In prostate cancer, is homologous recombination deficiency (HRD) testing preferred over simply labeling a tumor as homologous recombination repair (HRR) for guiding therapy?

HRR Gene Testing is Preferred Over HRD Testing in Prostate Cancer

In prostate cancer, testing for specific homologous recombination repair (HRR) gene mutations is the current standard and preferred approach over broader HRD phenotypic testing for guiding PARP inhibitor therapy. This is what current FDA approvals and major guidelines support, though the landscape is evolving.

Current Clinical Standard: HRR Gene Mutation Testing

The 2025 ASCO guideline explicitly recommends testing for specific HRR gene alterations (BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2, CDK12) in patients with metastatic castration-resistant prostate cancer (mCRPC) 11. The 2025 NCCN guidelines similarly recommend germline and tumor testing for mutations in these HRR genes 2.

Why HRR Gene Testing is Currently Preferred:

• FDA approval basis: Both olaparib and rucaparib are FDA-approved based on the presence of deleterious alterations in specific HRR genes, not HRD scores 34
• Strongest evidence for BRCA1/2: The PROfound trial demonstrated that patients with BRCA1/2 or ATM mutations (Cohort A) had significantly improved outcomes with olaparib (PFS HR 0.34, OS HR 0.69), while the broader panel of 12 other HRR genes (Cohort B) showed less consistent benefit 31
• Clinical validity established: HRR gene mutation testing has proven clinical utility with clear therapeutic implications 4

The HRD Testing Controversy

While HRD testing shows promise, it faces significant limitations in prostate cancer:

Evidence Supporting HRD Testing:

Recent research suggests HRD phenotypic testing may identify additional responders beyond those with HRR mutations:

• HRD scores (using genomic instability measures) were positive in only 19.2% of HRR-mutated tumors but also in 5.2% of HRR wild-type tumors 5
• A mutational signature-based approach (SigMA) showed better prediction of olaparib response than the current FDA label (PPV 77% vs 47%) 6
• HRD can arise through mechanisms beyond detectable HRR gene mutations, including epigenetic silencing and undefined pathways 777

Critical Limitations of HRD Testing:

The ESMO guidelines explicitly state that current HRD tests "lack negative predictive value and inadequately address the complex and dynamic nature of the HRD phenotype" 77. Key problems include:

• No standardization: Multiple HRD testing methodologies exist (genomic scars, mutational signatures, functional assays) with no consensus on which is optimal 777
• Dynamic phenotype: HRD status can change over time through reversion mutations that restore homologous recombination proficiency 77
• Lack of regulatory approval: No HRD test is currently FDA-approved for guiding PARP inhibitor use in prostate cancer
• Limited validation: Most HRD testing validation comes from ovarian cancer, not prostate cancer 777

Practical Clinical Algorithm

For patients with mCRPC being considered for PARP inhibitor therapy:

1. First-line testing: Order comprehensive HRR gene panel testing (minimum: BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2, CDK12) on tumor tissue 112

2. Germline testing: Simultaneously perform germline testing for these genes, as approximately 10-15% of prostate cancers harbor germline HRR mutations 42

3. Prioritize BRCA1/2 alterations: Patients with BRCA1/2 mutations, especially with biallelic inactivation (two-copy loss), have the strongest evidence for PARP inhibitor benefit 315

4. Consider ATM carefully: ATM mutations show intermediate benefit—less robust than BRCA1/2 but still included in FDA approvals 3

5. Other HRR genes: CDK12, CHEK2, and other HRR gene alterations have weaker evidence; consider clinical trial enrollment or alternative therapies 3

6. HRD testing as investigational: If HRR gene testing is negative but clinical suspicion for HRD remains high (platinum-sensitive disease, aggressive features), consider HRD testing in a research or clinical trial context 68

Common Pitfalls to Avoid

• Don't assume all HRR mutations predict equal benefit: BRCA2 two-copy loss shows the highest HRD scores and best PARP inhibitor responses 56
• Don't skip germline testing: This has implications for family members and cascade testing 32
• Don't use tissue age >5 years: Older samples have higher failure rates 9
• Don't forget about tumor heterogeneity: Metastatic sites may have different mutation profiles; consider liquid biopsy (ctDNA) if tissue is inadequate 1011

Future Direction

The field is moving toward integrating both approaches. Emerging evidence suggests that combining HRR gene mutation status with HRD phenotypic markers (mutational signatures, genomic instability scores, fragmentomics) may provide superior patient selection 6108. However, until these multimodal approaches are validated in prospective trials and gain regulatory approval, HRR gene mutation testing remains the standard of care.

Bottom line: Test for specific HRR gene mutations now, as this is what guidelines recommend and what FDA approvals are based on. Consider HRD testing as complementary or investigational, particularly in research settings, but do not rely on it alone for treatment decisions 114.