Darolutamide with standard or higher-dose targeted prostate radiotherapy plus hormone therapy for men with high-risk localized prostate cancer

A Randomized Phase III Trial With a Factorial Design Evaluating the Efficacy and Safety of Darolutamide and Stereotactic Dose Escalated Radiotherapy in Patients With Localized Prostate Cancer and High-risk Features of Relapse, From the Prostate Cancer Consortium in Europe (PEACE)

This trial tests whether adding darolutamide and/or using higher-dose targeted prostate radiotherapy together with hormone therapy and pelvic nodal radiotherapy helps men with localized high‑risk prostate cancer stay free of metastatic disease longer.

Quick facts

• Phase: PHASE3
• Study type: Interventional
• Enrollment: 700 (estimated)
• Ages: 18 Years to 80 Years
• Sex: Male
• Sponsor: UNICANCER (other)
• Drugs / interventions: chemotherapy, immunotherapy
• Locations: 6 sites (Brest and 5 other locations)
• Trial ID: NCT06625970 on ClinicalTrials.gov

What this trial studies

This is an international, multicenter, open‑label phase III trial using a 2x2 factorial design to compare darolutamide versus no darolutamide and stereotactic dose‑escalated prostate radiotherapy versus conventional/moderately hypofractionated radiotherapy, all given with androgen‑deprivation therapy and pelvic nodal radiotherapy. Patients are randomized 1:1:1:1 into four arms combining those interventions. The primary endpoint is metastasis‑free survival. Safety and tolerability are also monitored throughout follow‑up.

Who should consider this trial

Good fit: Men aged 18–80 with histologically confirmed localized prostate adenocarcinoma who meet at least two NCCN high‑risk criteria (Gleason ≥8, T3/T4, or PSA ≥20 ng/mL), with ECOG 0–1 and prostate size <100 cc are ideal candidates.

Not a fit: Patients with metastatic disease, major comorbidities that prevent long‑term follow‑up, inadequate blood or liver function, or who do not meet the high‑risk criteria are unlikely to benefit from this trial.

Why it matters

Potential benefit: If successful, the combined approach could delay or prevent metastasis and extend the period patients remain free of detectable cancer spread, potentially improving survival and quality of life.

How similar studies have performed: Related trials combining intensified androgen‑receptor pathway inhibitors with radiotherapy have shown benefit in some prostate cancer settings, but the specific combination of darolutamide with stereotactic dose‑escalated prostate radiotherapy in this factorial design for localized high‑risk disease is relatively novel.

Eligibility criteria

Inclusion Criteria:

1. Signed a written informed consent form prior to any trial specific procedures

   Note: In case of physical incapacitation, a trusted representative of their choice, which is not the investigator or sponsor, can sign on the behalf of the patients
2. Men, 18 years ≤ Age ≤ 80 years
3. ECOG performance status of 0 or 1
4. No significant co-morbidities that might prevent long-term follow-up
5. Histologically confirmed adenocarcinoma of the prostate
6. Meet at least 2 of the following criteria from NCCN classification:

   * Gleason score ≥8
   * T3 or T4 disease (T3 defined by MRI is acceptable)
   * Prostate-specific antigen ≥20 ng/mL
7. Prostate size on MRI \<100 cc
8. Absolute neutrophil count ≥ 1.5 x 10⁹/L
9. Platelet count ≥100 x 10⁹/L
10. Haemoglobin ≥90 g/L (in absence of red blood cell transfusion within 4 weeks prior to randomization)
11. Hepatic function: serum alanine aminotransferase (ALT) and/or aspartate transaminase (AST) ≤2.5 x upper limit of normal (ULN), total bilirubin ≤1.5 x ULN
12. Creatinine ≤2.0 x ULN
13. Sexually active patients must agree to use an effective contraceptive method while on treatment and for 1 week after the final dose of investigational product
14. Patient must be affiliated to a Social Security System or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials)
15. Patient must be willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up

Exclusion Criteria:

1. 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
2. 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
3. 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)
4. 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
5. Cardiac disease such as uncontrolled hypertension (systolic BP ≥160 mmHg or diastolic BP ≥95 mmHg; 3 consecutive measures taken 5 minutes apart), stroke, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infarction within one year, coronary/peripheral artery bypass graft, LVEF \> grade 2
6. Uncontrolled diabetes mellitus
7. Current active hepatic or biliary disease (with exception of subjects with Gilbert's syndrome, asymptomatic gallstones, stable chronic liver disease per investigator assessment)
8. Gastrointestinal disorder or procedure, which expects to interfere significantly with absorption of study treatment. Severe GI disorders precluding pelvic irradiation
9. Known severely impaired lung function (spirometry and DLCO 70% or less of normal and O2 saturation of 88% or less at rest on room air)
10. Other prior malignancy within the last 3 years, except basal cell skin cancer
11. Known hypersensitivity to the study treatment or any of its ingredients.
12. Physical or psychological condition or any condition that in the opinion of the investigator would impair the patients' ability to comply with the study procedures
13. Previous treatment for prostate cancer (surgery or radiotherapy) or previous pelvic irradiation that would make prostate/pelvis radiotherapy impossible
14. Concomitant prohibited treatment. Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5. A one-week washout period is necessary for patients who are already on these treatments
15. Prior treatment with second generation androgen receptor (AR) inhibitors, other investigational AR inhibitors, or CYP17 enzyme inhibitor
16. Use of oestrogens or 5-α reductase inhibitors or AR inhibitors
17. Acute toxicities of prior treatments and procedures not resolved to grade ≤1 or baseline before randomization
18. Prior chemotherapy or immunotherapy for prostate cancer
19. Major surgery within 28 days before randomization
20. Participation in another therapeutic trial within 30 days prior to inclusion
21. Persons deprived of their liberty or under protective custody or guardianship
22. Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons

Where this trial is running

Brest and 5 other locations

• Clinique Pasteur Lanroze - Brest — Brest, France (RECRUITING)
• Centre Georges Francois Leclerc — Dijon, France (RECRUITING)
• Groupe Hospitalier Paris Saint-Joseph — Paris, France (RECRUITING)
• CHU Saint-Etienne — Saint-Etienne, France (RECRUITING)
• Gustave Roussy, Cancer Campus, Grand Paris — Villejuif, France (RECRUITING)
• CHU Martinique — Fort-de-France, Martinique (RECRUITING)

Study contacts

• Study coordinator: Carine LA

Conditions: High Risk Prostate Carcinoma, Prostate Cancer, HPRC, PSMA-PET, Prostate Cancer, High-Risk