Can circulating tumor DNA (ctDNA) tests be used for diagnosing or monitoring metastatic castration-resistant prostate cancer (mCRPC)?

Can ctDNA Testing Be Used for mCRPC?

Yes, circulating tumor DNA (ctDNA) testing can and should be used for metastatic castration-resistant prostate cancer (mCRPC), specifically for somatic genomic profiling to guide biomarker-directed therapies, though it has important limitations for monitoring that preclude routine use for treatment response assessment. 1

When to Use ctDNA Testing in mCRPC

Initial Somatic Testing

• All mCRPC patients being considered for biomarker-directed systemic treatment should undergo somatic testing with next-generation sequencing technologies. 1
• ctDNA is the preferred specimen when there is no accessible metastatic site to biopsy or for sequential testing. 1
• However, archival tissue samples are preferred for initial testing, and in settings of minimal disease burden with low ctDNA fraction, metastatic biopsy is preferred over ctDNA. 1

Sequential Testing

• Sequential somatic testing may be offered when there has been a meaningful change in the patient's status or treatment plan, especially when prior tests were negative or uninformative (e.g., insufficient or low tumor content). 1
• ctDNA is preferred for this sequential testing scenario. 1

Clinical Utility: What ctDNA Can Identify

Actionable Therapeutic Targets

• ctDNA testing identifies mutations in homologous recombination repair (HRR) genes including BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2, and CDK12 that predict response to PARP inhibitors. 1
• Patients with pathogenic somatic alterations in BRCA1 and BRCA2 are candidates for PARP inhibitor monotherapy, PARP inhibitor with androgen receptor pathway inhibitor combination therapy, and platinum-based agents. 1
• ctDNA can detect microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status, which predicts response to pembrolizumab. 1
• Tumor mutation burden (TMB) testing via ctDNA can inform possible use of pembrolizumab in later lines of therapy. 1

Prognostic Information

• ctDNA fraction strongly predicts overall survival and progression-free survival independent of therapeutic context and outperforms established clinical prognostic factors. 2
• ctDNA-positive patients (59% in one phase 3 trial) have significantly worse median overall survival than ctDNA-negative patients (29.0 months vs. 47.4 months). 3
• Higher ctDNA levels correlate with serum and radiographic metrics of disease burden and are highest in patients with liver metastases. 2

Critical Limitations and Pitfalls

Not for Routine Treatment Monitoring

• There are insufficient data to recommend routine use of ctDNA to monitor response to therapy among patients with mCRPC. 1
• Neither measurement of dynamic changes in ctDNA as a marker of treatment responsiveness nor identification of specific mutations to direct therapy has been prospectively shown to improve patient outcomes over standard imaging-based detection of tumor progression. 1

False Negatives from Low Tumor Content

• Low ctDNA fraction is a major limitation, particularly after androgen deprivation therapy (ADT), which rapidly reduces ctDNA availability (median 11% before treatment vs. 1.0% after short-term ADT). 4
• In settings of minimal disease burden with low ctDNA fraction, metastatic biopsy is preferred over ctDNA. 1
• Approximately 41% of mCRPC patients may be ctDNA-negative, limiting the utility of liquid biopsy in these cases. 3

Technical Considerations

• Assays must correct for clonal hematopoiesis of indeterminate potential (CHIP) and germline variants to avoid false positives. 5
• Optimal assay design requires adequate plasma volume and appropriate sequencing depth. 5

Complementary Role with Tissue Testing

• Combined ctDNA and tissue analysis identifies potential driver alterations in 94% of patients, whereas ctDNA or prostate biopsy alone is insufficient in 36% of cases. 4
• The optimal approach for biomarker development should utilize both tissue and liquid biopsy at diagnosis, as neither captures clinically relevant somatic alterations in all patients. 4
• Concordance for mutation detection between matched ctDNA and tissue samples is approximately 80%. 4

Practical Algorithm for ctDNA Use in mCRPC

1. At mCRPC diagnosis: Obtain metastatic lesion biopsy for somatic testing if accessible; if not accessible, use ctDNA. 1

2. If initial tissue testing was negative or uninformative: Consider ctDNA testing, recognizing that combined approaches detect alterations in more patients. 1, 4

3. At disease progression or treatment change: Consider sequential ctDNA testing, particularly when metastatic biopsy is not feasible. 1

4. If ctDNA fraction is low (<5-10%): Consider metastatic biopsy instead, as low ctDNA may yield false-negative results. 1, 2

5. Do NOT use ctDNA for routine treatment response monitoring: Continue standard PSA monitoring every 3-6 months and conventional imaging every 6-12 months. 1