Short Versus Long-term Androgen Deprivation Therapy With Salvage Radiotherapy in Prostate Cancer. URONCOR 0624

Study Overview
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Brief Summary
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The optimal indication for ADT has long been a point of controversy, at least until the results of randomised trials comparing RT with and without ADT were published. NCCN guidelines and most retrospective series and left the decision to prescribe ADT in combination with RT to the discretion of the treating physician, despite a lack of clear scientific evidence to support this recommendation. The percentage of patients in those retrospective series who received hormone therapy ranged from 33% to 71%, but generally involved patients with adverse prognostic factors (Gleason score > 7, stage pT3-T4, PSA > 1 ng/mL in cases with biochemical recurrence [BCR], and PSA doubling time [PSA-DT] < 6 months). Despite the heterogeneity in those studies in terms of treatment duration, RT dose, and treatment volumes, most of the studies found that ADT significantly prolonged biochemical relapse-free survival (BRFS), especially in patients with PSA levels > 1 ng/mL at recurrence. The results of two randomised trials evaluating SRT with or without ADT were published in 2017, with both trials demonstrating a benefit for ADT in this clinical setting. A follow-up study confirmed the value of ADT in combination with SRT in terms of better PFS and, in the RTOG study, an improvement in overall survival (OS). Despite the lack of data from phase III trials regarding the influence of PSA-DT, the BRFS interval, and the Gleason score in terms of their effects on the clinical course of patients who develop BCR, there is strong evidence from other studies to support the use of these variables (together with age and comorbidities). Given the available evidence, we believe that these variables should be considered when determining the indications for ADT. In line with the philosophy underlying the approach used by D'Amico to develop a risk classification system for prostate cancer patients at diagnosis, we propose three risk groups. According to Pollack et al. and Spratt et al., low-risk patients would not benefit from hormone therapy, especially long-term ADT, due to the deleterious effects of such treatment. By contrast, intermediate and high risk patients would be candidates for ADT combined with RT. However, the optimal duration of ADT in these patients (6 months vs. 2 years) remains undefined and needs to be determined prospectively in a randomised trial, similar to the approach used in the DART 05.01 trial. SRT and ADT are widely used in routine clinical practice to treat patients who develop BCR after prostatectomy. In this context, we intend to perform a multicentre, phase III trial to define the optimal duration of ADT (6 vs. 24 months).

Official Title
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Short Versus Long-term Androgen Deprivation Therapy Combined With Salvage Radiotherapy in Prostate Cancer Patients With Biochemical Recurrence After Prostatectomy: a Multicentre Phase III Randomised Controlled Trial

Conditions
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Prostate Cancer, Salvage Radiotherapy, Biochemical Recurrence, Androgen Deprivation Therapy, Metastases-free Survival

Intervention / Treatment
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* Drug: triptorelin, goserelin, leuprorelin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically-confirmed prostate cancer treated with radical prostatectomy. Patients who have not undergone lymph node dissection are eligible for inclusion. Biochemical recurrence after prostatectomy: BCR is defined as a PSA value ≥ 0.2 ng/mL, with at least one confirmatory PSA determination ≥ two weeks after the first test (the confirmatory PSA level must be higher than the initial value). Patients with Gleason 8-10, pT3b or R1 are eligible for inclusion in the trial with PSA ≥ 0.15 ng/mL; however, in patients with PSA > 0.4 ng/mL, imaging tests (conventional CT and bone scans or advanced imaging techniques such as PSMA or choline PET/CT) should be performed to check for metastases. In patients with PSA levels between 0.15 and 0.4 ng/mL, no further tests are required to check for distant metastases prior to inclusion. Intermediate and high-risk patients according to the classification criteria proposed by González San Segundo et al. (18): CHARACTERISTICS INTERMEDIATE RISK (≥ 2) HIGH RISK(≥ 1) PSA at diagnosis, ng/mL 0.6-1.0 ≥1.0 PSA doubling time, months 6-12 < 6 GLEASON / ISUP 7/3 ≥8/≥4 TNM (prostatectomy specimen) pT2-3a pN0-Mx pT3b pN0-Mx Time to biochemical recurrence, months >18 <18 Margins Positive Positive Testosterone level > 150 ng/dL at inclusion ECOG 0-1 Life expectancy > 5 years Signed informed consent Exclusion Criteria: Presence of pN1 disease in the original surgical specimen Presence of macroscopic disease on imaging tests. If the PSA at diagnosis is > 0.4 ng/mL, then imaging tests (CT and bone scan and/or PET/CT or body magnetic resonance imaging [MRI]) are required. PSA <0.2 or <0.15 ng/mL (if Gleason score=10, pT3b, or R1 in the radical prostatectomy specimen). Previous pelvic radiotherapy Radiotherapy contraindicated Ongoing treatment with ADT or PSA-modulating drugs (e.g., finasteride, dutasteride, high dose steroids) Inability to understand the treatment protocol or sign informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: short-term ADT (6 months)<br>ARM 1: LHRH analogues for 6 months + bicalutamide 50 for 30 days | Drug: triptorelin, goserelin, leuprorelin<br>* ADT will consist of LHRH analogues (triptorelin, goserelin, leuprorelin) with bicalutamide 50 mg/day started 10 days before the first ADT injection to avoid LHRH-related flare-ups. Bicalutamide will be discontinued after 30 days. The LHRH analogue will be initiated prior to the start of radiotherapy and administered for 6 or 24 months depending on treatment allocation. The maximum time permitted between randomisation and administration of the first LHRH dose is 30 days. The maximum time from the first LHRH dose to the start of SRT is 60 days.<br>|
| Active Comparator: long-term ADT (24 months)<br>LHRH analogues for 24 months + bicalutamide 50 for 30 days | Drug: triptorelin, goserelin, leuprorelin<br>* ADT will consist of LHRH analogues (triptorelin, goserelin, leuprorelin) with bicalutamide 50 mg/day started 10 days before the first ADT injection to avoid LHRH-related flare-ups. Bicalutamide will be discontinued after 30 days. The LHRH analogue will be initiated prior to the start of radiotherapy and administered for 6 or 24 months depending on treatment allocation. The maximum time permitted between randomisation and administration of the first LHRH dose is 30 days. The maximum time from the first LHRH dose to the start of SRT is 60 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare 5-year MFS rates in prostate cancer patients treated with long- versus short-term ADT in combination with salvage radiotherapy | Distant metastasis-free survival: time from administration of the first LHRH analogue (this same starting point applies to all secondary objectives) until the patient develops M1a disease (involved retroperitoneal lymph nodes) or M1b-c disease (bone/visceral involvement) according to RECIST 1.1 criteria based on conventional computed tomography (CT) imaging and bone scans. The use of advanced molecular imaging-PSMA or choline positron-emission tomography (PET)/CT-is subject to the centre-specific protocols in place at the participating hospitals; however, metastatic progression will be determined according to RECIST 1.1 criteria based on conventional imaging tests. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the two study arms in terms of the Biochemical-relapse free interval | BRFS: time to biochemical progression defined as an increase in PSA confirmed by a second PSA determination (0.2 ng/mL above the salvage radiotherapy nadir or a sustained elevation in PSA levels). | 5 years | 
| To compare the two study arms in terms of the Pelvic progression-free survival | Pelvic PFS: time to local recurrence (prostate bed) and/or N1 disease (positive lymph nodes below the aortic bifurcation) according to RECIST 1.1 criteria by conventional CT imaging and bone scan. The use of advanced molecular imaging (PSMA or choline PET/CT) will depend on centre-specific protocols; determination of metastatic progression will be based on RECIST 1.1 criteria from conventional imaging tests. | 5 years | 
| To compare the two study arms in terms of the Time to start of cytotoxic treatment | Cytotoxic treatment-free interval: time to the start of the first cytotoxic treatment or local treatment for oligorecurrence. | 5 years | 
| To compare the two study arms in terms of the Time to castration resistance | Time interval to castration resistance: the time to biochemical and/or clinical progression with castration levels (testosterone < 50 ng/dL). Progression to castration resistance is defined as three consecutive increases in PSA (one-week intervals) with at least two PSA increases > 2 ng/mL and a 50% increase over the PSA nadir, progression of bone lesions (≥ two lesions on the bone scan), progression of soft tissue lesions (RECIST 1.1 criteria), or the development of ≥ one soft tissue or visceral metastases (including lymph nodes). | 5 years | 
| To compare the two study arms in terms of the Cancer-specific survival | time to death due to prostate cancer or treatment-related complications | 5 years | 
| To compare the two study arms in terms of the Overall survival | time to death from any cause | 5 years | 
| To compare the two study arms in terms of the Acute and late toxicity | Acute toxicity: toxicity (CTCAE criteria, v. 4.0; https://evs.nci.nih.gov) appearing any time from treatment initiation up to three months after completion of RT. | 5 years | 
| To compare the two study arms in terms of the Late toxicity | -Late toxicity: from 3 months to 5 years after completing RT (CTCAE v 4.0). | 5 years | 
| To compare the two study arms in terms of Quality of life (QoL) | Quality of life (QoL): from baseline (prior to RT) to five years after completion of RT, assessed with the EORTC QLQ-C30 and QLQ-PR25 questionnaires. | 5 years |