The Impact of Metastatic Directed Radiotherapy (MDRT) on Oligoprogressive Castration Resistant Prostate Cancer (CRPC) (OLYMPIAN)

Oligometastatic Directed Radiotherapy for Patients With Castration Resistant Prostate Cancer

In patients with metastatic prostate cancer (PCa) who receive androgen deprivation therapy (ADT), the sensitivity to castration will eventually disappear due to the selection of castration-refractory clones. This will lead to the stage of metastatic castration-refractory prostate can-cer (mCRPC), which is incurable and results in a median overall survival of 2-3 years.

Treatment options for patients with mCRPC include several systemic agents, such as andro-gen receptor-targeted agents (ARTA), chemotherapy (docetaxel, cabazitaxel) and bone-targeting agents (radium- 223). Clinical progression and, to a lesser extent, biochemical pro-gression traditionally imply a switch to the next line systemic treatment (NEST). Within patients with mCRPC, there is a subgroup showing oligo-progression, defined as the progression of up to 3 lesions, including both metastatic and/or local relapse. Oligoprogression reflects a heterogeneous treatment response, which, in turn, reflects the heterogeneity of the clonogenic cells that give rise to mCRPC. Retrospective studies suggest that metastasis-directed radiotherapy (MDRT) to these oligoprogressive lesions delayed the need for NEST. Recently, promising results were published on the use of MDRT in the oligopro-gressive mCRPC (omCRPC) setting, with a NEST-free survival (NEST-FS) of 21 months in well selected patients. Currently, in The Netherlands, patients with omCRPC are frequently referred and treated with MDRT, but a clear treatment protocol and inclusion/selection criteria are missing. Moreover, the exact benefit of MDRT in patients with omCRPC remains unclear, as prospective evi-dence for MDRT in omCRPC is lacking.

Study Overview

• Status: Recruiting
• Conditions: Radiotherapy; Prostate Cancer (Adenocarcinoma); Castration Resistant Metastatic Prostate Cancer; OligoProgressive Metastatic Disease
• Intervention / Treatment: Radiation: Metastasis directed radiotherapy

Detailed Description

The primary aim of this study is to test the hypothesis that the addition of MDRT to standard of care (ADT or ADT + chemotherapy or ARTA) in well-selected PCa patients with oligometastatic progressive disease, defined on PSMA PET, prolongs the radiological progression-free survival (rPFS) and postpones the start of next line systemic therapy (NEST). Patients included in this study already have an indication to start NEST, and any delay introduced by adding MDRT will result in a net benefit for the patients.

Primary objectives include: Postponement of the start of next line systemic treatment (NEST), and enhancement of the radiological progression-free survival (rPFS) In this single arm multicenter prospective phase II trial, we aim to include 35 patients with omCRPC (1-3 metastases and/or local recurrence) who will be treated with MDRT to the visible progressive lesions (up to max of 3). Progression is based on PSMA PET.

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Shafak Aluwini; Phone Number: +31625649975; Email: s.al-uwini@umcg.nl

Study Locations

• Netherlands
  • Groningen, Netherlands
    • Recruiting
    • UMC Groningen
    • Contact: Shafak Aluwini; Phone Number: +31625649975; Email: s.al-uwini@umcg.nl
  • Nijmegen, Netherlands
    • Not yet recruiting
    • Radboud UMC
    • Contact: Robert Jan Smeenk; Phone Number: +31 (024) 361 45 05; Email: RobertJan.Smeenk@radboudumc.nl

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Adenocarcinoma of the prostate.
• mCRPC setting, with testosterone level < 50 ng/dl or 1.7 nmol/l.
• Oligoprogressive disease diagnosed on PSMAscan; defined as the progression of pre-existing metastatic disease, and/or the appearance of new metastases and/or the appearance of a local relapse with a maximum of 3 lesions in total.
• Patients currently treated with ADT, whether combined with another systemic treatment such as ARTA, chemotherapy.
• For patients treated with chemotherapy, the course should be completed or stopped before start MORT - In case of treatment with ARTA, a minimal of 3 months response (PSA or clinical response).
• WHO performance status 0-2.
• Age > = 18 years old.
• Patiënt should be presented at the multidisciplinary tumor board of the local hospital in which the therapy will be given.
• Before patiënt registration, written informed consent must be given according to ICH/GCO and national/local regulations.

Exclusion Criteria:

• Serum testosterone level > 50 ng/ml or > 1.7 nmol/l.
• Presence of more than 3 progressive/new metastatic lesions and/or local recurrence (which counts for 1 lesion).
• Active malignancy other than prostate cancer that can potentially interfere with the interpretation of the trial, except non-melanoma skin cancer or non-invasive urothelial cell carcinoma.
• Local recurrence in the prostate after previous radiotherapy
• Previous treatments (RT, surgery) or comorbidities making new treatment with MDRT impossible.
• Disorder precluding understanding of trial Information or informed consent or signing informed consent.
• Evidence of PSMA-negative disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MDRT to oligoprogression; Patients included in the study with a post prostatectomy local recurrence on the PSMA PET with up to 3 oligometastases will be treated preferably with SBRT to all oligometastatic lesions and to the local recurrence in prostate bed	Radiation: Metastasis directed radiotherapy; According to guidelines, in the case of oligoprogression next line systemic treatment is recommended. This study investigates the potential delay of NEST and rPFS by MDRT.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NEST-FS	Next line systemic treatment free survival	6, 12-and 24-months
rPFS	radiologic progression free survival	6, 12-and 24-months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute grade ≥ 2 gastrointestinal toxicity	As assessed using physician-reported score: Common Terminology Criteria for adverse events version 5.0 (CTCAE-5) toxicity score with a scale of 1 - 4.	Up to 3 months after completion of the RT
Acute grade ≥ 2 genitourinary toxicities	As assessed using physician-reported score using questionnaires (CTCAE 5.0 toxicity score).	Up to 3 months after completion of the RT
Acute grade ≥ 2 gastrointestinal toxicity	Using patient-reported questionnaires (Radiation Therapy Oncology Group (RTOG) / European platform of cancer research (EORTC) toxicity questionnaires with grade 1 to 4).	Up to 3 months after completion of the RT
Acute grade ≥ 2 genitourinary toxicities	Using patient-reported questionnaires (Radiation Therapy Oncology Group (RTOG) / European platform of cancer research (EORTC) toxicity questionnaires with grade 1 to 4).	Up to 3 months after completion of the RT
Quality of Life (QoL)	Evaluated using the EORTC QLQ-C30 for health related QoL.	baseline, 6 months, 12 months, 24 months
Biochemical progression	after an initial decline in PSA: the time from start of therapy to first PSA increase that is ≥25% and ≥ 2 ng/ml above the nadir, and which is confirmed by a second value ≥3 weeks later.	From date of randomization until the date of first documented biochmical progression, assessed up to 36 months
Overall survival (OS)	Overall survival	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months
Quality of life (QoL)	EORTC PR-25 for prostate symptom specific QoL.	baseline, 6 months, 12 months, 24 months
Late grade ≥ 2 genitourinary toxicities	Using patient-reported questionnaires (Radiation Therapy Oncology Group (RTOG) / European platform of cancer research (EORTC) toxicity questionnaires with grade 1 to 4).	Up to 2 years after completion of the RT
Late grade ≥ 2 genitourinary toxicity	Using physician-reported score (CTCAE 5.0 toxicity score).	Up to 2 years after completion of the RT
Late grade ≥ 2 gastrointestinal toxicity	As assessed using physician-reported score (CTCAE 5.0 toxicity score).	Up to 2 years after completion of the RT
Late grade ≥ 2 gastrointestinal toxicity	Using patient-reported questionnaires (Radiation Therapy Oncology Group (RTOG) / European platform of cancer research (EORTC) toxicity questionnaires with grade 1 to 4).	Up to 2 years after completion of the RT

Collaborators and Investigators

• Sponsor: University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2025
• Primary Completion (Estimated): January 3, 2028
• Study Completion (Estimated): January 3, 2029

Study Registration Dates

• First Submitted: March 4, 2025
• First Submitted That Met QC Criteria: June 17, 2025
• First Posted (Actual): June 26, 2025

Study Record Updates

• Last Update Posted (Actual): June 26, 2025
• Last Update Submitted That Met QC Criteria: June 17, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Pathologic Processes; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Neoplastic Processes; Prostatic Neoplasms; Neoplasm Metastasis
• Other Study ID Numbers: NL87430.042.24

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