Treatment of High-Risk Prostate Cancer Guided by Novel Diagnostic Radio- and Molecular Tracers
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.
official title
Treatment of High-Risk Prostate Cancer Guided by Novel Diagnostic Radio- and Molecular Tracers (THUNDER): A Two-part Phase 2/ 3 Trial