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Multigene Copy Number Alteration Risk Score Biomarker-Based Enrichment Study Designs in Metastatic Castrate-Resistant
Yeonjung Jo1,2, Jonathan J Chipman1,2, Benjamin Haaland3
1Division of Biostatistics, Department of Population Health Sciences, School of Medicine, University of Utah, Salt Lake City, UT.
JCO Precision Oncology
|December 3, 2024
Summary
A novel plasma multi-copy number alteration (multi-CNA) risk score can guide biomarker-based enrichment trials for metastatic castrate-resistant prostate cancer (mCRPC). Enriching 25% of screened patients with a risk score >1 offers an optimal, powered clinical trial design.
Area of Science:
- Oncology
- Genetics
- Clinical Trial Design
Background:
- Metastatic castrate-resistant prostate cancer (mCRPC) presents challenges for clinical trial design due to patient heterogeneity.
- Biomarker-based enrichment strategies are crucial for efficiently detecting treatment efficacy in specific patient subgroups.
Purpose of the Study:
- To evaluate a composite multigene risk score derived from tumor-biology alterations as a classifier for designing biomarker-based enrichment clinical trials in mCRPC.
- To determine the feasibility of using a plasma cell-free DNA (cfDNA) copy number alteration (CNA) risk score for patient stratification.
Main Methods:
- Simulated a plasma cfDNA CNA risk score based on alterations in 24 genes to develop a biomarker classifier for clinical trial design.
- Modeled enrichment strategies for high-risk mCRPC patients to detect a survival advantage (hazard ratio of 0.70 with 80% power).
- Analyzed trade-offs between screened and enrolled patients based on enrichment type and extent.
Main Results:
- Fully enriching patients with a high-risk score (≥3, 95th percentile) required screening up to 4,149 patients to enroll 259, compared to 689 for a non-enriched trial.
- A pragmatic approach enriching 25% of patients with a risk score ≥1 (67th percentile) required screening 658 patients to enroll 584.
- This pragmatic enrichment maximized the ability to detect treatment effect differences based on risk score.
Conclusions:
- A plasma multi-CNA risk score classifier can be effectively used to design enrichment trials in mCRPC.
- Enriching 25% of screened patients with a risk score >1 represents an optimal strategy for achieving an adequately powered, biomarker-based mCRPC clinical trial.
