodal disease. These observations form the biological foundation of the central hypothesis underlying PRO-BOOST-N.

Prostate Dose Escalation as the Primary Hypothesis The primary hypothesis of PRO-BOOST-N is that durable intraprostatic tumor control is a major determinant of long-term systemic disease suppression in patients with PSMA PET-staged node-positive prostate cancer. According to this hypothesis, effective treatment of the primary tumor may reduce the reservoir of clonogenic cells capable of seeding distant metastases, thereby improving metastasis-free survival.

PRO-BOOST-N is designed to prospectively test this hypothesis in a randomized setting by comparing contemporary SBRT-based definitive prostate radiotherapy without additional boost to ablative prostate dose escalation delivered using established high-dose techniques.

Uncertainty and Rationale Regarding Nodal Dose Escalation In contrast to the relatively consistent signal supporting prostate dose escalation, the role of aggressive dose escalation to involved pelvic lymph nodes remains uncertain. While the biological rationale for nodal ablation is compelling, clinical evidence remains heterogeneous. Retrospective series have demonstrated the technical feasibility and safety of delivering escalated doses to involved pelvic lymph nodes using modern intensity-modulated techniques, including simultaneous integrated boost approaches.

However, the incremental clinical benefit of escalating nodal dose beyond moderate biologically effective levels has not been consistently demonstrated. Some analyses suggest a dose-response relationship up to approximately 55-60 Gy EQD2, with a potential plateau thereafter. Other studies have not demonstrated an independent association between nodal dose and survival outcomes when prostate dose and systemic therapy are taken into account. In addition, aggressive nodal dose escalation may increase the risk of gastrointestinal and genitourinary toxicity, particularly in hypofractionated or ultrahypofractionated regimens.

Given these uncertainties, PRO-BOOST-N incorporates nodal dose escalation as a key secondary objective, evaluated hierarchically after the primary prostate dose escalation comparison. This design reflects both biological plausibility and the current state of clinical evidence, while minimizing the risk of overinterpreting potentially marginal effects.

Rationale for Ultrahypofractionated Whole-Pelvis Radiotherapy Prostate cancer exhibits a low alpha/beta ratio, making it suitable for hypofractionated and ultrahypofractionated radiotherapy schedules. Advances in treatment planning, image guidance, and motion management have enabled delivery of large fraction sizes with acceptable toxicity profiles. Emerging clinical data suggest that whole-pelvis radiotherapy can be delivered in a limited number of fractions when modern techniques are applied, including in high-risk and node-positive settings.

An ultrahypofractionated whole-pelvis radiotherapy platform offers several advantages. It provides a standardized treatment backbone that minimizes variability in fractionation and overall treatment time, improves patient convenience, and facilitates protocol adherence across multiple centers. It also enables direct comparison of prostate and nodal dose escalation strategies within a unified fractionation framework.

Study Design and Overall Structure PRO-BOOST-N is a prospective, multicenter, randomized phase II/III clinical trial designed to evaluate the relative and combined impact of prostate-directed and nodal-directed radiotherapy dose escalation in patients with PSMA PET-staged node-positive (cN1M0) prostate cancer. All eligible patients undergo mandatory baseline PSMA PET/CT to confirm pelvic lymph node involvement and exclude distant metastatic disease. Multiparametric magnetic resonance imaging of the prostate is strongly recommended to support local staging and target delineation.

All enrolled patients receive a standardized ultrahypofractionated external beam radiotherapy backbone consisting of whole-pelvis radiotherapy delivered in five fractions. This backbone includes elective pelvic nodal volumes and the prostate and is delivered using modern intensity-modulated techniques with daily image guidance. All patients receive long-term ADT as the systemic therapy backbone, with optional use of androgen receptor pathway inhibitors according to contemporary clinical practice and local availability.

Randomization Framework and Treatment Factors The trial employs a 2 x 2 factorial randomized design incorporating two independent treatment factors. The first factor evaluates prostate dose escalation strategy and constitutes the primary randomized comparison. Patients are assigned to receive either contemporary SBRT-based definitive prostate radiotherapy without additional boost or ablative prostate dose escalation delivered using one of three protocol-defined modalities: high-dose-rate brachytherapy, low-dose-rate brachytherapy, or single-fraction SBRT boost.

Before the main factorial randomization, the prostate boost modality eligibility set is documented for each patient. If two or more prostate boost modalities are available at the enrolling center and technically suitable for the patient, embedded subrandomization is performed among the eligible modalities in an equal ratio. If only one prostate boost modality is available and technically suitable, that modality is prospectively assigned as the single feasible modality. The assigned prostate boost modality is used only if the patient is randomized to the prostate boost arm.

The second factor evaluates nodal dose escalation strategy and constitutes a key secondary, hierarchically tested comparison. Patients are randomized to receive one of two predefined dose levels to PSMA PET-positive pelvic lymph nodes, corresponding to intermediate versus higher biologically effective doses. Nodal boost doses are delivered using a simultaneous integrated boost approach within the ultrahypofractionated whole-pelvis radiotherapy plan. Protocol-defined organ-at-risk-driven nodal dose de-escalation is permitted within the higher-dose arm to ensure patient safety and feasibility.

Systemic Therapy Integration and Real-World Relevance All patients enrolled in PRO-BOOST-N receive long-term androgen deprivation therapy in accordance with contemporary standards of care. The use of androgen receptor pathway inhibitors is permitted and encouraged based on clinical indications, local availability, and patient comorbidities. Systemic therapy is not randomized, reflecting real-world practice, but planned use of androgen receptor pathway inhibitors is recorded at baseline and incorporated into stratification and exploratory analyses.

This approach ensures that the trial evaluates radiotherapy dose escalation strategies within the context of modern systemic treatment, enhancing the external validity and clinical relevance of the results.

Endpoints and Outcome Assessment The primary endpoint of PRO-BOOST-N is metastasis-free survival, defined as the time from randomization to the occurrence of distant metastatic disease or death from any cause. Pelvic nodal progression alone does not constitute a metastasis-free survival event and is analyzed separately under regional control endpoints.

Secondary endpoints include overall survival, radiographic progression-free survival assessed primarily using PSMA PET imaging, intraprostatic local control, regional nodal control, time to castration-resistant prostate cancer, time to next systemic therapy, acute and late treatment-related toxicity graded according to CTCAE version 6.0, and patient-reported outcomes assessing urinary, bowel, sexual, and global quality of life.

Imaging, Follow-up, and Failure Pattern Characterization PSMA PET imaging is central to both baseline staging and assessment of disease progression. Imaging is performed at baseline and at the time of suspected progression based on PSA kinetics or clinical findings. This strategy enables precise localization and characterization of disease recurrence and allows differentiation between local recurrence, regional nodal progression, oligometastatic dissemination, and polymetastatic disease.

Patients are followed longitudinally with standardized clinical assessments, PSA and testosterone monitoring, toxicity reporting, and patient-reported outcome measures. Long-term follow-up is planned to capture late disease events, late toxicity, and survival outcomes.

Statistical Philosophy and Phase II/III Transition PRO-BOOST-N is designed as a seamless phase II/III trial. The initial phase II component focuses on feasibility, treatment compliance, and early safety. Upon meeting predefined criteria, the trial transitions seamlessly into the phase III component without interruption of accrual. Hierarchical testing preserves statistical power for the primary hypothesis while allowing formal evaluation of the key secondary hypothesis.

Expected Clinical and Scientific Impact By prospectively and hierarchically evaluating prostate-first versus combined prostate and nodal dose escalation strategies within a PSMA PET-guided and ultrahypofractionated radiotherapy framework, PRO-BOOST-N seeks to address one of the most important unresolved questions in contemporary prostate cancer management. The results of this trial have the potential to inform clinical practice, refine guideline recommendations, and optimize treatment individualization for patients with node-positive prostate cancer in the PSMA PET era.

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the prostate.
• Prostate cancer with clinically positive pelvic lymph nodes (cN1) without evidence of distant metastatic disease.
• Pelvic lymph node involvement limited to regional pelvic lymph nodes (obturator, internal iliac, external iliac, presacral), as assessed by conventional imaging and/or PSMA PET/CT.
• No evidence of distant metastatic disease (M0), including absence of non-regional nodal, bone, or visceral metastases.
• Candidate for definitive radiotherapy to the prostate and elective pelvic lymph nodes.
• Planned treatment with androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Adequate organ function allowing delivery of protocol-defined radiotherapy and systemic therapy.
• Age ≥18 years.
• Ability to understand and willingness to sign a written informed consent.

Exclusion Criteria:

• Evidence of distant metastatic disease (M1), including non-regional lymph node, bone, or visceral metastases.
• Prior definitive local therapy for prostate cancer, including radical prostatectomy, whole-gland radiotherapy, or brachytherapy.
• Prior pelvic radiotherapy for any indication that would overlap planned treatment fields.
• Prior systemic therapy for prostate cancer other than protocol-allowed neoadjuvant androgen deprivation therapy.
• History of castration-resistant prostate cancer.
• Concurrent malignancy requiring active treatment, except non-melanoma skin cancer or other malignancies with negligible risk of interference with study outcomes.
• Severe uncontrolled comorbidities that would preclude safe delivery of radiotherapy or systemic therapy.
• Any condition that, in the opinion of the investigator, would interfere with patient safety or compliance with the study protocol.