Prostate-cancer Treatment Using Stereotactic Radiotherapy for Oligometastases Ablation in Hormone-sensitive Patients

Study Overview
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Brief Summary
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INDICATION: Oligometastatic hormone-sensitive prostate cancer patients. METHODOLOGY: Open label, double arm, randomized 1:1, multicenter phase III study. PRIMARY OBJECTIVE: To assess the efficacy of ablative radiotherapy (SBRT applied to all oligometastases) administered to all gross tumor sites (metastases and prostate if applicable), in oligometastatic hormone-sensitive prostate cancer patients.

Official Title
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Prostate-cancer Treatment Using Stereotactic Radiotherapy for Oligometastases Ablation in Hormone-sensitive Patients - a GETUG-AFU Phase III Randomized Controlled Trial

Conditions
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Oligometastatic Hormone Sensitive Prostate Cancer

Intervention / Treatment
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* Radiation: Stereotactic Body Radiotherapy (SBRT) + Standard of care
* Drug: Standard of care


Participation Criteria
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Eligibility Criteria
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DIAGNOSIS AND INCLUSION CRITERIA: Histologically proven adenocarcinoma of the prostate (any T stage, Gleason score or prostate-specific antigen (PSA) level); Defined as M1 based on the presence of at least one bone or lung metastasis; Diagnostic workup including functional imaging (F or C-Choline-PET/CT or Prostate Specific Membrane Antigen (PSMA) PET/CT or whole body MRI) - done prior to the start of hormonal therapy; With up to 5 asymptomatic or paucisymptomatic metastatic sites including at least one bone or pulmonary lesion +/- nodal mestastases. Are counted as a separate metastatic site : each bone lesion, whatever the location (including pelvic localization), except if two lesions show hyperfixation in the same bone and are located < 1cm from each other they can be counted as one lesion each node or nodal area located outside the true pelvis with a small diameter of 1cm or greater or with univoqual abnormal function imaging (PET Scan hyperfixation or hypersignal in whole body MRI); if multiple nodes are in close vicinity (<1cm distance between them and <4cm in total distance including the nodes, amenable to one SBRT treatment) they can be counted as one lesion and patients with lung metastasis can be included Patients with a previous prostatectomy or radiotherapy to the prostate and/or pelvic lymph nodes are eligible provided they have no active disease within the irradiated areas, based on functional imaging findings; Age ≥18 years; Eastern Cooperative Oncology Group (ECOG) ≤2; Suitable for long term anti androgen therapy; Patient not suitable for docetaxel or abiraterone can be included; Patient that have started long term hormonal therapy are eligible if hormonal therapy has been initiated less than 2 months before randomization; Patients must agree to use adequate contraception methods for the duration of study treatment and for 6 months after completing treatment; Patient must have received the information sheet and signed the consent form; Patients must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures; Patient must be affiliated to the social security system. NON-INCLUSION CRITERIA: Patient with more than 5 metastatic sites; Patient with metastatic sites other than bone, lymph nodes or lung; Metastases not amenable to radiotherapy treatment with high/curative doses by multidisciplinary meeting [i.e. SBRT as per protocol or curative doses using moderate hypofractionation (55-60Gy/20) or conventional fractionation (≥74 Gy)] (e.g. gross epidural involvement, involvement of three contiguous vertebral bodies, major soft tissue involvement, and previous radiation treatment); Metastases requiring immediate treatment due to significant pain (use of opioid medication), or at risk of fracture or neurological deficit; Prior radiotherapy or focal ablative treatment (cryotherapy, radiofrequency ablation,…) to metastatic lesions; Castrate testosterone level <50 ng/dL or ≤0.50 ng/mL or 1.73 nmol/L prior use of ADT; Prior invasive (except non-melanoma skin cancer) malignancy unless disease-free for ≥5 years; Contra-indication to MRI (needed for spinal SBRT); Persons deprived of their liberty or under protective custody or guardianship; Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons; Participation in another therapeutic trial within 30 days prior to randomization.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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 |
| --- | --- |
| Experimental: Arm A<br>Standard of care + Stereotactic Body Radiotherapy to oligometastases | Radiation: Stereotactic Body Radiotherapy (SBRT) + Standard of care<br>* Definition of standard of care (prior to randomization): Radiotherapy to the prostate in de novo metastatic patients Radiotherapy to the pelvic lymph nodes in patients with positive pelvic nodes (given as full dose to the positive lymph node and prophylactic dose to the pelvic nodal basin) Long term ADT +/- intermittent treatment Additional therapy following tumor board meeting : new generation hormonal therapy (abiraterone, enzalutamide, apalutamide or other approved) or chemotherapy (docetaxel). SBRT is delivered using the following regimen: 30 Grays (10 Gy x 3 fractions) for axial and appendicular bones and lymph node metastases if present. In case the dose cannot be safely delivered while maintaining a safe dose to the organs at risk, an alternate regimen (35 Gy in 5 fractions of 7 Gy) can be used.<br>|
| Active Comparator: Arm B<br>Standard of care | Drug: Standard of care<br>* Definition of standard of care (prior to randomization): Radiotherapy to the prostate in de novo metastatic patients Radiotherapy to the pelvic lymph nodes in patients with positive pelvic nodes (given as full dose to the positive lymph node and prophylactic dose to the pelvic nodal basin) Long term ADT +/- intermittent treatment Additional therapy following tumor board meeting : new generation hormonal therapy (abiraterone, enzalutamide, apalutamide or other approved) or chemotherapy (docetaxel).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Castration-resistant prostate cancer free survival | Castration-resistant prostate cancer free survival, defined as the time from randomization to castration resistance or death from any cause. Castration resistance is defined as either biochemical progression or radiological progression, with serum testosterone being at a castrated level (<50 ng/dL or <1.7 nmol/L). | From randomization to castration resistance or death from any cause, up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The overall survival is the length of time from randomization that patients enrolled in the study are still alive. The outcome is to evaluate whether SRBT improves overall survival compared to standard of care | From randomization to death from any cause, up to 5 years | 
| Prostate cancer specific survival | To evaluate, compared to standard of care, whether SRBT improves survival of patients until death from prostate cancer | From randomization to death from prostate cancer, up to 5 years | 
| Time to castration resistance | The length of time patients leave without resistance to castration treatment, where deaths occurring with no castration resistance (i.e. unrelated to prostate cancer) are censored | Time from randomization to castration resistance, up to 5 years | 
| Time to next symptomatic skeletal event | The length of time until manifestation of the first symptomatic skeletal event among the following: symptomatic bone fracture, surgery to bone or use of palliative radiotherapy to bone | Time from randomization to the first symptomatic skeletal event, up to 5 years | 
| Time to next symptomatic skeletal event at the treated metastatic bone sites | The length of time until manifestation of the first symptomatic skeletal event, at a site irradiated during the study for patients in the experimental arm, among the following: symptomatic bone fracture, the use of bone surgery, or palliative bone radiotherapy and spinal cord compression | Time from randomization to the first symptomatic skeletal event, 5 years | 
| Time to use of intermittent hormonal therapy | The length of time patients receive continuous androgen deprivation therapy before the switch to the intermittent androgen deprivation therapy | Time from randomization to the use of intermittent androgen deprivation therapy, up to 5 years | 
| Duration of intermittent hormonal therapy | The length of time patients receive intermittent androgen deprivation therapy | From the end of continuous therapy to the end of intermittent therapy, up to 5 years | 
| Time to secondary treatments (local or systemic) | The interval between the randomization and the initiation of the first treatment after disease progression: systemic chemotherapy, second line hormonal therapy, bone directed treatment (bisphosphonate or denosumab), or the use an antalgic palliative bone treatment (interventional radiology or radiotherapy) | From randomization to initiation of secondary treatment, up to 5 years | 
| Acute and late toxicity of stereotactic radiotherapy of oligometastases: Adverse events | The National Cancer Institute-Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5) is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale will assess the severity of sensory neuropathic disorders, this derivative into 5 grades determined by the investigator. | Throughout study completion, up to 5 years | 
| Severity of pain during treatment | The Brief Pain Inventory (BPI) questionnaire rapidly assesses the severity of pain and its impact on functioning. This self-report questionnaire includes: A body schema The maximum pain, lowest pain, usual pain within the last 15 days (Numerical Numeric rating scales (NRS) 0 to 10 Description of current analgesic treatment An assessment of relief by a percentage scale (0-100%), Assessment of the impact of pain on: mood, relationships with others, walking, sleep, work, happiness the joy - of living, recreation, activities in general (digital scales, rating from 0 [normal] to 10 [no activity]). | At baseline before radiotherapy, week 6, and at every follow-up (every three months for the first three years then every 6 months for the last two years after randomization), up to 5 years | 
| The 3-level version of EQ-5D (EQ-5D-3L) questionnaire | This self-reported questionnaire that assesses the health-related quality of life of cancer patients in clinical trials consists of a descriptive system and a visual analogue scale (VAS). The EQ-5D-3L descriptive system comprises five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each dimension has 3 levels (1 = no problems, 2 = some problems, and 3 = extreme problems). This questionnaire provide a 5-digit score which generate a health state profile. The VAS records the patient's self-rated health on a vertical visual analogue scale where the score range from 0 (Best imaginable health state) to 100 (Worst imaginable health state). The VAS is used as a quantitative measure of health outcome that reflects the patient's own judgement. | At baseline, week 6, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, and at castration resistance (up to 5 years) | 
| Expanded Prostate Cancer Index Composite (EPIC) short form | This self-reported questionnaire, designed to evaluate patient function and bother after prostate cancer treatment, contains 26 item divided in 5 domains (Urinary Incontinence, Urinary Irritative/Obstructive, Bowel, Sexual, and Hormonal). Response options for each EPIC item form a Likert scale, and multi-item scale scores are transformed linearly to a 0-100 scale, with higher scores representing better health-related quality of life. | At baseline, week 6, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, and at castration resistance (up to 5 years) | 
| Cost-effectiveness analysis of the proposed therapeutic strategy | To evaluate the economic cost of the SBRT treatment as compared to the treatment without radiotherapy in terms of cost assessments, incremental cost-effectiveness ratio and quality of life adjusted life years | At baseline, week 6, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, castration resistance (up to 5 years) |