HRR Deficiency from a Blood Draw: What Plasma ctDNA Reveals

The clinical question

When a man's prostate cancer progresses to the metastatic castration-resistant stage (mCRPC), one of the sharpest questions we can ask is whether his tumor carries a defect in the homologous recombination repair (HRR) pathway. Genes in this pathway, BRCA2 most prominently, along with BRCA1, ATM, and a longer tail of others, encode the machinery cells use to fix double-strand DNA breaks accurately. When that machinery is broken, tumors become dependent on backup repair processes, and that dependency is exactly what PARP inhibitors exploit. So the practical question a clinician brings to the lab is straightforward: does this patient have a pathogenic HRR-gene alteration that would make him eligible for a PARP-inhibitor drug class, the alteration set (a 15-gene HRR panel, with BRCA2 the most actionable) on which olaparib eligibility in mCRPC was established [7]?

The complication is that HRR alterations come in two flavors that matter differently. Germline alterations are inherited and carry implications well beyond therapy, they inform cascade screening for relatives and prognosis. Somatic alterations arise in the tumor itself. A complete picture usually needs both a germline test (from blood leukocytes) and a somatic test (from tumor tissue or plasma); the PROfound companion-diagnostic program that established olaparib eligibility assayed somatic tumor status and did not itself resolve germline versus somatic origin [7]. The plasma-based somatic assay is where liquid biopsy earns its place, and precision about what it does matters.

What's measured, and how

The analyte is circulating tumor DNA (ctDNA), fragments of tumor-derived DNA shed into the bloodstream, isolated from a plasma draw. A next-generation sequencing (NGS) panel then interrogates HRR genes for pathogenic alterations, reporting a binary clinically actionable result: an HRR/BRCA alteration is present, or it's absent, with BRCA2 being the most actionable finding.

The FDA-approved instantiation of this approach is FoundationOne Liquid CDx, which the agency cleared in August 2020 as a plasma ctDNA NGS companion diagnostic covering BRCA1/2 and HRR alterations across multiple tumor types, including prostate cancer [1]. The label supports blood-only companion diagnostic testing to help identify mCRPC patients who may be candidates for the PARP-inhibitor class, olaparib and rucaparib among them, when tissue is unavailable or insufficient [1]. The assay remains commercially available with updated labeling as a plasma ctDNA CDx for somatic HRR detection in mCRPC [5].

Here's the honest caveat that governs everything downstream: a plasma assay can only detect what the tumor sheds. Sensitivity depends on the ctDNA fraction in a given sample, and that fraction varies enormously, with tumor burden, disease tempo, and metastatic site. A patient with low-volume or minimally shedding disease can produce a plasma sample in which a genuine tumor alteration isn't represented. That's why a plasma "absent" result is not the same as a tissue "absent" result. Concordance is strong when ctDNA is abundant and much weaker when it's scarce, in matched prostate plasma, tissue analysis, once the ctDNA fraction exceeds roughly 2% all tissue-identified mutations were recovered in plasma, with copy-number concordance of 88.9% (n=45), so a negative plasma finding in a patient with low ctDNA shedding often warrants reflex to tissue testing rather than being taken as definitive [8].

The other structural limitation: a somatic plasma NGS assay is not a germline test. It samples tumor-derived and, incidentally, blood-cell-derived DNA together, which can complicate interpretation, clonal hematopoiesis can produce ATM or other alterations that look somatic but originate in blood cells, not the tumor [9]. Distinguishing these requires care, and germline questions still belong to a dedicated germline sequencing pathway from leukocyte DNA.

The evidence

The clinical utility rests on demonstrating that a plasma HRR result can stand in for a tissue result closely enough to guide the same therapeutic decision. Recent peer-reviewed work has directly examined this. A 2025 multicenter cohort study (PMC12921449) reported real-world HRR genetic testing variables and diagnostic paths in prostate cancer, describing concordance, and, importantly, discordance, among germline, tumor-tissue, and ctDNA testing [2]. (This cohort is cited as reported; its performance figures are not independently vault-verified.) The value of such multi-institutional data is that it reflects the messiness clinicians encounter: samples that fail, results that disagree across compartments, and the judgment calls those disagreements force when selecting PARP-inhibitor therapy [2].

A companion review in Prostate Cancer and Prostatic Diseases (part one of two, published in early 2025) synthesizes the broader strategy for germline plus somatic HRD testing, including liquid-biopsy ctDNA [3]. Its practical contribution is sequencing logic, when to test, which compartment to start with, how to choose an assay, and how each result feeds PARP-inhibitor eligibility in mCRPC [3]. The recurring theme across both papers is that plasma and tissue are complementary rather than interchangeable; the evidence suggests the strongest workflows treat ctDNA as a rapid, accessible first pass that still needs a tissue fallback when it comes back negative or when ctDNA content is low.

Validated and reimbursable

The plasma HRR indication in mCRPC is validated and reimbursable, not investigational, a distinction that matters. FoundationOne Liquid CDx carries an FDA companion-diagnostic approval for this use [1][5]. That regulatory standing matters to the clinician because it is what reimbursement tracks: a Blue Cross Blue Shield of Michigan / Blue Care Network joint medical policy, effective March 2025, covers both germline sequencing and somatic NGS, explicitly including liquid biopsy, for BRCA1/2 and HRR alterations in prostate cancer, aligned with the FDA-approved CDx indications [4]. Carelon's somatic tumor testing guideline, effective November 2025 with a scheduled April 2026 update, likewise addresses NGS-based somatic testing including ctDNA for HRR alterations, setting appropriateness criteria that shape authorization for testing meant to guide PARP-inhibitor use [6].

What remains investigational is the use of ctDNA for minimal residual disease (MRD) or for HRR-status-guided treatment decisions outside the established mCRPC companion-diagnostic setting. Serial ctDNA monitoring to detect emerging resistance, or to time therapy in earlier disease states, is an active research area, not yet a validated basis for HRR-driven decisions, even though plasma assays for other prostate ctDNA analytes (such as the AR-V7 splice variant) are the most clinically mature liquid-biopsy readouts in this disease [10][11][12].

A final orienting note: none of this substitutes for clinical judgment, and none of it is treatment advice for any individual. A plasma HRR result gates eligibility for a drug class; it does not prescribe. Used with an understanding of its detection limits, and with a tissue backstop when plasma comes up empty, ctDNA HRR testing is one of the more mature liquid-biopsy applications we have in solid oncology.

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References

1. U.S. Food and Drug Administration. FDA Approves Liquid Biopsy Next-Generation Sequencing Companion Diagnostic Test (FoundationOne Liquid CDx). FDA Drug Approvals and Databases, FDA.gov; 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-liquid-biopsy-next-generation-sequencing-companion-diagnostic-test

2. Multiple authors (multicenter cohort). Homologous recombination repair genetic testing variables and diagnostic paths for prostate cancer patients: a multicenter cohort study. PMC / PubMed Central, PMC12921449; 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC12921449

3. Multiple authors (review article). Germline and somatic testing for homologous repair deficiency in patients with prostate cancer (part 1 of 2). Prostate Cancer and Prostatic Diseases, Nature Publishing Group; 2025. https://www.nature.com/articles/s41391-024-00901-4

4. Blue Cross Blue Shield of Michigan / Blue Care Network. Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Prostate Cancer (BRCA1/2, Homologous Recombination Repair Gene Alterations, NTRK Gene Fusion). BCBSM Medical Policy, effective 3/1/2025; 2025. https://www.bcbsm.com/amslibs/content/dam/public/mpr/mprsearch/pdf/2183047.pdf

5. Foundation Medicine, Inc. FoundationOne Liquid CDx, Companion Diagnostic and Complete Genomic Profiling. Foundation Medicine Product Page, foundationmedicine.com; 2024. https://www.foundationmedicine.com/test/foundationone-liquid-cdx

6. Carelon Medical Benefits Management. Somatic Tumor Testing 2025-11-15 updated 2026-04-01 (Doc ID: GEN02-1125.3-UC0426). Carelon Medical Benefits Management Clinical Appropriateness Guidelines; 2026. https://guidelines.carelonmedicalbenefitsmanagement.com/somatic-tumor-testing-2025-11-15-updated-2026-04-01

7. de Bono J, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer (PROfound). N Engl J Med; 2020. PMID 32343890.

8. Wyatt AW, et al. Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer. J Natl Cancer Inst; 2017. PMID 29206995.

9. National Complete Cancer Network. NCCN Clinical Practice Guidelines in Oncology, diagnostic/biomarker notes (cfDNA/clonal-hematopoiesis interpretation). NCCN; accessed 2026.

10. Antonarakis ES, et al. AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer. N Engl J Med; 2014. PMID 25184630.

11. Scher HI, et al. Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer. JAMA Oncol; 2016. PMID 27262168.

12. Armstrong AJ, et al. Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer (PROPHECY). J Clin Oncol; 2019. PMID 30865549.