Liquid Pulse: Reading HRR Deficiency in Plasma — What ctDNA Can and Can't Tell You in Prostate Cancer

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 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 plasma-based somatic assay is where liquid biopsy earns its place, and it's worth being precise about what it does.

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 simply 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, so a negative plasma finding in a patient with low ctDNA shedding often warrants reflex to tissue testing rather than being taken as definitive.

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. 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 characterized HRR genetic testing variables and diagnostic paths in prostate cancer, mapping the real-world concordance — and, importantly, the discordance — among germline, tumor-tissue, and ctDNA testing [2]. The value of such multi-institutional data is that it reflects the messiness clinicians actually 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.

Where it stands

The plasma HRR indication in mCRPC is validated and reimbursable, not merely investigational — a distinction worth stating plainly. FoundationOne Liquid CDx carries an FDA companion-diagnostic approval for this use [1][5], and payer coverage has followed. 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 genuinely 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.

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 Comprehensive 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