What additional next‑generation sequencing (NGS) testing should be performed in patients with prostate cancer?

NGS Testing in Prostate Cancer Patients

All patients with metastatic prostate cancer should undergo BOTH germline genetic testing AND somatic tumor testing using next-generation sequencing panel-based assays. 1111

Who Should Be Tested

Germline Testing (Strong Recommendation)

• All patients with metastatic prostate cancer should receive germline genetic testing with NGS technologies, regardless of disease stage (castration-sensitive or castration-resistant) 111
• This applies even if the patient has no family history of cancer, as approximately 13% of men with prostate cancer harbor germline pathogenic variants 2
• Testing is critical for:
  • Identifying hereditary cancer risk for the patient and family members
  • Enabling cascade testing in relatives
  • Guiding treatment decisions with PARP inhibitors

Somatic Testing (Strong Recommendation)

• All patients with metastatic prostate cancer being considered for biomarker-directed systemic treatment should undergo somatic NGS testing 111
• This includes both metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC)
• While no FDA-approved biomarker-directed treatments currently exist for mCSPC, somatic testing is warranted when:
  • High-volume disease is present
  • High likelihood of progression to CRPC exists
  • Patient is a candidate for future PARP inhibitor or checkpoint inhibitor therapy 1

What Genes to Test

High-Priority Genes

The panel should include homologous recombination repair (HRR) genes:

• BRCA1 and BRCA2 (most critical - predict PARP inhibitor response)
• ATM
• PALB2
• FANCA
• RAD51D
• CHEK2
• CDK12 3

Additional Testing

• MSI/MMR testing (microsatellite instability/mismatch repair) - if MSI-high or dMMR found, refer for genetic counseling to assess Lynch syndrome 3
• Tumor mutational burden (TMB) - to inform possible pembrolizumab use in later lines 3

When to Test

Initial Testing

• At diagnosis of metastatic disease for both germline and somatic testing 11

Sequential/Repeat Testing (Weak Recommendation)

Sequential somatic testing should be offered when:

• Meaningful change in patient status or treatment plan occurs
• Prior tests were negative or uninformative (insufficient or low tumor content)
• Disease progresses after first-line hormonal therapy 14

The evidence for optimal timing of repeat testing is limited, but the panel recommends considering retesting when clinical circumstances change significantly 1

What Specimen Type to Use

For Initial Somatic Testing

Archival tissue samples are preferred 11

For Sequential Testing or When Archival Tissue Unavailable

The choice depends on clinical context:

• Circulating tumor DNA (ctDNA/liquid biopsy) is preferred when:

  • No accessible metastatic site exists for biopsy
  • Sequential testing is needed
  • Feasibility studies show 100% success rate vs. 88% for tissue 5

• Metastatic biopsy is preferred when:

  • Minimal disease burden with low ctDNA fraction exists
  • Prior liquid biopsy was unsuccessful 11

Important caveat: Combined testing (both tissue and liquid biopsy) yields higher detection rates - 20% vs. 9% for BRCA1/2 alterations in one real-world study 5. Ideally, BRCA1/2 testing should utilize both approaches to identify all eligible patients for PARP inhibitor therapy.

Clinical Utility of Testing Results

Therapeutic Implications (Strong Recommendation)

Patients with pathogenic BRCA1/2 variants (germline or somatic) are candidates for:

• PARP inhibitor monotherapy (olaparib, talazoparib, niraparib, rucaparib)
• PARP inhibitor + androgen receptor pathway inhibitor (ARPI) combination therapy
• Platinum-based chemotherapy 111

These patients demonstrate poorer outcomes but have survival benefit with PARP inhibitors, particularly in mCRPC (demonstrated in the PROFOUND trial with overall survival benefit) 1

Prognostic-Only Biomarkers (Strong Recommendation)

Treatment recommendations should NOT be made based on prognostic-only biomarkers 11

• However, they may direct patients to clinical trials
• Germline information remains important for patient counseling and informing hereditary risk for families

Common Pitfalls to Avoid

1. Don't skip germline testing in patients without family history - 13% of prostate cancer patients have germline variants regardless of family history 2

2. Don't rely solely on founder variant testing - One-third of disease-causing variants identified through NGS are unique rather than founder variants 2

3. Don't use small gene panels - Comprehensive panels detect druggable mutations in approximately one-third of mCRPC patients; limited 18-gene panels miss important actionable variants 4

4. Don't delay testing until late-stage disease - Testing should occur at metastatic diagnosis, not just at castration resistance 11

5. Don't assume tissue biopsy alone is sufficient - Combined tissue and liquid biopsy approaches increase detection rates significantly 5

6. Ensure adequate tumor content - Approximately 4% of tissue samples have insufficient DNA for NGS analysis 4