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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 600
- 试验地点
- 1
- 主要终点
- Metastasis-Free Survival (MFS)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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-
- •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.
排除标准
- •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.
研究组 & 干预措施
Arm 1: A0B1 - No Prostate Boost + Intermediate Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) with a simultaneous integrated boost to the prostate delivering 36.25 Gy in 5 fractions, without additional prostate boost. PSMA PET-positive pelvic lymph nodes receive an intermediate nodal dose escalation (27.75 Gy in 5 fractions). All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Ultrahypofractionated Whole-Pelvis Radiotherapy (Radiation)
Arm 1: A0B1 - No Prostate Boost + Intermediate Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) with a simultaneous integrated boost to the prostate delivering 36.25 Gy in 5 fractions, without additional prostate boost. PSMA PET-positive pelvic lymph nodes receive an intermediate nodal dose escalation (27.75 Gy in 5 fractions). All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: SBRT-Based Prostate Radiotherapy (No Boost) (Radiation)
Arm 1: A0B1 - No Prostate Boost + Intermediate Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) with a simultaneous integrated boost to the prostate delivering 36.25 Gy in 5 fractions, without additional prostate boost. PSMA PET-positive pelvic lymph nodes receive an intermediate nodal dose escalation (27.75 Gy in 5 fractions). All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Intermediate Nodal Dose Escalation (Radiation)
Arm 1: A0B1 - No Prostate Boost + Intermediate Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) with a simultaneous integrated boost to the prostate delivering 36.25 Gy in 5 fractions, without additional prostate boost. PSMA PET-positive pelvic lymph nodes receive an intermediate nodal dose escalation (27.75 Gy in 5 fractions). All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Androgen Deprivation Therapy (ADT) (Drug)
Arm 1: A0B1 - No Prostate Boost + Intermediate Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) with a simultaneous integrated boost to the prostate delivering 36.25 Gy in 5 fractions, without additional prostate boost. PSMA PET-positive pelvic lymph nodes receive an intermediate nodal dose escalation (27.75 Gy in 5 fractions). All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Androgen Receptor Pathway Inhibitors (ARPIs) (Drug)
Arm 2: A0B2 - No Prostate Boost + Higher Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) with a simultaneous integrated boost to the prostate delivering 36.25 Gy in 5 fractions, without additional prostate boost. PSMA PET-positive pelvic lymph nodes receive a higher nodal dose escalation (30 Gy in 5 fractions), with protocol-defined organ-at-risk-driven dose de-escalation permitted if required. All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Ultrahypofractionated Whole-Pelvis Radiotherapy (Radiation)
Arm 2: A0B2 - No Prostate Boost + Higher Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) with a simultaneous integrated boost to the prostate delivering 36.25 Gy in 5 fractions, without additional prostate boost. PSMA PET-positive pelvic lymph nodes receive a higher nodal dose escalation (30 Gy in 5 fractions), with protocol-defined organ-at-risk-driven dose de-escalation permitted if required. All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: SBRT-Based Prostate Radiotherapy (No Boost) (Radiation)
Arm 2: A0B2 - No Prostate Boost + Higher Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) with a simultaneous integrated boost to the prostate delivering 36.25 Gy in 5 fractions, without additional prostate boost. PSMA PET-positive pelvic lymph nodes receive a higher nodal dose escalation (30 Gy in 5 fractions), with protocol-defined organ-at-risk-driven dose de-escalation permitted if required. All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Higher Nodal Dose Escalation (Radiation)
Arm 2: A0B2 - No Prostate Boost + Higher Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) with a simultaneous integrated boost to the prostate delivering 36.25 Gy in 5 fractions, without additional prostate boost. PSMA PET-positive pelvic lymph nodes receive a higher nodal dose escalation (30 Gy in 5 fractions), with protocol-defined organ-at-risk-driven dose de-escalation permitted if required. All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Androgen Deprivation Therapy (ADT) (Drug)
Arm 2: A0B2 - No Prostate Boost + Higher Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) with a simultaneous integrated boost to the prostate delivering 36.25 Gy in 5 fractions, without additional prostate boost. PSMA PET-positive pelvic lymph nodes receive a higher nodal dose escalation (30 Gy in 5 fractions), with protocol-defined organ-at-risk-driven dose de-escalation permitted if required. All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Androgen Receptor Pathway Inhibitors (ARPIs) (Drug)
Arm 3: A1B1 - Prostate Boost + Intermediate Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) to the prostate and pelvic lymph nodes, followed by ablative whole-gland prostate dose escalation. The prostate boost modality is assigned before main randomization: if two or more modalities are available and technically suitable, the modality is assigned by embedded subrandomization; if only one modality is feasible, that modality is prospectively assigned. Protocol-defined boost modalities include high-dose-rate brachytherapy, low-dose-rate brachytherapy, or single-fraction SBRT boost. PSMA PET-positive pelvic lymph nodes receive an intermediate nodal dose escalation (27.75 Gy in 5 fractions). All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Ultrahypofractionated Whole-Pelvis Radiotherapy (Radiation)
Arm 3: A1B1 - Prostate Boost + Intermediate Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) to the prostate and pelvic lymph nodes, followed by ablative whole-gland prostate dose escalation. The prostate boost modality is assigned before main randomization: if two or more modalities are available and technically suitable, the modality is assigned by embedded subrandomization; if only one modality is feasible, that modality is prospectively assigned. Protocol-defined boost modalities include high-dose-rate brachytherapy, low-dose-rate brachytherapy, or single-fraction SBRT boost. PSMA PET-positive pelvic lymph nodes receive an intermediate nodal dose escalation (27.75 Gy in 5 fractions). All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Ablative Prostate Boost (Radiation)
Arm 3: A1B1 - Prostate Boost + Intermediate Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) to the prostate and pelvic lymph nodes, followed by ablative whole-gland prostate dose escalation. The prostate boost modality is assigned before main randomization: if two or more modalities are available and technically suitable, the modality is assigned by embedded subrandomization; if only one modality is feasible, that modality is prospectively assigned. Protocol-defined boost modalities include high-dose-rate brachytherapy, low-dose-rate brachytherapy, or single-fraction SBRT boost. PSMA PET-positive pelvic lymph nodes receive an intermediate nodal dose escalation (27.75 Gy in 5 fractions). All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Intermediate Nodal Dose Escalation (Radiation)
Arm 3: A1B1 - Prostate Boost + Intermediate Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) to the prostate and pelvic lymph nodes, followed by ablative whole-gland prostate dose escalation. The prostate boost modality is assigned before main randomization: if two or more modalities are available and technically suitable, the modality is assigned by embedded subrandomization; if only one modality is feasible, that modality is prospectively assigned. Protocol-defined boost modalities include high-dose-rate brachytherapy, low-dose-rate brachytherapy, or single-fraction SBRT boost. PSMA PET-positive pelvic lymph nodes receive an intermediate nodal dose escalation (27.75 Gy in 5 fractions). All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Androgen Deprivation Therapy (ADT) (Drug)
Arm 3: A1B1 - Prostate Boost + Intermediate Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) to the prostate and pelvic lymph nodes, followed by ablative whole-gland prostate dose escalation. The prostate boost modality is assigned before main randomization: if two or more modalities are available and technically suitable, the modality is assigned by embedded subrandomization; if only one modality is feasible, that modality is prospectively assigned. Protocol-defined boost modalities include high-dose-rate brachytherapy, low-dose-rate brachytherapy, or single-fraction SBRT boost. PSMA PET-positive pelvic lymph nodes receive an intermediate nodal dose escalation (27.75 Gy in 5 fractions). All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Androgen Receptor Pathway Inhibitors (ARPIs) (Drug)
Arm 4: A1B2 - Prostate Boost + Higher Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) to the prostate and pelvic lymph nodes, followed by ablative whole-gland prostate dose escalation. The prostate boost modality is assigned before main randomization: if two or more modalities are available and technically suitable, the modality is assigned by embedded subrandomization; if only one modality is feasible, that modality is prospectively assigned. Protocol-defined boost modalities include high-dose-rate brachytherapy, low-dose-rate brachytherapy, or single-fraction SBRT boost. PSMA PET-positive pelvic lymph nodes receive a higher nodal dose escalation (30 Gy in 5 fractions), with protocol-defined organ-at-risk-driven dose de-escalation permitted if required. All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Ultrahypofractionated Whole-Pelvis Radiotherapy (Radiation)
Arm 4: A1B2 - Prostate Boost + Higher Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) to the prostate and pelvic lymph nodes, followed by ablative whole-gland prostate dose escalation. The prostate boost modality is assigned before main randomization: if two or more modalities are available and technically suitable, the modality is assigned by embedded subrandomization; if only one modality is feasible, that modality is prospectively assigned. Protocol-defined boost modalities include high-dose-rate brachytherapy, low-dose-rate brachytherapy, or single-fraction SBRT boost. PSMA PET-positive pelvic lymph nodes receive a higher nodal dose escalation (30 Gy in 5 fractions), with protocol-defined organ-at-risk-driven dose de-escalation permitted if required. All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Ablative Prostate Boost (Radiation)
Arm 4: A1B2 - Prostate Boost + Higher Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) to the prostate and pelvic lymph nodes, followed by ablative whole-gland prostate dose escalation. The prostate boost modality is assigned before main randomization: if two or more modalities are available and technically suitable, the modality is assigned by embedded subrandomization; if only one modality is feasible, that modality is prospectively assigned. Protocol-defined boost modalities include high-dose-rate brachytherapy, low-dose-rate brachytherapy, or single-fraction SBRT boost. PSMA PET-positive pelvic lymph nodes receive a higher nodal dose escalation (30 Gy in 5 fractions), with protocol-defined organ-at-risk-driven dose de-escalation permitted if required. All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Higher Nodal Dose Escalation (Radiation)
Arm 4: A1B2 - Prostate Boost + Higher Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) to the prostate and pelvic lymph nodes, followed by ablative whole-gland prostate dose escalation. The prostate boost modality is assigned before main randomization: if two or more modalities are available and technically suitable, the modality is assigned by embedded subrandomization; if only one modality is feasible, that modality is prospectively assigned. Protocol-defined boost modalities include high-dose-rate brachytherapy, low-dose-rate brachytherapy, or single-fraction SBRT boost. PSMA PET-positive pelvic lymph nodes receive a higher nodal dose escalation (30 Gy in 5 fractions), with protocol-defined organ-at-risk-driven dose de-escalation permitted if required. All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Androgen Deprivation Therapy (ADT) (Drug)
Arm 4: A1B2 - Prostate Boost + Higher Nodal Dose
Participants receive ultrahypofractionated whole-pelvis radiotherapy (25 Gy in 5 fractions) to the prostate and pelvic lymph nodes, followed by ablative whole-gland prostate dose escalation. The prostate boost modality is assigned before main randomization: if two or more modalities are available and technically suitable, the modality is assigned by embedded subrandomization; if only one modality is feasible, that modality is prospectively assigned. Protocol-defined boost modalities include high-dose-rate brachytherapy, low-dose-rate brachytherapy, or single-fraction SBRT boost. PSMA PET-positive pelvic lymph nodes receive a higher nodal dose escalation (30 Gy in 5 fractions), with protocol-defined organ-at-risk-driven dose de-escalation permitted if required. All patients receive long-term androgen deprivation therapy with or without androgen receptor pathway inhibitors according to protocol.
干预措施: Androgen Receptor Pathway Inhibitors (ARPIs) (Drug)
结局指标
主要结局
Metastasis-Free Survival (MFS)
时间窗: Up to 10 years from randomization
Metastasis-free survival is defined as the time from randomization to the first occurrence of distant metastatic disease or death from any cause, whichever occurs first. Distant metastases include non-regional lymph node, bone, or visceral metastases confirmed by PSMA PET imaging or other clinically indicated imaging modalities. Pelvic nodal progression alone does not constitute a metastasis-free survival event.
次要结局
- Regional Pelvic Nodal Control (rNC)(Up to 10 years from randomization)
- Acute treatment-related adverse events(Up to 90 days after completion of radiotherapy)
- Late treatment-related adverse events(Up to 10 years after completion of radiotherapy)
- Overall Survival (OS)(Up to 10 years from randomization)
- Radiographic Progression-Free Survival (rPFS)(Up to 10 years from randomization)
- Intraprostatic Local Control (iLC)(Up to 10 years from randomization)
- Time to Castration-Resistant Prostate Cancer (CRPC)(Up to 10 years from randomization)
- Time to Next Systemic Therapy (TTNS)(Up to 10 years from randomization)
- Acute Treatment-Related Toxicity(Up to 90 days after completion of radiotherapy)
- Late Treatment-Related Toxicity(Up to 10 years after completion of radiotherapy)
- International Index of Erectile Function-5 (IIEF-5)(From baseline to 10 years after randomization)
- Time to Polyprogressive or Polyrecurrent Disease (TTPD)(Up to 10 years from randomization)
- Expanded Prostate Cancer Index Composite-26 (EPIC-26) Urinary Domain Score(Up to 10 years from randomization)
- EPIC-26 Bowel Domain Score(From baseline to 10 years after randomization)
- EPIC-26 Sexual Domain Score(From baseline to 10 years after randomization)
- International Prostate Symptom Score (IPSS)(From baseline to 10 years after randomization)
- EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status(From baseline to 10 years after randomization)
- EORTC Quality of Life Questionnaire-Prostate Module (EORTC QLQ-PR25)(From baseline to 10 years after randomization)
研究者
Mateusz Bilski
MD, PhD
Affidea Nu-med Center of Oncological DIagnostics and Therapy