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.
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.
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.
Factorial
Ultrahypofractionated Whole-Pelvis Radiotherapy
RadiationWhole-pelvis external beam radiotherapy delivered using VMAT or IMRT techniques to elective pelvic lymph node volumes and the prostate. Treatment is prescribed as 25 Gy in 5 fractions and delivered with daily image guidance, serving as the standardized radiotherapy backbone for all study arms.
SBRT-Based Prostate Radiotherapy (No Boost)
RadiationDefinitive prostate radiotherapy delivered as a simultaneous integrated boost within the ultrahypofractionated whole-pelvis radiotherapy plan. The prostate receives a total dose of 36.25 Gy in 5 fractions without additional prostate boost beyond this dose.
Ablative Prostate Boost
RadiationAblative whole-gland prostate dose escalation delivered after completion of ultrahypofractionated whole-pelvis radiotherapy. The prostate boost modality is prospectively assigned before main randomization. If two or more protocol-defined boost modalities are available and technically suitable, the modality is assigned by embedded subrandomization; if only one modality is feasible, that modality is assigned as the single feasible option. Boost modalities include high-dose-rate brachytherapy (15 Gy in 1 fraction), low-dose-rate brachytherapy (110 Gy permanent implant), or single-fraction SBRT boost (15 Gy in 1 fraction).
Intermediate Nodal Dose Escalation
RadiationDose escalation to PSMA PET-positive pelvic lymph nodes delivered using a simultaneous integrated boost technique within the ultrahypofractionated whole-pelvis radiotherapy plan. The prescribed nodal boost dose is 27.75 Gy in 5 fractions.
Higher Nodal Dose Escalation
RadiationDose escalation to PSMA PET-positive pelvic lymph nodes delivered using a simultaneous integrated boost technique within the ultrahypofractionated whole-pelvis radiotherapy plan. The prescribed nodal boost dose is 30 Gy in 5 fractions, with protocol-defined organ-at-risk-driven dose de-escalation permitted if required.
Androgen Deprivation Therapy (ADT)
DrugAndrogen deprivation therapy administered as long-term systemic treatment in all study arms. ADT is delivered using luteinizing hormone-releasing hormone (LHRH) agonists or antagonists according to institutional practice and protocol-defined duration. ADT is initiated before or during radiotherapy and continued after completion of radiotherapy as specified in the study protocol.
Androgen Receptor Pathway Inhibitors (ARPIs)
DrugAndrogen receptor pathway inhibitors may be administered in combination with androgen deprivation therapy according to contemporary clinical practice, local availability, and patient-specific considerations. The use of ARPIs is permitted but not randomized and includes approved agents targeting androgen receptor signaling.
Metastasis-Free Survival (MFS)
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.
Overall Survival (OS)
Overall survival is defined as the time from randomization to death from any cause. Patients alive at the time of analysis will be censored at the date of last follow-up.
Radiographic Progression-Free Survival (rPFS)
Radiographic progression-free survival is defined as the time from randomization to radiographic disease progression or death from any cause, whichever occurs first. Radiographic progression is assessed primarily using PSMA PET imaging and includes local, regional nodal, or distant disease progression according to protocol-defined criteria.
Intraprostatic Local Control (iLC)
Intraprostatic local control is defined as the absence of radiographic or histologically confirmed recurrence within the prostate gland after completion of radiotherapy, assessed using PSMA PET imaging, multiparametric MRI, or biopsy when clinically indicated.
Regional Pelvic Nodal Control (rNC)
Regional pelvic nodal control is defined as the absence of progression or recurrence within pelvic lymph node regions after radiotherapy. Pelvic nodal progression is assessed using PSMA PET imaging or other clinically indicated imaging modalities.
Patterns of First Disease Progression
Characterization of the first site and extent of disease progression, categorized as local (prostate), regional pelvic nodal, or distant metastatic progression, and classified as oligoprogressive or oligorecurrent disease (≤5 new or regrowing metastatic lesions) or polyprogressive or polymetastatic disease (\>5 lesions).
Hazard Ratio for Metastasis-Free Survival per 10 Gy Increase in Delivered Prostate EQD2
Hazard ratio for metastasis-free survival associated with each 10 Gy increase in delivered prostate equivalent dose in 2 Gy fractions (EQD2, α/β = 1.5), estimated using Cox proportional hazards regression.
Impact of OAR-Driven Nodal Dose De-Escalation
Assessment of the impact of protocol-defined organ-at-risk-driven nodal dose de-escalation on regional nodal control and treatment-related toxicity.
Interaction Effect Between Radiotherapy Intensification and Systemic Therapy Intensification
Interaction term between radiotherapy intensification strategy (prostate-first vs combined prostate and nodal dose escalation) and systemic therapy intensification (androgen deprivation therapy with or without androgen receptor pathway inhibitors) evaluated in Cox proportional hazards models for metastasis-free survival. Reported as hazard ratio with interaction p-value.
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