Treatment of High-Risk Prostate Cancer Guided by Novel Diagnostic Radio- and Molecular Tracers (THUNDER): A Two-part Phase 2/ 3 Trial
Overview
- Phase
- Phase 2
- Intervention
- Darolutamide
- Conditions
- Prostate Cancer
- Sponsor
- Cancer Research Antwerp
- Enrollment
- 493
- Locations
- 9
- Primary Endpoint
- Phase 3: PSMA PET metastasis free survival (ppMFS)
- Status
- Recruiting
- Last Updated
- last month
Overview
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.
Detailed Description
Approximately 360 evaluable patients determined to have high-risk localized or locally advanced PCa, with PSMA positive non-localized disease or a Decipher high score (\> 0.6) will be enrolled to the Phase 3 trial. Subjects with PSMA positive non-localized disease for which a Decipher result cannot be obtained, will also be enrolled to the Phase 3 study. All Phase 3 subjects will be randomly assigned in a 1:1 ratio to receive darolutamide plus Luteinizing hormone releasing hormone (ant)-agonists (LHRHA), or darolutamide matched placebo plus LHRHA, for up to 96 weeks (24 months). All Phase 3 subjects will also receive primary standard of care (SOC) radiation therapy (RT). Subjects in Phase 3 should be commenced on an LHRHA and darolutamide or placebo within 14 days after randomization (unless started earlier) plus SOC RT. Only patients with a PSMA PET-CT showing more than 5 M1 lesions are allowed to receive docetaxel in both arms of the Phase 3 trial. Docetaxel should be started within 4 weeks from randomization. Randomization of Phase 3 subjects will be stratified by 1 versus \> 1 high-risk features, N1 versus M1 PSMA positive versus PSMA negative disease, Decipher low/ intermediate versus high versus unknown score and clinical trial site. Approximately 133 evaluable patients determined to have localized PCa by PSMA PET/ CT (PSMA negative) with a low/ intermediate Decipher test score (≤ 0.85) will enter the non-randomized, Phase 2, single treatment arm, de-intensification study. Subjects with localized PCa by PSMA PET/ CT who return a high Decipher score (\> 0.85) will be enrolled and randomized into the Phase 3 study. Subjects with localized PCa by PSMA PET/ CT for which a Decipher result cannot be obtained, will be deemed ineligible for study participation. All Phase 2 study subjects will receive darolutamide for the study duration for up to 96 weeks (24 months) and primary SOC RT.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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 cN
- •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
- •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
- •Pending confirmation of their Decipher score, subjects who are PSMA PET/ CTnegative for regional or distant lesions at screening (PSMA PET scans will be assessed as described in the study imaging manual), will be eligible for inclusion in either the Phase 3 study (if a high \[\> 0.85\] Decipher score is confirmed) or the non-randomized Phase 2 study (if a low/ intermediate \[≤ 0.85\] Decipher score is confirmed).
- •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.
Exclusion Criteria
- •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
Arms & Interventions
Phase 2 Open Label
Darolutamide for up to 96 weeks (24 months) and primary SOC RT
Intervention: Darolutamide
Phase 2 Open Label
Darolutamide for up to 96 weeks (24 months) and primary SOC RT
Intervention: Radiotherapy
Phase 3 Blinded Experimental
Darolutamide + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Darolutamide
Phase 3 Blinded Experimental
Darolutamide + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Radiotherapy
Phase 3 Blinded Experimental
Darolutamide + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Zoladex 3.6Mg Implant
Phase 3 Blinded Experimental
Darolutamide + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Zoladex LA
Phase 3 Blinded Experimental
Darolutamide + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Decapeptyl sustained release 22.5 mg
Phase 3 Blinded Experimental
Darolutamide + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Decapeptyl sustained release 11.25 mg
Phase 3 Blinded Experimental
Darolutamide + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Depo-Eligard 45 mg
Phase 3 Blinded Experimental
Darolutamide + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Depo-Eligard 22.5 mg
Phase 3 Blinded Experimental
Darolutamide + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Depo-Eligard 7.5 mg
Phase 3 Blinded Experimental
Darolutamide + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Firmagon 120 MG Injection
Phase 3 Blinded Experimental
Darolutamide + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Firmagon 80 MG Injection
Phase 3 Blinded Experimental
Darolutamide + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Docetaxel
Phase 3 Blinded Comparator
Darolutamide matched placebo + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Darolutamide matched placebo
Phase 3 Blinded Comparator
Darolutamide matched placebo + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Radiotherapy
Phase 3 Blinded Comparator
Darolutamide matched placebo + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Zoladex 3.6Mg Implant
Phase 3 Blinded Comparator
Darolutamide matched placebo + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Zoladex LA
Phase 3 Blinded Comparator
Darolutamide matched placebo + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Decapeptyl sustained release 22.5 mg
Phase 3 Blinded Comparator
Darolutamide matched placebo + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Decapeptyl sustained release 11.25 mg
Phase 3 Blinded Comparator
Darolutamide matched placebo + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Depo-Eligard 45 mg
Phase 3 Blinded Comparator
Darolutamide matched placebo + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Depo-Eligard 22.5 mg
Phase 3 Blinded Comparator
Darolutamide matched placebo + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Depo-Eligard 7.5 mg
Phase 3 Blinded Comparator
Darolutamide matched placebo + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Firmagon 120 MG Injection
Phase 3 Blinded Comparator
Darolutamide matched placebo + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Firmagon 80 MG Injection
Phase 3 Blinded Comparator
Darolutamide matched placebo + LHRHA for up to 96 weeks (24 months) and primary SOC RT
Intervention: Docetaxel
Outcomes
Primary Outcomes
Phase 3: PSMA PET metastasis free survival (ppMFS)
Time Frame: 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
Improvement in PSMA PET metastasis free survival (ppMFS)
Phase 2: quality of life (sexual subdomain)
Time Frame: At 12 months
EPIC mean changes in sexual subdomain scores over time will be compared, both for change from baseline and absolute scores
Phase 2: quality of life (hormonal subdomain)
Time Frame: At 12 months
EPIC mean changes in hormonal subdomain scores over time will be compared, both for change from baseline and absolute scores
Secondary Outcomes
- 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)
- Frequency and severity of adverse events(From signing ICF until 30 days after the last dose of study treatment.)
- 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)