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

PEACE-9 - ESCALATE-RT: A Phase III Randomized Study in Patients With High-risk PSA Relapse After Local Therapy Treated With Enzalutamide Plus Androgen Deprivation Therapy and Comparing MDT ± Pelvic Radiotherapy Versus no Further Treatment

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Prostatic Neoplasms; Biochemical Recurrence; Oligometastatic Prostate Cancer
• Intervention / Treatment: Drug: Androgen Deprivation Therapy (ADT); Drug: Enzalutamide; Radiation: Radiotherapy for MDT ± WPRT

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Thomas Zilli, MD; Phone Number: + 41 918118675; Email: thomas.zilli@eoc.ch
• Study Contact Backup: Name: Tatiana Terrot; Email: Tatiana.Terrot@eoc.ch

Study Locations

• Belgium
  • Aalst, Belgium
    • AZorg Aalst
    • Contact: Mark De Ridder, MD
  • Antwerp, Belgium
    • Iridium Netwerk
    • Contact: Piet Ost, MD, PhD
  • Bruges, Belgium
    • AZ Sint-Jan
    • Contact: Sarah Roels, MD
  • Brussels, Belgium
    • Institut Bordet - HUB Brussel
    • Contact: Dirk Van Gestel, MD
  • Hasselt, Belgium
    • Jessa Ziekenhuis
    • Contact: Philippe Bulens, MD
  • Kortrijk, Belgium
    • AZ Groeninge
    • Contact: Aurélie De Bruycker, MD
  • Mechelen, Belgium
    • AZ Sint-Maarten Mechelen
    • Contact: Cédric Draulans, MD
• France
  • Bordeaux, France
    • Institut Bergonie
    • Contact: Vérane Achard, MD, PhD
  • Lille, France
    • Centre Oscar Lambret
    • Contact: David Pasquier, MD, PhD
  • Saint-Etienne, France
    • CHU de Saint-Etienne
    • Contact: Nicolas Vial, MD; Email: nicolas.vial@chu-st-etienne.fr
    • Contact: Email: nicolas.vial@chu-st-etienne.fr
  • Saint-Herblain, France
    • Institut de cancérologie de l'Ouest
    • Contact: Stéphane Supiot, MD, PhD
  • Villejuif, France
    • Institut Gustave Roussy
    • Contact: Pierre Blanchard, MD, PhD
• Switzerland
  • Aarau, Switzerland
    • KSA
    • Contact: Stephanie Thoma, MD; Email: stephanie.thoma@ksa.ch
  • Bellinzona, Switzerland, 6500
    • IOSI-EOC
    • Contact: Thomas Zilli, MD; Phone Number: + 41 918118675; Email: thomas.zilli@eoc.ch
  • Bern, Switzerland
    • Inselspital
    • Contact: Mohamed Shelan, MD; Email: Mohamed.Shelan@insel.ch
  • Chur, Switzerland
    • KSGR
    • Contact: Efstratios Karagiannis, MD, PhD; Email: Efstratios.Karagiannis@ksgr.ch
  • Münsterlingen, Switzerland
    • Spital Thurgau
    • Contact: Michael Mayinger, MD; Email: michael.mayinger@team-radiologie.ch
  • Winterthur, Switzerland
    • KSW
    • Contact: Daniel Zwahlen, MD; Email: daniel.zwahlen@ksw.ch
  • Zurich, Switzerland
    • USZ
    • Contact: Matthias Guckenberger, MD; Email: Matthias.Guckenberger@usz.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: ADT plus Enzalutamide; 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); 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 RPpostoperative 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.; Drug: Enzalutamide; 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.
Experimental: ADT plus Enzalutamide plus Radiotherapy (MDT +/- WPRT); 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	Drug: Androgen Deprivation Therapy (ADT); 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 RPpostoperative 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.; Drug: Enzalutamide; 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.; Radiation: Radiotherapy for MDT ± WPRT; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to PSA progression	Time to PSA progression: defined by the time from the day of PSA nadir and the day when the PSA increase of ≥ 25% and an absolute increase of ≥ 2 ng/mL above the nadir.	From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date
PFS (Progression-Free Survival)	PFS: defined as the time from randomization to the first progression or death (progression being defined by the appearance of a new recurrence (any N1 or M1) as suggested by PET-CT, or symptoms related to progressive prostate cancer, or death due to any cause).	From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date
MFS (Metastasis-Free Survival)	MFS: defined as time between randomization and the appearance of a new metastatic recurrence (any M1) as suggested by PET-CT, or death due to any cause.	From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date
OS (Overall Survival)	OS: defined as the time from randomization to death to any cause.	From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date
PSA response	PSA response: defined by a PSA < 0.2 ng/ml at 9 months.	From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date
Pattern of progression	Local/regional/distant recurrence will be analyzed: A local recurrence is defined as the appearance of evidence of a recurrence on imaging inside a PTV_M volume or the PTV_PB volume or the PTV_LNN.; A regional nodal recurrence is defined as the appearance of evidence of a lymphadenopathy in the pelvis but outside the PTV_LNN volume, in a patient without the diagnosis of hematologic/lymphatic disorder associated with lymphadenopathy or if there is histopathological evidence.; Distant recurrence is defined as the appearance of evidence of a lymphadenopathy outside the PTV_LNN and outside all the PTV_M (for lymph nodes previously treated as metastasis), or distant metastases (M1b, M1c) outside all the PTV_M.	From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date
Time to castration-resistant disease	Time to castration-resistant disease is defined as the time from trial randomization until castration-resistant status, defined as a castrate serum testosterone level below 50 ng/dL (1.7 nmol/L) plus either biochemical progression or radiological progression. Biochemical progression is defined as three consecutive rises in PSA at least 1 week apart, resulting in two 50% increases over the nadir, with a PSA level above 2 ng/mL. Radiological progression is defined as the appearance of two or more new bone lesions on bone scan, or enlargement of a soft tissue lesion using RECIST (Response Evaluation Criteria in Solid Tumours). Symptomatic progression alone is not sufficient to diagnose castration-resistant prostate cancer (CRPC).	From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date
Adverse events	Adverse events: acute (during the first 3 months after the end of MDT ± WPRT and late (3 months after the end of MDT ± WPRT).	From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date
Quality of life (QoL) - EORTC QLQ-C30	EORTC Quality of Life Questionnaire Core 30 (QLQ-C30), version 3, a 30-item questionnaire. Items are rated on a 4-point scale (1 = "Not at all" to 4 = "Very much"), except the two global health status/QoL items, rated on a 7-point scale (1 = "Very poor" to 7 = "Excellent"). Raw scores are linearly transformed to a 0-100 scale. Higher scores indicate better functioning/quality of life on the functional and global health scales, and greater symptom burden on the symptom scales.	From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date
Quality of Life - EORTC QLQ-PR25	EORTC Quality of Life Questionnaire Prostate Cancer Module (QLQ-PR25), a 25-item module supplementing the QLQ-C30. Items are rated on a 4-point scale (1 = "Not at all" to 4 = "Very much"). Raw scores are linearly transformed to a 0-100 scale. Higher scores indicate greater symptom burden, except for sexual activity/functioning scales, where higher scores indicate better functioning.	From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date
Quality of Life - EORTC IL-249	A customised 22-item list from the EORTC IL-249, assessing general symptoms, weight-related issues, and sexual quality of life. Items are rated on a 4-point scale (1 = "Not at all" to 4 = "Very much"). Raw scores are linearly transformed to a 0-100 scale; higher scores indicate a greater burden of symptoms or issues.	From the start of Androgen Deprivation Therapy plus Enzalutamide to 5 years after this date

Collaborators and Investigators

• Sponsor: Ente Ospedaliero Cantonale, Bellinzona
• Collaborators: Clinical Trial Unit Ente Ospedaliero Cantonale
• Investigators: Principal Investigator: Thomas Zilli, MD, IOSI-EOC; Study Chair: 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

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): July 1, 2030
• Study Completion (Estimated): July 1, 2030

Study Registration Dates

• First Submitted: August 19, 2026
• First Submitted That Met QC Criteria: August 21, 2026
• First Posted (Actual): August 24, 2026

Study Record Updates

• Last Update Posted (Actual): August 24, 2026
• Last Update Submitted That Met QC Criteria: August 21, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Enzalutamide; Metastasis-directed therapy; Androgen Deprivation Therapy; Pelvic radiotherapy; Salvage treatment; High-risk PSA relapse; Oligometastatic recurrence
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Therapeutics; Pharmacologic Actions; Chemical Actions and Uses; Androgen Antagonists; Radiotherapy; enzalutamide
• Other Study ID Numbers: PEACE-9 - ESCALATE-RT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No