Treatment of High-Risk Prostate Cancer Guided by Novel Diagnostic Radio- and Molecular Tracers

NCT06282588 | Recruiting Phase 2 DMC

• 1 other identifier: CTO21042GZA
• Study Type: interventional
• Target: 493
• Locations: 1 country
• Sites: 9

Brief Summary

This Investigator-initiated, Treatment of High-Risk Prostate Cancer Guided by Novel Diagnostic Radio- and Molecular Tracers (THUNDER) study will be conducted in subjects with high-risk localized or locally advanced prostate cancer (PCa). The study contains both a randomized Phase 3 treatment intensification study, as well as a treatment de-intensification non-randomized Phase 2 study. The aim of the THUNDER study is to improve the outcome of high-risk PCa by improved risk stratification. Novel radiotracers and a genomic classifier (Decipher) will be used to guide treatment decisions, instead of standard imaging which is limited by lower sensitivity and specificity. The hypothesis for the study is that treatment intensification based on a positive PSMA PET/ CT scan or Decipher high score (\> 0.85) improves time to new metastases detected on PSMA PET/ CT in high-risk PCa. In patients who are PSMA PET/ CT negative with a low/ intermediate Decipher score (≤ 0.85), it is hypothesized that treatment de-intensification will improve patient quality of life while maintaining a good oncological outcome. The study will be conducted at multiple centers across Europe. Participation in the study will comprise a screening period, where the screening assessments must be completed before subjects are enrolled and randomized (only for Phase 3 subjects). Eligible, consenting subjects will then undergo treatment according to their assigned study phase and treatment group, to occur over up to 96 weeks (24 months) with a post-treatment follow-up period to monitor safety and efficacy. The study will be closed when 96 events have been registered for the primary endpoint, which is expected to be at 7-8 years from the time of randomization of the first subject.

Conditions

Prostate Cancer

Keywords

High-risk; PSMA PET/CT scan; Decipher

Outcome Measures

Primary Outcomes (3)

• Phase 3: PSMA PET metastasis free survival (ppMFS)

  Improvement in PSMA PET metastasis free survival (ppMFS)

  Time from randomization to the date of at least 1 new PSMA-PET positive distant lesion as compared to baseline or date of death from any cause, assessed up to 42 months

• Phase 2: quality of life (sexual subdomain)

  EPIC mean changes in sexual subdomain scores over time will be compared, both for change from baseline and absolute scores

  At 12 months

• Phase 2: quality of life (hormonal subdomain)

  EPIC mean changes in hormonal subdomain scores over time will be compared, both for change from baseline and absolute scores

  At 12 months

Secondary Outcomes (5)

• Overall survival

  Time interval between randomization and time of death, assessed up to 42 months

• Prostate-cancer specific survival

  Time interval between randomization and prostate cancer death, assessed up to 42 months

• Biochemical progression-free survival

  Measured from the date of randomization to the date event, or death or censored at the last known follow-up date, assessed up to 42 months

• Time to next systemic therapy

  Measured from date of randomization to time of death, or censored at the last known follow-up date, assessed up to 42 months

• Frequency and severity of adverse events

  From signing ICF until 30 days after the last dose of study treatment.

Study Arms (3)

Phase 2 Open Label

EXPERIMENTAL

Darolutamide for up to 96 weeks (24 months) and primary SOC RT

Drug: Darolutamide; Radiation: Radiotherapy

Phase 3 Blinded Experimental

EXPERIMENTAL

Darolutamide + LHRHA for up to 96 weeks (24 months) and primary SOC RT

Drug: Darolutamide; Radiation: Radiotherapy; Drug: Zoladex 3.6Mg Implant; Drug: Zoladex LA; Drug: Decapeptyl sustained release 22.5 mg; Drug: Decapeptyl sustained release 11.25 mg; Drug: Depo-Eligard 45 mg; Drug: Depo-Eligard 22.5 mg; Drug: Depo-Eligard 7.5 mg; Drug: Firmagon 120 MG Injection; Drug: Firmagon 80 MG Injection; Drug: Docetaxel

Phase 3 Blinded Comparator

PLACEBO COMPARATOR

Darolutamide matched placebo + LHRHA for up to 96 weeks (24 months) and primary SOC RT

Drug: Darolutamide matched placebo; Radiation: Radiotherapy; Drug: Zoladex 3.6Mg Implant; Drug: Zoladex LA; Drug: Decapeptyl sustained release 22.5 mg; Drug: Decapeptyl sustained release 11.25 mg; Drug: Depo-Eligard 45 mg; Drug: Depo-Eligard 22.5 mg; Drug: Depo-Eligard 7.5 mg; Drug: Firmagon 120 MG Injection; Drug: Firmagon 80 MG Injection; Drug: Docetaxel

Interventions

Radiotherapy RADIATION

Preferred regimens: 60 to 62 Gy delivered in 20 fractions of 3.0 to 3.1Gy per fraction; 36.25 Gy delivered in 5 fractions of 7.25 Gy per fraction, 2-3 fractions per week

Phase 2 Open Label; Phase 3 Blinded Comparator; Phase 3 Blinded Experimental

Zoladex 3.6Mg Implant DRUG

3.6 mg, subcutaneous use

Also known as: Goserelin acetate 3.6 mg

Phase 3 Blinded Comparator; Phase 3 Blinded Experimental

Zoladex LA DRUG

10.8 mg, subcutaneous use

Also known as: Goserelin acetate 10.8 mg

Phase 3 Blinded Comparator; Phase 3 Blinded Experimental

Decapeptyl sustained release 22.5 mg DRUG

22.5 mg, intramusculair injection

Also known as: Triptorelin 11.25 mg

Phase 3 Blinded Comparator; Phase 3 Blinded Experimental

Decapeptyl sustained release 11.25 mg DRUG

11.25 mg, intramusculair injection

Also known as: Triptorelin 11.25 mg

Phase 3 Blinded Comparator; Phase 3 Blinded Experimental

Depo-Eligard 45 mg DRUG

45 mg, subcutaneous use

Also known as: Leuprorelin acetate 45 mg

Phase 3 Blinded Comparator; Phase 3 Blinded Experimental

Depo-Eligard 22.5 mg DRUG

22.5 mg, subcutaneous use

Also known as: Leuprorelin acetate 22.5 mg

Phase 3 Blinded Comparator; Phase 3 Blinded Experimental

Depo-Eligard 7.5 mg DRUG

7.5 mg, subcutaneous use

Also known as: Leuprorelin acetate 7.5 mg

Phase 3 Blinded Comparator; Phase 3 Blinded Experimental

Firmagon 120 MG Injection DRUG

120 mg, subcutaneous use

Also known as: Degarelix 40 mg

Phase 3 Blinded Comparator; Phase 3 Blinded Experimental

Firmagon 80 MG Injection DRUG

80 mg, subcutaneous use

Also known as: Degarelix 20 mg

Phase 3 Blinded Comparator; Phase 3 Blinded Experimental

Docetaxel DRUG

75 mg per square m, IV infusion

Also known as: Taxotere

Phase 3 Blinded Comparator; Phase 3 Blinded Experimental

Darolutamide DRUG

2x300 mg tablets twice daily, for up to 96 weeks

Also known as: Nubeqa, BAY1841788

Phase 2 Open Label; Phase 3 Blinded Experimental

Darolutamide matched placebo DRUG

2x300 mg tablets twice daily, for up to 96 weeks

Also known as: BAY1841788 matched placebo

Phase 3 Blinded Comparator

Eligibility Criteria

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

You may qualify if:

• Histopathology-proven PCa
• High-risk locally advanced disease is defined as any of the following factors: PSA \> 20 ng/mL OR T-stage 3 or 4 OR Gleason score 8-10 OR cN1.
• Note: documentation of the clinical T-stage may be obtained from any clinical assessment acceptable for clinical T staging including physical exam (DRE), transrectal ultrasound, CT or MRI. Documentation for the N1 stage can be defined on CT or MRI.
• An Eastern Cooperative Oncology Group (ECOG) Performance Status grade of 0 or 1.
• Willingness to undergo a PSMA PET/ CT with or without contrast.
• Subjects who are PSMA PET/ CT positive for at least one regional or distant (extra-pelvic) lesion at screening (PSMA PET scans will be assessed as described in the study imaging manual), will be eligible to be randomized to either arm of the Phase 3 study. A lesion is considered positive if it has a E-PMSA score of 4 or 5.
• Willingness to have their primary tumor sequenced for determination of Decipher score
• Subjects who have a negative PSMA PET/ CT and a tumor with a low/ intermediate Decipher score (≤ 0.85) will be eligible to enter the non-randomized Phase 2 study.
• Subjects who have a negative PSMA PET/ CT and a tumor with a high Decipher score (\> 0.85) will be eligible to be randomized to either arm of the Phase 3 study.
• In subjects with positive PSMA PET/ CT, the Decipher score will not determine the treatment allocation.
• Willingness to undergo SOC RT and long-term ADT (treatment with darolutamide and/ or LHRHA)
• Subject is able and willing to provide written informed consent, which includes compliance with and ability to undergo all study procedures and attend the scheduled follow-up visit/s per protocol.
• Subject must be over 18 years of age.
• Subject able to swallow whole study drug tablets.
• To avoid risk of drug exposure through the ejaculate (even men with vasectomies), subjects must use a condom during sexual activity while on study drug and for 3 months after the last administration of study treatment. Donation of sperm is not allowed during the treatment phase and for 3 months after the last administration of study treatment.

You may not qualify if:

• Definitive radiologic evidence of metastatic disease outside of the pelvic nodes (M1a, M1b or M1c) on conventional imaging (i.e., bone scan, CT scan, MRI)
• PCa with predominant non-adenocarcinoma features (sarcomatoid or spindle or neuroendocrine small cell or squamous cell components or other non-adenocarcinoma)
• Prior pelvic radiotherapy
• Contraindications for pelvic radiotherapy
• Contraindications for ADT (treatment with darolutamide and/ or LHRHA)
• Contraindications or known allergy to PSMA PET/ CT tracers.
• Prior local therapy for PCa (e.g., radical prostatectomy, high-intensity focused ultrasound \[HIFU\], cryotherapy). Subjects with previous transurethral resection of the prostate (TURP) or Millin prostatectomy are eligible for participation
• Prior systemic therapy for PCa, except for patients with a positive PSMA PET/ CT staging with ADT started no more than 4 weeks prior to randomization.
• Current use of 5-alpha reductase inhibitor Note: if the alpha reductase inhibitor is stopped ≥ 2 weeks prior to enrollment, the subject is eligible.
• Current chronic use of opioid analgesics, for ≥3 weeks for oral or ≥7 days for non-oral formulations
• History of seizure or any condition that may predispose to seizure (including, but not limited to prior stroke, transient ischemic attack or loss of consciousness within ≤1 year prior to enrollment; brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect)
• Any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the subject
• Major surgery within 21 days prior to enrollment.
• History of:
• Loss of consciousness or transient ischemic attack or stroke within 6 months prior to enrollment, or

Sponsors & Collaborators

• Bayer: collaborator
• Veracyte, Inc.: collaborator
• Cancer Research Antwerp: lead

Study Sites (9)

ZAS Sint-Augustinus

Wilrijk, Antwerp, 2610, Belgium

RECRUITING

AZORG

Aalst, 9300, Belgium

RECRUITING

AZ Sint-Jan

Bruges, 8000, Belgium

RECRUITING

Saint Luc

Brussels, 1200, Belgium

RECRUITING

UZ Gent

Ghent, 9000, Belgium

RECRUITING

AZ Groeninge

Kortrijk, 8500, Belgium

RECRUITING

CHU Liège

Liège, 4000, Belgium

RECRUITING

AZ Delta

Roeselare, 8800, Belgium

RECRUITING

VITAZ

Sint-Niklaas, 9100, Belgium

RECRUITING

Related Publications (1)

• Kleiburg F, Dirix P, Fonteyne V, Bral S, De Troyer B, Sautois B, Lamande M, Liefhooghe N, Grisay G, Meersschout S, Vandermeulen A, Jullian N, Staelens L, Poelaert F, Strijbos M, Verschueren J, Goffin K, Withofs N, Ost P. Stage Migration on Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography in Comparison to Conventional Imaging in Patients with High-risk Prostate Cancer Referred for Radiation Therapy: Results from the Phase 2/3 THUNDER Trial. Eur Urol Oncol. 2025 Oct;8(5):1333-1339. doi: 10.1016/j.euo.2025.08.005. Epub 2025 Sep 25.

  PMID: 40998687 DERIVED

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

darolutamide; Radiotherapy; Goserelin; Drug Implants; Triptorelin Pamoate; Leuprolide; acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; Injections; Docetaxel

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; Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Delayed-Action Preparations; Dosage Forms; Pharmaceutical Preparations; Drug Administration Routes; Drug Therapy; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Piet Ost, MD,PhD

  Gasthuis Zusters Antwerpen

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Piet Ost, MD, PhD

CONTACT

003234433759; cancertrials@zas.be

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Phase 3 trial: blinded Phase 2 trial: open label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase 2: non randomised, 1 treatment arm, open label Phase 3: randomized 1:1 between two treatment arms, blinded

Study Record Dates

• First Submitted: January 19, 2024
• First Posted: February 28, 2024
• Study Start: December 13, 2023
• Primary Completion (Estimated): July 31, 2030
• Study Completion (Estimated): December 31, 2030
• Last Updated: March 19, 2026

Record last verified: 2026-03

Locations

BE (9)