A panel‐based mutational signature of homologous recombination deficiency associates with response to PARP inhibition in metastatic castration‐resistant prostate cancer
Abstract
Background: The PARP inhibitor (PARPi) olaparib is approved for homologous recombination repair (HRR) gene‐altered metastatic castration‐resistant prostate cancer (mCRPC). However, there is significant heterogeneity in response to PARPi in patients with mCRPC. Better clinical biomarkers are needed to identify patients likely to benefit from PARPi. Methods: Patients with prostate adenocarcinoma and panel sequencing at Dana‐Farber Cancer Institute were identified. Mutational signature analysis was performed using SigMA to characterize tumors as HRR deficient (HRD). The validity of SigMA to identify patients likely to benefit from olaparib was compared to the current FDA label (presence of a deleterious alteration in one of 14 HRR genes). Results: 546 patients were identified, of which 34% were HRD. Among patients with HRR gene alterations, only patients with BRCA2 two‐copy loss (2CL) were more likely to be HRD compared to patients without HRR gene alterations (74% vs 31%; P = 9.1 × 10‐7). 28 patients with mCRPC received olaparib, of which 13 were HRD and 9 had BRCA2 2CL. SigMA improved upon the current FDA label for predicting PSA50 (sensitivity: 100% vs 90%; specificity: 83% vs 44%; PPV: 77% vs 47%; NPV: 100% vs 89%) and rPFS > 6 months (sensitivity: both 92%; specificity: 93% vs 53%; PPV: 92% vs 63%; NPV: 93% vs 89%). On multivariate analysis, incorporating prognostic clinical factors and HR gene alterations, SigMA‐predicted HRD independently associated with improved PSA‐PFS (HR = 0.086, p = 0.00082) and rPFS (HR = 0.078, p = 0.0070). Conclusions: SigMA‐predicted HRD may better identify patients likely to benefit from olaparib as compared to the current FDA label. Larger studies are needed for further validation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In metastatic disease, germline and somatic sequencing are recommended to identify actionable alterations such as HRD and dMMR/MSI-H, which have direct implications for PARP inhibitor therapy and immune checkpoint blockade.
“In metastatic disease, genomic testing shifts toward predictive biomarkers. Germline and somatic sequencing are recommended to identify actionable alterations such as homologous recombination repair deficiency (HRD) and mismatch repair deficiency (dMMR/MSI-H), which have direct implications for PARP inhibitor therapy and immune checkpoint blockade [2, 8–10].”
From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [9]
The Introduction (page unavailable) says guidelines recommend germline and somatic testing in high-risk localized or advanced prostate cancer for HRR alterations associated with PARP inhibitor response. The paper also studies HRD as a predictor of olaparib response in metastatic castration-resistant prostate cancer, but the cited passages do not address dMMR/MSI-H or immune checkpoint blockade. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHRD is the most well-established predictive biomarker in advanced prostate cancer, with alterations in BRCA1, BRCA2, and ATM associated with sensitivity to PARP inhibitors.
“HRD represents the most well-established predictive biomarker, with alterations in genes such as BRCA1, BRCA2, and ATM associated with sensitivity to PARP inhibitors [8,9].”
From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [9]
The Introduction (page unavailable) says BRCA1/2 alterations strongly associate with PARP-inhibitor response, and Results §3.2 finds that the HRD signature predicts olaparib response in metastatic castration-resistant prostate cancer. But the Introduction says the association for ATM is less clear, while §3.3 says comparable HRD assays in prostate cancer have not been well validated. The source therefore does not support calling HRD the most well-established predictive biomarker or grouping ATM with BRCA1/2 as an established sensitivity marker. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPopulation-based data suggest that prostate MRI and genomic testing influence treatment pathways differently, highlighting the need to consider these tools as complementary rather than interchangeable components of risk assessment.
“Population-based data suggest that prostate magnetic resonance imaging (MRI) and genomic testing influence treatment pathways differently, highlighting the need to consider these tools as complementary rather than interchangeable components of risk assessment [9].”
From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [9]
The Introduction and section 3.3 discuss genomic biomarkers for selecting patients with metastatic castration-resistant prostate cancer for PARP-inhibitor treatment. The paper does not compare genomic testing with prostate MRI, establish that they influence treatment pathways differently, or present population-based evidence for treating them as complementary risk-assessment tools. (LLM, conf=0.82)
Experimental — accuracy not yet measuredGermline, somatic, and liquid biopsy-based approaches are increasingly indispensable in advanced disease, particularly when they identify actionable alterations such as HRD or dMMR.
“In contrast, germline, somatic, and liquid biopsy–based approaches are increasingly indispensable in advanced disease, particularly when they identify actionable alterations such as homologous recombination repair deficiency or mismatch repair deficiency [8–10, 18].”
From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [9]
The Introduction and section 3.3 support the value of somatic tumor testing for HRD in metastatic castration-resistant prostate cancer: the paper reports that a panel-based HRD signature may help identify patients likely to benefit from olaparib. Section 2.1.1 also describes curation of germline variants, but the paper does not establish that germline testing is increasingly indispensable. The passages do not address liquid biopsy or mismatch repair deficiency, so the full claim is broader than this source supports. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn advanced prostate cancer, germline and somatic testing identify predictive biomarkers linked to therapy selection.
“in advanced disease, germline and somatic testing identify predictive biomarkers linked to therapy selection”
From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [9]
Therapeutic benefit from PARP inhibitors is not uniform across HRD genes, with BRCA2 alterations typically conferring the strongest response.
“However, therapeutic benefit is not uniform across genes, with BRCA2 alterations typically conferring the strongest response.”
From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [9]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Pan-cancer landscape of homologous recombination deficiency.
Nguyen, L., W. M. Martens, J., Van Hoeck, A., & Cuppen, E. (2020) · Nature communications · doi:10.1038/s41467-020-19406-4 · Cited by 532 · see citing works
Rucaparib or Physician’s Choice in Metastatic Prostate Cancer
Fizazi, K., Piulats, J. M., Reaume, M. N., Ostler, P., McDermott, R., Gingerich, J. R., Pintus, E., Sridhar, S. S., Bambury, R. M., Emmenegger, U., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2214676 · Cited by 449 · see citing works
Flagged first, then by citations
Research works printed but not linked: 38
- Robinson D, Van Allen EM, Wu Y-M, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215-1228.
- de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration- resistant prostate cancer. N Engl J Med. 2020;382:2091-2102.
- Hussain M, Mateo J, Fizazi K, et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020;383:2345-2357.
- Carreira S, Porta N, Arce-Gallego S, et al. Biomarkers associating with PARP inhibitor benefit in prostate cancer in the TOPARP-B trial. Cancer Discov. 2021;11:2812-2827.
- Taza F, Holler AE, Fu W, et al. Differential activity of PARP inhibitors in BRCA1-versus BRCA2-Altered metastatic Castration-Resistant prostate cancer. JCO Precis Oncol. 2021;5:1200-1220. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575434/
- Mateo J, Porta N, Bianchini D, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, rando- mised, phase 2 trial. Lancet Oncol. 2020;21:162-174.
- Tate JG, Bamford S, Jubb HC, et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res. 2019;47:D941- D947.
- Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of muta- tional processes in human cancer. Nature. 2013;500:415-421.
- Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as First-Line maintenance in ovarian cancer. N Engl J Med. 2019;381: 2416-2428. Available from: https://www.nejm.org/doi/full/10. 1056/nejmoa1911361 · DOI
- González-Martín A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;81:2391-2402. Available from: https://www.nejm.org/doi/ full/10.1056/NEJMoa1910962 · DOI
- Sztupinszki Z, Diossy M, Krzystanek M, et al. Detection of molecular signatures of homologous recombination deficiency in prostate cancer with or without BRCA1/2 mutations. Clin Cancer Res. 2020;26:2673-2680.
- Gulhan DC, Lee JJ, Melloni GEM, Cortés-Ciriano I, Park PJ. Detecting the mutational signature of homologous recombination deficiency in clinical samples. Nat Genet. 2019;51:912-919. Availa- ble from: https://pubmed.ncbi.nlm.nih.gov/30988514/
- Färkkilä A, Gulhan DC, Casado J, et al. Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer. Nat Commun. 2020;11:1459. Available from: https:// pubmed.ncbi.nlm.nih.gov/32193378/
- Nik-Zainal S, Davies H, Staaf J, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016;534: 47-54. Available from: https://pubmed.ncbi.nlm.nih.gov/27135926/
- Polak P, Kim J, Braunstein LZ, et al. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat Genet. 2017;49(10):1476-1486. Available from: https://pubmed.ncbi.nlm.nih.gov/28825726/
- Batalini F, Gulhan DC, Mao V, et al. Mutational signature 3 detected from clinical panel sequencing is associated with responses to ola- parib in breast and ovarian cancers. Clin Cancer Res. 2022;28: 4714-4723. Available from: https://pubmed.ncbi.nlm.nih.gov/ 36048535/
- Wagle N, Berger MF, Davis MJ, et al. High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing. Cancer Discov. 2012;2(1):82-93. Available from: https://pubmed.ncbi.nlm.nih.gov/22585170/
- Garcia, Minkovsky EP, Jia A, et al. Validation of OncoPanel: A targeted Next-Generation sequencing assay for the detection of somatic var- iants in cancer. Arch Pathol Lab Med. 2017;141(6):751-758. Available from: https://pubmed.ncbi.nlm.nih.gov/28557599/
- Sholl LM, Do K, Shivdasani P, et al. Institutional implementation of clinical tumor profiling on an unselected cancer population. JCI Insight. 2016;1(19):e87062. Available from: https://pubmed.ncbi. nlm.nih.gov/27882345/
- Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7: 248-249.
- Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31(13):3812-3814. Availa- ble from: https://pubmed.ncbi.nlm.nih.gov/12824425/
- Landrum MJ, Lee JM, Riley GR, et al. ClinVar: public archive of re- lationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42(Database issue):D980-D985. Available from: https://pubmed.ncbi.nlm.nih.gov/24234437/
- Davies H, Glodzik D, Morganella S, et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med. 2017;23(4):517-525. Available from: https://pubmed.ncbi.nlm. nih.gov/28288110/
- Scher HI, Morris MJ, Stadler WM, et al. Trial design and objectives for Castration-Resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3. J Clin Oncol. 2016;34(12):1402-1418. Available from: https://pubmed.ncbi.nlm. nih.gov/26903579/
- Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023;402:291-303.
- Chi KN, Sandhu S, Smith MR, et al. Niraparib plus abiraterone ace- tate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Ann Oncol. 2023;34(9):772-782. Available from: https://pubmed.ncbi.nlm.nih.gov/37399894/
- Saad F, Clarke NW, Oya M, et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a ran- domised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(10): p1094-1108. Available from: http://www.thelancet.com/article/ S1470204523003820/abstract
- Kim JW, McKay RR, Radke MR, et al. Randomized trial of olaparib with or without cediranib for metastatic Castration-Resistant pros- tate cancer: the results from national cancer institute 9984. J Clin Oncol. 2022;41:871-880. Available from: doi:10.1200/JCO.21. 02947 · DOI
- Brenneman MA, Weiss AE, Nickoloff JA, Chen DJ. XRCC3 is required for efficient repair of chromosome breaks by homologous recombination. Mutat Res. 2000;459:89-97.
- Armenia J, Wankowicz SAM, Liu D, et al. The long tail of oncogenic drivers in prostate cancer. Nat Genet. 2018;50:645-651.
- Abida W, Armenia J, Gopalan A, et al. Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that May affect clinical decision making. JCO Precis Oncol. 2017;1:1-16. Available from: doi:10.1200/PO.17. 00029 · DOI · Paper page
- De Sarkar N, Dasgupta S, Chatterjee P, et al. Genomic attributes of homology-directed DNA repair deficiency in metastatic prostate cancer. JCI Insight. 2021;6(23):e152789. Available from: https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC8675196/
- Jr Conway, Ak Tewari, Sy Camp, Van Allen EM, et al. Analysis of evolutionary dynamics and clonal architecture in prostate cancer [Internet]. Available from: doi:10.1101/2023.03.23.533974v1. full.pdf · DOI
- Lotan TL, Kaur HB, Salles DC, et al. Homologous recombination deficiency (HRD) score in germline BRCA2-versus ATM-altered prostate cancer. Mod Pathol. 2021;34:1185-1193.
- Sokol ES, Pavlick D, Khiabanian H, et al. Pan-Cancer analysis of BRCA1 and BRCA2 genomic alterations and their association with genomic instability as measured by Genome-Wide loss of hetero- zygosity. JCO Precision Oncol. 2020;4:442-465. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446440/
- Moore JA, Chen K-T, Madison R, et al. Pan-Cancer analysis of Copy- Number features identifies recurrent signatures and a homologous recombination deficiency biomarker to predict poly (ADP-Ribose) polymerase inhibitor response. JCO Precision Oncol. 2023;7:e2300093. Available from: doi:10.1200/PO.23.00093 · DOI
- Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609-615. Available from: https://pubmed.ncbi.nlm. nih.gov/21720365/
- Nindra U, Hong JH, Balakrishnar B, Pal A, Chua W. Review of toxicities of PARP inhibitors in metastatic castrate resistant prostate cancer. Clin Genitourin Cancer. 2023;21(1):183-193. Available from: https://pubmed.ncbi.nlm.nih.gov/35927195/
Cited by
Sorted by citations
A decision-oriented framework for genomic testing across the prostate cancer continuum
Cobran, E. K., Samadder, N. J., Schaid, D. J., Conti, D. V., Haiman, C., Vargas, L., Gionfriddo, M. R., & Tilburt, J. C. (2026) · Cancer Genetics · doi:10.1016/j.cancergen.2026.06.002 · Cited by 1 · see citing works
- Authors
- Boiarsky, D., Tewari, A. K., Gulhan, D. C., Bakouny, Z., Ananda, G., Savignano, H., Lakshminarayanan, G., McClure, H. M., Silver, R., Choueiri, T. K., Taplin, M., Park, P. J., & Berchuck, J. E.
- Affiliations
- Department of Medicine Tufts Medical Center Boston Massachusetts USA
- Department of Medical Oncology Dana‐Farber Cancer Institute Boston Massachusetts USA
- Department of Biomedical Informatics Harvard Medical School Boston Massachusetts USA
- Department of Medical Oncology Memorial Sloan Kettering Cancer Center NY New York USA
- Department of Data Science Dana‐Farber Cancer Institute Boston Massachusetts USA
- Winship Cancer Institute Emory University School of Medicine Atlanta Georgia USA
- Venue
- The Prostate
- Publisher
- Wiley
- Published
- 2024-09-09
- Volume
- 84
- Issue
- 16
- Pages
- 1479-1489
- ISSN
- 0270-4137
- 1097-0045
- Cited by
- 4
- References
- 2
- Language
- en
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
