Best Salvage Treatment for High-risk Relapsing Prostate Cancer (PEACE-9 - ESCALATE-RT)

NCT07782112 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: PEACE-9 - ESCALATE-RT
• Study Type: interventional
• Target: 140
• Locations: 3 countries
• Sites: 19

Brief Summary

The goal of this clinical trial is to learn if adding metastasis-directed radiotherapy with or without pelvic salvage radiotherapy, to intermittent prostate cancer drugs (intensified hormone therapy) can delay the need to restart these drugs in men with oligometastactic prostate cancer recurrence. In practice, this study is open to men whose PSA level (a blood marker of cancer activity) is rising as defined by biochemical recurrence, and who have 1 to 5 areas of cancer spread (1 to 5 metastases defining oligometastatic status) found on a specialized scan (PSMA PET/CT). Since intensified hormone therapy, including androgen deprivation therapy combined with a next-generation hormone therapy, represents the standard treatment strategy for these patients, researchers want to find out if adding radiation therapy can help patients to spend more time off cancer drugs while keeping their cancer under control. The main questions this trial aims to answer are:

• Does adding radiation therapy to each metastases with or without pelvic area, lengthen the time before participants need to restart drug treatment?
• Does adding radiation therapy increase the number of participants whose PSA drops to a very low level (0.2 ng/mL or lower)?
• Does adding radiation therapy affect participants' quality of life? Researchers will randomly assign participants (chosen by chance) to receive either enzalutamide (next-generation hormone therapy) plus androgen-deprivation therapy (first-generation hormone therapy ) alone, or the same association of these drugs combined with radiation therapy aimed at each metastases with or without pelvic area. This comparison will show whether adding radiation therapy helps participants reach a deeper PSA response and go longer without needing cancer drugs. Participants will:
• Take enzalutamide and androgen-deprivation therapy for 9 months
• Have an equal chance of also receiving radiation therapy to each metastases with or without pelvic area
• Stop drug treatment after 9 months if their PSA drops below 0.2 ng/mL, a level showing the cancer is well controlled
• Restart drug treatment if their PSA rises again during the treatment-free period
• Have regular blood tests and clinic visits to check their PSA, testosterone, and overall health
• Complete short quality-of-life questionnaires during the study
• Take part in a study conducted at several hospitals in Switzerland, Belgium, and France.

Conditions

Prostatic Neoplasms; Biochemical Recurrence; Oligometastatic Prostate Cancer

Keywords

High-risk PSA relapse; Oligometastatic recurrence; Salvage treatment; Metastasis-directed therapy; Pelvic radiotherapy; Androgen Deprivation Therapy; Enzalutamide

Outcome Measures

Primary Outcomes (1)

• Time to first re-initiation of treatment

  • Time to first re-initiation of treatment calculated from randomization to the occurrence of one of the following events: * PSA ≥ 0.2 ng/mL at week 36 (treatment is continued until progression), * For patients in the off-period, a rise of PSA to ≥ 5 ng/mL after primary RT or to ≥ 2 ng/mL after RP ± postoperative RT (treatment is restarted as per EMBARK criteria) * For patients in the off-period with rising PSA \< 5 ng/mL after primary RT or \<2ng/mL after RP ± postoperative RT, the investigator decision to start same or new treatment. Death in the absence of progressive disease will be considered as a competing risk for this endpoint.

  From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date

Secondary Outcomes (11)

• Time to PSA progression

  From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date

• PFS (Progression-Free Survival)

  From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date

• MFS (Metastasis-Free Survival)

  From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date

• OS (Overall Survival)

  From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date

• PSA response

  From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date

Study Arms (2)

ADT plus Enzalutamide

ACTIVE COMPARATOR

Enzalutamide 160 mg daily + androgen deprivation therapy for 9 months, suspended if PSA \< 0.2 ng/mL, followed by PSA monitoring until progression

Drug: Androgen Deprivation Therapy (ADT); Drug: Enzalutamide

ADT plus Enzalutamide plus Radiotherapy (MDT +/- WPRT)

EXPERIMENTAL

Enzalutamide 160 mg daily + androgen deprivation therapy for 9 months, suspended if PSA \< 0.2 ng/mL, followed by PSA monitoring until progression + Radiotherapy for MDT ± WPRT

Radiation: Radiotherapy for MDT ± WPRT; Drug: Androgen Deprivation Therapy (ADT); Drug: Enzalutamide

Interventions

Radiotherapy for MDT ± WPRT RADIATION

Participants receive metastasis-directed therapy (MDT) alone or combined with prostate-bed radiotherapy (PB-RT) and/or whole pelvic radiotherapy (WPRT), as follows (radiotherapy is tailored to each participant's prior curative treatment for prostate cancer, to avoid re-irradiating previously treated volumes) : * Prior radical prostatectomy (RP) alone: MDT plus PB-RT, with or without WPRT. WPRT is mandatory for pelvic nodal involvement (N1) and recommended for node-negative (N0) participants. * Prior RP plus PB-RT: MDT, with or without WPRT. WPRT is mandatory for N1 and recommended for N0 participants. * Prior RP plus PB-RT plus WPRT: MDT alone. * Prior definitive prostate radiotherapy (no prostatectomy): MDT, with or without WPRT. WPRT is mandatory for N1 and recommended for N0 participants.

ADT plus Enzalutamide plus Radiotherapy (MDT +/- WPRT)

Androgen Deprivation Therapy (ADT) DRUG

* All arms should receive ADT for a duration of at least 36 weeks. * The prescription of ADT in both treatment arms will be in accordance with standard practice for the indication, the chosen molecules, and the selected doses. * ADT should be suspended at the end of week 36, if PSA \< 0.2 ng/mL at week 36. In the off-period, ADT will be restarted with a rise of PSA to ≥ 5 ng/mL after primary RT or to ≥ 2 ng/mL after RP ± postoperative RT. For patients in the off-period with rising PSA \< 5 ng/mL after primary RT or \< 2ng/mL after RP * postoperative RT, the decision to restart treatment is led to each investigator. * ADT should be continued until progression at the end of week 36, if PSA ≥ 0.2 ng/mL at week 36.

ADT plus Enzalutamide; ADT plus Enzalutamide plus Radiotherapy (MDT +/- WPRT)

Enzalutamide DRUG

* All arms should receive enzalutamide 160mg daily for a duration of at least 36 weeks. * Enzalutamide should be suspended at the end of week 36, if PSA \< 0.2 ng/mL at week 36. In the off-period, Enzalutamide will be restarted with a rise of PSA to ≥ 5 ng/mL after primary RT or to ≥ 2 ng/mL after RP ± postoperative RT. For patients in the off-period with rising PSA \< 5 ng/mL after primary RT or \< 2ng/mL after RP ± postoperative RT, the decision to restart treatment is led to each investigator. * Enzalutamide should be continued until progression at the end of week 36, if PSA ≥ 0.2 ng/mL at week 36.

ADT plus Enzalutamide; ADT plus Enzalutamide plus Radiotherapy (MDT +/- WPRT)

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically proven initial diagnosis of adenocarcinoma of the prostate
• Rising PSA after local therapy as defined by PSA ≥ 0.2 ng/mL after RP +/- adjuvant/salvage prostate bed RT and at least 2 ng/mL above nadir for primary RT, with a PSADT ≤ 9 months
• Serum Testosterone ≥ 150 ng/dl (6.9343 nM/L)
• On PSMA PET/CT restaging presence of: 1 to 5 distant metastases that are amenable to MDT ± N1 patients (no limit in the number of nodes)
• ECOG performance status 0 - 2
• Age \> or =18 years
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations

You may not qualify if:

• More than 5 distant PSMA positive metastases and/or brain or leptomeningeal metastases.
• Prostate recurrence (positive PSMA disease) after primary prostate irradiation
• Prostate bed recurrence (positive PSMA disease) after salvage/adjuvant irradiation
• Pelvic nodal recurrence (positive PSMA disease) after primary WPRT irradiation
• Contraindications to pelvic RT and/or MDT
• Prior evidence of distant metastatic disease
• Contraindications to ADT
• Contraindication for treatment with enzalutamide
• Prior hormonal therapy (Neoadjuvant/adjuvant therapy to treat PCa ≤ 36 months in duration and ≥ 9 months before randomization is allowed)
• Previous treatment with cytotoxic agent for PCa
• Any active malignancies (i.e., progressing or requiring any treatment in the previous 36 months) other than prostate cancer (except non-muscle invasive bladder cancer; non-melanomatous skin cancer or a malignancy that is considered cured with minimal risk of recurrence

Sponsors & Collaborators

• Ente Ospedaliero Cantonale, Bellinzona: lead
• Clinical Trial Unit Ente Ospedaliero Cantonale: collaborator

Study Sites (19)

AZorg Aalst

Aalst, Belgium

Location

Iridium Netwerk

Antwerp, Belgium

Location

AZ Sint-Jan

Bruges, Belgium

Location

Institut Bordet - HUB Brussel

Brussels, Belgium

Location

Jessa ziekenhuis

Hasselt, Belgium

Location

AZ Groeninge

Kortrijk, Belgium

Location

AZ Sint-Maarten Mechelen

Mechelen, Belgium

Location

Institut Bergonié

Bordeaux, France

Location

Centre Oscar Lambret

Lille, France

Location

CHU de Saint-Etienne

Saint-Etienne, France

Location

Institut de Cancérologie de l'Ouest

Saint-Herblain, France

Location

Institut Gustave Roussy

Villejuif, France

Location

KSA

Aarau, Switzerland

Location

IOSI-EOC

Bellinzona, 6500, Switzerland

Location

Inselspital

Bern, Switzerland

Location

KSGR

Chur, Switzerland

Location

Spital Thurgau

Münsterlingen, Switzerland

Location

KSW

Winterthur, Switzerland

Location

USZ

Zurich, Switzerland

Location

Related Publications (7)

• Nguyen PL, Kollmeier MA, Rathkopf DE, Hoffman KE, Zurita AJ, Spratt DE, Dess RT, Liauw SL, Szmulewitz RZ, Einstein DJ, Bubley GJ, Yu JB, An Y, Wong AC, Feng FY, McKay RR, Rose BS, Shin KY, Kibel AS, Taplin ME. FORMULA-509: A Multicenter Randomized Trial of Postprostatectomy Salvage Radiotherapy and 6 months of a GNRH Agonist with Either Bicalutamide or Abiraterone Acetate plus Prednisone and Apalutamide. Eur Urol. 2026 Feb 10:S0302-2838(25)04854-7. doi: 10.1016/j.eururo.2025.12.001. Online ahead of print.

  PMID: 41672869 BACKGROUND

• Tang C, Sherry AD, Hwang H, Farris DP, Francolini G, Di Cataldo V, Livi L, Tran P, Corn PG, Aparicio A, Simontacchi G, Kiess AP, Wang JH, Fonteyne V, Bultijnck R, Phillips R, Deek MP, Olson R, Harrow S, Marvaso G, Lorubbio C, Jereczek-Fossa BA, Ludmir EB, Blanchard P, Warner A, Sun R, Palma DA, Ost P. Metastasis-directed therapy and standard of care versus standard of care for oligometastatic prostate cancer (WOLVERINE): a systematic review and individual patient data meta-analysis from the X-MET collaboration. Lancet Oncol. 2026 Feb;27(2):181-190. doi: 10.1016/S1470-2045(25)00658-8.

  PMID: 41643695 BACKGROUND

• Tang C, Sherry AD, Haymaker C, Bathala T, Liu S, Fellman B, Cohen L, Aparicio A, Zurita AJ, Reuben A, Marmonti E, Chun SG, Reddy JP, Ghia A, McGuire S, Efstathiou E, Wang J, Wang J, Pilie P, Kovitz C, Du W, Simiele SJ, Kumar R, Borghero Y, Shi Z, Chapin B, Gomez D, Wistuba I, Corn PG. Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer: The EXTEND Phase 2 Randomized Clinical Trial. JAMA Oncol. 2023 Jun 1;9(6):825-834. doi: 10.1001/jamaoncol.2023.0161.

  PMID: 37022702 BACKGROUND

• Holzgreve A, Armstrong WR, Clark KJ, Benz MR, Smith CP, Djaileb L, Gafita A, Thin P, Nickols NG, Kishan AU, Rettig MB, Reiter RE, Czernin J, Calais J. PSMA-PET/CT Findings in Patients With High-Risk Biochemically Recurrent Prostate Cancer With No Metastatic Disease by Conventional Imaging. JAMA Netw Open. 2025 Jan 2;8(1):e2452971. doi: 10.1001/jamanetworkopen.2024.52971.

  PMID: 39752157 BACKGROUND

• Bukavina L, Luckenbaugh AN, Hofman MS, Hope T, Kamran SC, Murphy DG, Yamoah K, Ost P. Incorporating Prostate-specific Membrane Antigen Positron Emission Tomography in Management Decisions for Men with Newly Diagnosed or Biochemically Recurrent Prostate Cancer. Eur Urol. 2023 Jun;83(6):521-533. doi: 10.1016/j.eururo.2022.10.024. Epub 2022 Nov 18.

  PMID: 36404204 BACKGROUND

• Shore ND, Luz MA, De Giorgi U, Gleave M, Gotto GT, Pieczonka CM, Haas GP, Kim CS, Ramirez-Backhaus M, Rannikko A, Kalac M, Sridharan S, Rosales M, Tang Y, Tutrone RF Jr, Venugopal B, Villers A, Woo HH, Wang F, Freedland SJ. Improved Survival with Enzalutamide in Biochemically Recurrent Prostate Cancer. N Engl J Med. 2026 Feb 5;394(6):563-575. doi: 10.1056/NEJMoa2510310. Epub 2025 Oct 19.

  PMID: 41124201 BACKGROUND

• Crook JM, O'Callaghan CJ, Duncan G, Dearnaley DP, Higano CS, Horwitz EM, Frymire E, Malone S, Chin J, Nabid A, Warde P, Corbett T, Angyalfi S, Goldenberg SL, Gospodarowicz MK, Saad F, Logue JP, Hall E, Schellhammer PF, Ding K, Klotz L. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med. 2012 Sep 6;367(10):895-903. doi: 10.1056/NEJMoa1201546.

  PMID: 22931259 BACKGROUND

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

Radiotherapy; Androgen Antagonists; enzalutamide

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Thomas Zilli, MD

  IOSI-EOC

  PRINCIPAL INVESTIGATOR

• Bertrand Tombal, MD, PhD

  Urology, Cliniques Universitaires Saint Luc, Bruxelles, Belgium

  STUDY CHAIR

• Piet Ost, MD, PhD

  Department of Human Structure and Repair, Ghent University, Ghent, Belgium; Department of Radiation Oncology, Iridium Network, Wilrijk, Belgium

  STUDY CHAIR

• Silke Gillessen, MD

  IOSI-EOC

  STUDY CHAIR

• Piet Dirix, MD, PhD

  Department of Radiation Oncology, Iridium Network, Wilrijk, Belgium

  STUDY CHAIR

• Salvatore Cozzi, MD

  IOSI-EOC

  STUDY CHAIR

• Nicolas Vial, MD

  University Hospital of Saint-Etienne

  STUDY CHAIR

Central Study Contacts

Thomas Zilli, MD

CONTACT

+ 41 918118675; thomas.zilli@eoc.ch

Tatiana Terrot

CONTACT

Tatiana.Terrot@eoc.ch

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor and Head Department of Radiation Oncology

Model Details: Superiority design

Study Record Dates

• First Submitted: August 19, 2026
• First Posted: August 24, 2026
• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): July 1, 2030
• Study Completion (Estimated): July 1, 2030
• Last Updated: August 24, 2026

Record last verified: 2026-08

Locations

BE (7); FR (5); CH (7)