PEACE 7 is an international, multicenter, randomized, open-label phase III study that aims at evaluating the efficacy and safety of darolutamide and of stereotactic dose escalated prostate radiotherapy in patients with localised prostate cancer and high-risk features of relapse (defined as patients with at least 2 high-risk criteria from National Comprehensive Cancer Network (NCCN) classification) using a factorial (2x2) design.
The primary objective of this study is to assess the efficacy of darolutamide and of a stereotactic dose escalated radiotherapy targeting prostate in combination with ADT and pelvic nodal radiotherapy in terms of metastasis-free survival (MSF).
Patients will be randomized (1:1:1:1) to receive either:
* Arm A (Standard arm): ADT + conventional fractionated or moderately hypo-fractionated prostate radiotherapy including pelvic nodal radiotherapy * Arm B (Experimental arm): ADT + conventional fractionated or moderately hypo-fractionated prostate radiotherapy including pelvic nodal radiotherapy + darolutamide * Arm C (Experimental arm): ADT + conventional fractionated or moderately hypo-fractionated pelvic nodal radiotherapy + Prostate SBRT * Arm D (Experimental arm): ADT + conventional fractionated or moderately hypo-fractionated pelvic nodal radiotherapy + Prostate SBRT + darolutamide
Patient will receive systemic treatments (ADT and/or darolutamide) during 2 years where visits on site are planned at D45, D90, D180 and then every 3 months for checkups and follow prostate specific antigen (PSA) level.
Metastasis-free survival (MFS) is defined as the time interval from randomization to the date of the appearance of metastasis (on next generation imaging) or death (from any cause), whichever occurs first. Radiographic evaluation will be carried out at the time of biochemical failure (Phoenix criteria) or in case of clinical suspicion. After biochemical failure (Phoenix criteria) radiographic evaluation on next generation imaging (prostate-specific membrane antigen (PSMA) positron emission tomography (PET) scan (any European Medicines Agency (EMA) approved PSMA tracer)) will be performed every 6 months until a metastatic site of relapse is identified and will be repeated at each subsequent PSA progression.
Signed a written informed consent form prior to any trial specific procedures
Men, 18 years ≤ Age ≤ 80 years
ECOG performance status of 0 or 1
No significant co-morbidities that might prevent long-term follow-up
Clinically or radiologically detectable metastasis, including no evidence of pelvic lymph node metastasis on next generation imaging (PSMA PET/CT), nor enlarged pelvic lymph nodes (≥1 cm in small diameter) on MRI Note: Patients with infra-centimetric nodal disease (<1 cm in small diameter) on conventional imaging and equivocal hyperfixation on next generation imaging may be included
Recent history of TURP or prostate enucleation (less than 6 months) Note: patients with severe obstructive symptoms (defined as International Prostate Symptom Score (IPSS) ≥20) should be carefully evaluated to rule out the need for TURP/Prostate enucleation
Prior treatment for prostate cancer, including prostatectomy, except lymph node dissection (patients with PN- disease only can be accrued) or ADT (started more than 6 weeks before randomization)
Patient with other known concurrent severe and/or uncontrolled concurrent medical disease or infection (such as active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease) or co-morbidity, which could compromise participation in the study
Factorial
Darolutamide
DrugPharmaceutical form: 300 mg tablets Administration route: oral (PO) Posology: 600 mg twice daily (BID)
Stereotactic Body RadioTherapy (SBRT)
RadiationFollowing randomization, patients will receive dose escalated intensity modulated radiotherapy (IMRT) using normo-fractionation or moderate hypo-fractionation including whole pelvic nodal radiotherapy (WPRT). At study entry, each investigational site will be asked to choose one regimen (normo-fractionation or moderate hypo-fractionation) which will be applied for all patients included by the investigational site in the study. SBRT, experimental treatment, will be used as a boost in Arms C \& D. The placement of 3 to 4 fiducial markers for stereotactic boost is mandatory. SBRT will be applied only on Prostate: 2 times 10 Gy delivered to the prostate with a gap of one week between each SBRT fraction.
ADT (Standard of Care)
DrugAndrogen Deprivation Therapy (ADT) The ADT treatment will be chosen at the investigator's discretion, and will be administered according to local standard procedures for up to 2 years. Patients who may have received ADT prior joining the study should have started the ADT treatment within a maximum of 6 weeks before randomization. Otherwise ADT will be started on Day 1 (or 14 days at the latest after the randomization).
radiotherapy
RadiationFollowing randomization, patients will receive dose escalated intensity modulated radiotherapy (IMRT) using normo-fractionation or moderate hypo-fractionation including whole pelvic nodal radiotherapy (WPRT). Arm A and Arm B: If Normo-fractionated radiotherapy: Pelvic nodes 46 Gy, seminal vesicles 46-54 Gy and prostate 78 Gy (39 fractions over 8 weeks). If Hypo-fractionated radiotherapy: Pelvic nodes and seminal vesicles 44 Gy in 20 fractions; prostate 60 Gy delivered concomitantly in 20 fractions over 4 weeks. Arm C and Arm D: If Normo-fractionated radiotherapy: Pelvic nodes 46 Gy, seminal vesicles 46 Gy in 23 fractions over 4.5 weeks. If Hypo-fractionated radiotherapy: Pelvic nodes and seminal vesicles 44 Gy in 20 fractions over 4 weeks.
Metastasis-free survival
Metastasis-free survival (MFS) is defined as the time interval from randomization to the date of the appearance of metastasis (on next generation imaging) or death (from any cause), whichever occurs first.
Clinical Progression-Free Survival
Clinical Progression-Free Survival (cPFS) is the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse. Clinical disease progression is defined as metastatic relapse or proven local relapse (by either biopsy or unequivocal imaging), unequivocal nodal progression on imaging, or death (from any cause), whichever occurs first.
Biochemical Progression-Free Survival
Biochemical Progression-Free Survival is the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse. Biological disease progression is defined as the time interval from randomization to the date of PSA relapse or death (from any cause), whichever occurs first.
Time to local relapse
Time to local relapse is defined as the time interval from randomization to the date of the appearance of the first proven local relapse (by either biopsy or unequivocal imaging).
Prostate Cancer-Specific Survival (PCSS)
Prostate Cancer-Specific Survival (PCSS) is defined as the time interval between randomization and the date of death due to prostate cancer.
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UNICANCER
Lead sponsor
Bayer
Collaborator
