Patients with prostate cancer and pelvic lymph node involvement (cN1M0) identified on PSMA PET imaging represent a biologically aggressive yet potentially curable disease population. Contemporary management relies on multimodality treatment combining definitive radiotherapy to the prostate and pelvic lymph nodes with long-term androgen deprivation therapy (ADT), often intensified with androgen receptor pathway inhibitors. Despite these advances, a substantial proportion of patients still develop distant metastatic disease, highlighting the need to optimize local-regional treatment strategies in the era of molecular imaging.

The introduction of PSMA PET has fundamentally altered staging accuracy in prostate cancer, enabling earlier and more precise detection of pelvic nodal disease. However, most existing evidence guiding radiotherapy dose prescription in node-positive prostate cancer originates from the pre-PSMA era. As a result, it remains unclear how best to integrate prostate-directed and nodal-directed dose escalation strategies when disease extent is defined by modern molecular imaging. In particular, it is unknown whether long-term disease control is primarily driven by durable intraprostatic tumor eradication, by aggressive treatment of involved lymph nodes, or by a combination of both.

PRO-BOOST-N is a prospective, multicenter, randomized phase II/III clinical trial designed to address this critical evidence gap. The trial evaluates prostate-first versus combined prostate and nodal dose escalation strategies in patients with PSMA PET-staged node-positive (cN1M0) prostate cancer treated within a standardized ultrahypofractionated whole-pelvis radiotherapy framework. All enrolled patients indicated for definitive treatment undergo mandatory baseline PSMA PET/CT to confirm pelvic lymph node involvement and exclude distant metastatic disease.

All patients receive a uniform radiotherapy backbone consisting of ultrahypofractionated whole-pelvis radiotherapy delivered in five fractions, combined with long-term ADT. Use of androgen receptor pathway inhibitors is permitted and encouraged according to contemporary clinical practice and local availability, ensuring the relevance of the trial to real-world treatment settings.

Using a 2×2 factorial randomized design, PRO-BOOST-N evaluates two independent treatment factors. The primary randomized comparison assesses whether ablative prostate dose escalation improves oncologic outcomes compared with contemporary SBRT-based definitive prostate radiotherapy without additional boost. Prostate dose escalation may be delivered using one of three protocol-defined modalities-high-dose-rate brachytherapy, low-dose-rate brachytherapy, or single-fraction SBRT-according to institutional expertise. This comparison directly tests the hypothesis that durable intraprostatic disease control is the dominant determinant of long-term systemic disease suppression in node-positive prostate cancer.

The key secondary, hierarchically tested comparison evaluates the role of nodal dose escalation by comparing two predefined dose levels delivered to PSMA PET-positive pelvic lymph nodes. These dose levels reflect intermediate versus higher nodal boost strategies based on biologically effective dose concepts specific to prostate cancer radiobiology. To ensure patient safety and protocol feasibility, organ-at-risk-driven nodal dose de-escalation is permitted within the higher-dose arm, without altering randomization assignment.

The primary endpoint of the trial is metastasis-free survival. Secondary endpoints include overall survival, radiographic progression-free survival assessed primarily using PSMA PET imaging, intraprostatic and regional nodal control, time to castration-resistant prostate cancer, time to next systemic therapy, treatment-related toxicity graded according to CTCAE version 5.0, and patient-reported outcomes assessing urinary, bowel, sexual, and global quality of life.

By prospectively and hierarchically evaluating prostate and nodal dose escalation strategies within a modern PSMA PET-guided and ultrahypofractionated radiotherapy platform, PRO-BOOST-N aims to define the optimal radiotherapy intensification approach for patients with node-positive prostate cancer. The results of this study are expected to directly inform clinical practice, guideline development, and future treatment individualization in the PSMA PET era.

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 the 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 profoundly transformed staging and risk stratification in prostate cancer. PSMA PET offers markedly superior sensitivity and specificity compared with conventional imaging for the detection of both nodal and distant metastatic disease. This improvement has led to significant 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 distinct cohort compared with historical node-positive populations. Many of these patients harbor small-volume nodal disease that would previously have remained undetected and untreated. Consequently, existing evidence guiding radiotherapy dose prescription and target volume selection-largely derived from the pre-PSMA era-may no longer be directly applicable to current clinical practice.

Importantly, while PSMA PET improves detection of nodal disease, it does not in itself define the optimal therapeutic response. The identification of 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, multistep process in which the primary tumor and regional nodal metastases may serve as ongoing sources of metastatic dissemination. Molecular and phylogenetic studies suggest that, in many patients, nodal metastases arise directly from dominant intraprostatic tumor clones and may retain limited metastatic competence. In this context, effective eradication of both intraprostatic disease and regional nodal deposits may interrupt further metastatic seeding 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 a dominant influence on systemic disease control. Patients receiving high biologically effective doses to the prostate, particularly through brachytherapy boost techniques, appear to 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 eradication represents the principal determinant of long-term systemic disease suppression in patients with PSMA PET-staged node-positive prostate cancer. According to this hypothesis, effective sterilization of the primary tumor reduces the reservoir of clonogenic cells capable of seeding distant metastases, thereby improving metastasis-free survival regardless of the presence of limited nodal disease.

This hypothesis is supported by multiple lines of evidence. In high-risk and very high-risk prostate cancer, prostate dose escalation has consistently been associated with improved disease control. In node-positive cohorts, retrospective analyses have demonstrated that higher prostate dose correlates with improved outcomes, while nodal dose escalation has shown less consistent benefit once prostate dose and systemic therapy are optimized.

PRO-BOOST-N is designed to prospectively and rigorously 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 fail to demonstrate an independent association between nodal dose and survival outcomes when prostate dose and systemic therapy are taken into account. Furthermore, 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 α/β ratio, making it particularly suitable for hypofractionated and ultrahypofractionated radiotherapy schedules. Advances in treatment planning, image guidance, and motion management have enabled safe 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, even 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, enhances patient convenience, and facilitates protocol adherence across multiple centers. Importantly, it enables direct comparison of prostate and nodal dose escalation strategies within a unified fractionation framework, reducing confounding and improving interpretability of results.

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 2×2 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. The choice of boost modality is based on institutional expertise and availability, with optional sub-randomization where multiple modalities are available.

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 ARPIs 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 5.0, 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 secondary hypotheses.

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 directly 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.

Eligibility for this study is restricted to individuals with biological male sex, as prostate cancer is a sex-specific malignancy. Gender identity does not influence eligibility.

De-identified individual participant data (IPD) underlying the results reported in primary and secondary publications will be shared. This includes baseline demographic and clinical characteristics, treatment allocation, radiotherapy and systemic treatment variables, outcome measures, and safety data necessary to reproduce the main analyses.

IPD and supporting information will be available beginning 12 months after publication of the primary study results and will remain available for a period of 5 years thereafter.

Access to de-identified IPD will be granted to qualified researchers for approved research purposes following submission of a written proposal. Requests will be reviewed by the study steering committee for scientific merit, feasibility, and ethical appropriateness. A data use agreement will be required prior to data access.