Leuprorelin Associated With Radiotherapy Versus Leuprorelin Alone in T3 - T4 or pT3 (on Biopsy) N0, M0 Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy and safety of combined radiotherapy and hormone therapy and hormone therapy alone in the treatment of clinically locally advanced prostate cancer (T3-T4 or pT3 on biopsy, N0, M0).

Detailed Description
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The drug being tested in this study is called leuprorelin SR. Leuprorelin SR is being tested to treat people who have prostate cancer. This study will look at the overall survival of people who take leuprorelin SR in addition to radiation therapy compared to those who take only leuprorelin SR. The study will enroll approximately 273 patients. Participants will be randomly assigned to one of the two treatment groups. Combined Radiotherapy and Hormone Therapy Hormone Therapy alone. All participants will receive leuprorelin injection every 3 months and flutamide tablets thrice daily for first 30 days as part of hormone therapy. Participants randomized to combined radiotherapy and hormone therapy group, will also receive radiotherapy 70 +/- 4 Gy in 35 fractions at a rate of 5 fractions of 2 Gy per week. This multi-center trial will be conducted in France and Tunisia. The overall time to participate in this study is 8 years. The scheduled duration of hormone therapy was 3 years in both arms, with an additional treatment-free follow-up period of 2 years i.e. a total follow-up period of 5 years. Post-protocol collection of information relative to survival will be performed after the end the 5-year follow-up period.

Official Title
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Comparative Efficacy and Safety of Combined Radiotherapy and Adjuvant Hormone Therapy (Leuprorelin SR 11.25 mg) and Hormone Therapy Alone (Leuprorelin SR 11.25 mg) in Locally Advanced Prostate Cancer (T3-T4 or pT3 on Biopsy, N0, M0)

Conditions
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Prostatic Neoplasms, Locally Advanced

Intervention / Treatment
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* Drug: Leuprorelin SR
* Radiation: Radiotherapy
* Drug: Flutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed locally advanced adenocarcinoma of the prostate, graded: T3 or T4 or pT3 on biopsies (presence of tumour tissue in periprostatic fat observed on biopsies), N0 (absence of metastatic), M0 (no distant metastases detectable on the following examinations: bone scan, chest x-ray, abdominal and pelvic ultrasound). Patient in whom the prostatic adenocarcinoma has received no prior treatment of any type, with the possible exception of transurethral resection due to obstructive symptoms. Patient with a Karnofsky index greater than or equal to (≥) 70. Patient aged under 80 years on the randomization date. Patient with a life expectancy of at least 7 years. Patient who, after having received clear information, gave his written consent to participate and cooperate in the study. Patient for whom a recent blood test (less than [<] 2 months) has not revealed elevated transaminases ≥ 3 times the normal laboratory range. Exclusion Criteria: Patient incapable of understanding the information supplied concerning the study or of giving his consent, or having refused to sign the informed consent form, Patient for whom there is a risk that follow-up in compliance with the conditions stipulated by the protocol will not be possible, Patient having already received prior treatment for prostate cancer, excluding transurethral resection of the prostate to relieve obstruction, Patient having undergone surgical castration, or with a history of bilateral adrenalectomy or hypophysectomy, Patient having had another cancer within the previous 5 years (including carcinoma in situ of the bladder) excluding basocellular epithelioma or carcinoma in situ (other than in the bladder), Patient with lymph node or metastatic spread of the prostatic adenocarcinoma suspected on imaging, Patient with a non-controlled severe active disease, Patient with a contraindication to external prostatic radiotherapy, Patient receiving or having received another experimental treatment within 3 months prior to inclusion in the study, Patient with impaired liver function or elevated transaminases ≥3 times the normal laboratory range.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Combined Radiotherapy and Hormone Therapy<br>Leuprorelin 11.25 milligram (mg) sustained release (SR), injection, subcutaneously, once every 3 months up to 3 years and flutamide 250 mg, tablet, orally, thrice daily for 30 days from the first dose of leuprorelin. Radiotherapy 70 +/- 4 Gray (Gy) in 35 fractions at a rate of 5 fractions of 2 Gy per week up to 3 years. An interval of a maximum of 2 weeks is authorized between radiation of the pelvis with 50 Gy (±4) (5 weeks) and radiation of the prostate with an additional 20 Gy. | Drug: Leuprorelin SR<br>* Leuprorelin SR injection<br>* Other names: ENANTONE SR;Radiation: Radiotherapy<br>* Radiotherapy 70 +/- 4 Gy<br>Drug: Flutamide<br>* Flutamide tablets<br>|
| Active Comparator: Hormone Therapy alone<br>Leuprorelin 11.25 mg SR, injection, subcutaneously, once every 3 months up to 3 years and flutamide 250 mg, tablet, orally, thrice daily for 30 days from the first dose of leuprorelin. | Drug: Leuprorelin SR<br>* Leuprorelin SR injection<br>* Other names: ENANTONE SR;Drug: Flutamide<br>* Flutamide tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival at 5 years | PFS=time from randomization to first documentation of progression (death, biological progression or clinical progression). PFS at Year 5=probability of participants' PFS at Year 5. Biological progression definition I: halfway point between nadir and first rise with prostate-specific antigen (PSA) ≥1 nanogram per milliliter (ng/mL) signifying progression and date of introduction of prostate treatment for all participants, including those leaving prematurely for reason other than progression/death; definition II: first date when PSA=nadir+2 ng/mL and date of introduction of prostate treatment, for participants leaving prematurely for reason other than progression/death. Clinical progression: local clinical progression->50% increase in prostate volume relative to lowest volume, recurrence of palpable prostatic tumor after complete regression, positive biopsy; locoregional progression=pelvic regional lymph node lesion development; metastatic progression=distant lesions identification. | Year 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Biological Progression | Biological progression as per definition I is defined as halfway point between nadir and first rise with PSA greater than or equal to (≥) 1 ng/mL signifying progression and date of introduction of prostate treatment for all participants, including those leaving prematurely for reason other than progression/death; and as per definition II, it is defined as first date when PSA=nadir+2 ng/mL and date of introduction of prostate treatment, for participants leaving prematurely for reason other than progression/death. Time to onset of biological progression will be performed using the Kaplan- Meier method taking into account the date of onset of the first biological progression. The participants will be censored on the date of death, lost to follow-up or living without biological progression on the date of the last news. | Baseline up to Year 5 | 
| Time to Clinical Progression | Clinical progression is based on three parameters: local clinical progression which is defined as greater than (>) 50 percent (%) increase in prostate volume relative to lowest volume, recurrence of palpable prostatic tumor after complete regression, positive biopsy; locoregional progression which is defined as pelvic regional lymph node lesion development; and metastatic progression which is defined as distant lesions identification. Time to onset of clinical progression will be performed using the Kaplan-Meier method based on the date of onset of the first progression among local, locoregional or metastatic clinical progressions. | Baseline up to Year 5 | 
| Overall Survival | Overall survival will be measured as the time from the date of randomization to the date of death. Participants will be censored in case of lost to follow-up or alive on the date of the last news. | Baseline up to Year 5 | 
| Time to Locoregional Progression | Locoregional progression is defined as the development of pelvic regional lymph node lesion(s) identified by computed tomography (CT) scan or ultrasound and confirmed by biopsy in the absence of any other signs of progression. It will be performed using the Kaplan-Meier method taking into account the date of onset of locoregional progression. | Baseline up to Year 5 | 
| Time to Onset of Metastatic Progression | Metastatic progression is defined as identification of distant lesions. Time to onset of metastatic progression will be performed using the Kaplan-Meier method taking into account the date of onset of the first metastatic progression. The participants will be censored in case of death, lost to follow-up or alive without metastatic progression on the date of the last news. | Baseline up to Year 5 | 
| Specific Survival | Analysis of specific survival using the Kaplan-Meier method takes into account the dates of death linked to the disease. The participants will be censored in case of death, lost to follow-up or alive on the date of the last news. | Baseline up to Year 5 | 
| Number of Deaths linked to the disease |  | Baseline up to Year 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy, Radiotherapy