Skip to main content

Advertisement

Springer Nature Link
Log in

Clinical efficacy of PARP inhibitors in breast cancer

  • Review
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

BRCA1 and BRCA2 are key tumor suppressor genes that are essential for the homologous recombination DNA repair pathway. Loss of function mutations in these genes result in hereditary breast and ovarian cancer syndromes, which comprise approximately 5% of cases. BRCA1/2 mutations are associated with younger age of diagnosis and increased risk of recurrences. The concept of synthetic lethality led to the development of PARP inhibitors which cause cell cytotoxicity via the inhibition of PARP1, a key DNA repair protein, in cells with germline BRCA1/2 mutations. Although still poorly understood, the most well-acknowledged proposed mechanisms of action of PARP1 inhibition include the inhibition of single strand break repair, PARP trapping, and the upregulation of non-homologous end joining. Olaparib and talazoparib are PARP inhibitors that have been approved for the management of HER2-negative breast cancer in patients with germline BRCA1/2 mutations. This review article highlights the clinical efficacy of PARP inhibitors in patients with HER2-negative breast cancer in early and advanced settings.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

Data availability

Enquiries about data availability should be directed to the authors.

References

  1. Rose M et al (2020) PARP inhibitors: clinical relevance, mechanisms of action and tumor resistance. Front Cell Dev Biol 8:564601

    Article  PubMed  PubMed Central  Google Scholar 

  2. Yi M et al (2019) Advances and perspectives of PARP inhibitors. Exp Hematol Oncol 8:29

    Article  PubMed  PubMed Central  Google Scholar 

  3. Casaubon JT, Kashyap S, Regan JP (2022) BRCA 1 and 2. StatPearls, Treasure Island

    Google Scholar 

  4. Tutt ANJ et al (2021) Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med 384(25):2394–2405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. RayChaudhuri A, Nussenzweig A (2017) The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol 18(10):610–621

    Article  CAS  Google Scholar 

  6. Murthy P, Muggia F (2019) PARP inhibitors: clinical development, emerging differences, and the current therapeutic issues. Cancer Drug Resistance. https://doi.org/10.20517/cdr.2019.002

    Article  PubMed  PubMed Central  Google Scholar 

  7. Stewart MD et al (2022) Homologous recombination deficiency: concepts, definitions, and assays. Oncologist 27(3):167–174

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bryant HE et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434(7035):913–917

    Article  CAS  PubMed  Google Scholar 

  9. Farmer H et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921

    Article  CAS  PubMed  Google Scholar 

  10. Fong PC et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123–134

    Article  CAS  PubMed  Google Scholar 

  11. Tutt A et al (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376(9737):235–244

    Article  CAS  PubMed  Google Scholar 

  12. Murai J et al (2014) Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther 13(2):433–443

    Article  CAS  PubMed  Google Scholar 

  13. de Bono J et al (2017) Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discov 7(6):620–629

    Article  PubMed  PubMed Central  Google Scholar 

  14. Turner NC et al (2019) A phase II study of talazoparib after platinum or cytotoxic nonplatinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations (ABRAZO). Clin Cancer Res 25(9):2717–2724

    Article  CAS  PubMed  Google Scholar 

  15. Robson M et al (2017) Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377(6):523–533

    Article  CAS  PubMed  Google Scholar 

  16. Robson ME et al (2019) OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol 30(4):558–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Litton JK et al (2018) Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 379(8):753–763

    Article  CAS  PubMed  Google Scholar 

  18. Litton JK et al (2020) Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. Ann Oncol 31(11):1526–1535

    Article  CAS  PubMed  Google Scholar 

  19. Lyons TG, Robson ME (2018) Resurrection of PARP inhibitors in breast cancer. J Natl Compr Cancer Netw 16(9):1150–1156

    Article  CAS  Google Scholar 

  20. Domchek SM et al (2020) Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol 21(9):1155–1164

    Article  CAS  PubMed  Google Scholar 

  21. Chabanon RM et al (2016) Mutational landscape and sensitivity to immune checkpoint blockers. Clin Cancer Res 22(17):4309–4321

    Article  CAS  PubMed  Google Scholar 

  22. Jiao S et al (2017) PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res 23(14):3711–3720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yap TA et al (2020) Abstract P1–19–03: JAVELIN PARP Medley, a phase 1b/2 study of avelumab plus talazoparib: results from advanced breast cancer cohorts. Cancer Res 80:P1-19-03-P1-19–03

    Article  Google Scholar 

  24. Tutt A et al (2022) VP1-2022: pre-specified event driven analysis of overall survival (OS) in the OlympiA phase III trial of adjuvant olaparib (OL) in germline BRCA1/2 mutation (gBRCAm) associated breast cancer. Ann Oncol 33(5):566–568

    Article  Google Scholar 

  25. Litton JK et al (2021) Neoadjuvant talazoparib in patients with germline BRCA1/2 (gBRCA1/2) mutation-positive, early HER2-negative breast cancer (BC): results of a phase 2 study. J Clin Oncol 39(15_suppl):505–505

    Article  Google Scholar 

  26. Takamatsu S et al (2022) Utility of homologous recombination deficiency biomarkers across cancer types. JCO Precis Oncol 6:e2200085

    Article  PubMed  PubMed Central  Google Scholar 

  27. Tung NM et al (2020) TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol 38(36):4274–4282

    Article  CAS  PubMed  Google Scholar 

  28. Telli ML et al (2016) Homologous recombination deficiency (HRD) Score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res 22(15):3764–3773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fasching PA et al (2021) Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study). Ann Oncol 32(1):49–57

    Article  CAS  PubMed  Google Scholar 

  30. Alba KP et al (2020) Abstract P3–10–05: Preliminary safety data from stage 1 and 2 of the phase II/III PARTNER trial: Addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients. Cancer Res 80(4_Supplement):P3-10-05-P3-10–05

    Article  Google Scholar 

  31. Wagner LM (2015) Profile of veliparib and its potential in the treatment of solid tumors. Onco Targets Ther 8:1931–1939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Puhalla S, Beumer J, Pahuja S (2014) Final results of a phase 1 study of single-agent veliparib (V) in patients (pts) with either BRCA1/2-mutated cancer (BRCA+), platinum-refractory ovarian, or basal-like breast cancer (BRCA-wt) [abstract]. J Clin Oncol 32(Suppl):2570

    Article  Google Scholar 

  33. Somlo G, Frankel P, Arun B (2017) Efficacy of the PARP inhibitor veliparib with carboplatin or as a single agent in patients with germline BRCA1- or BRCA2-associated metastatic breast cancer: California Cancer Consortium Trial NCT01149083. Clin Cancer Res 23:4066–4076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rugo HS et al (2016) Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med 375(1):23–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Loibl S et al (2018) Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol 19(4):497–509

    Article  CAS  PubMed  Google Scholar 

  36. Geyer CE et al (2022) Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial. Ann Oncol 33(4):384–394

    Article  CAS  PubMed  Google Scholar 

  37. Vinayak S et al (2019) Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol 5(8):1132–1140

    Article  PubMed  PubMed Central  Google Scholar 

  38. Madariaga A et al (2020) Manage wisely: poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events. Int J Gynecol Cancer 30(7):903–915

    Article  PubMed  PubMed Central  Google Scholar 

  39. LaFargue CJ et al (2019) Exploring and comparing adverse events between PARP inhibitors. Lancet Oncol 20(1):e15–e28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. McCrea C, Hettle R (2019) Indirect treatment comparison of the efficacy and safety of olaparib 300 mg tablets BID and talazoparib 1 mg once daily in the treatment of patients with germline BRCA-mutated (gBRCA) HER2-negative metastatic breast cancer. J Clin Oncol 37(15):e12570–e12570

    Article  Google Scholar 

  41. Diéras V et al (2020) Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 21(10):1269–1282. https://doi.org/10.1016/S1470-2045(20)30447-2

Download references

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA

    Karan Pandya & Alyssa Scher

  2. Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA

    Coral Omene, Shridar Ganesan, Shicha Kumar, Nisha Ohri, Lindsay Potdevin, Bruce Haffty, Deborah L. Toppmeyer & Mridula A. George

Authors
  1. Karan Pandya
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Alyssa Scher
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Coral Omene
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Shridar Ganesan
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Shicha Kumar
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Nisha Ohri
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Lindsay Potdevin
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Bruce Haffty
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Deborah L. Toppmeyer
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Mridula A. George
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Mridula A. George.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pandya, K., Scher, A., Omene, C. et al. Clinical efficacy of PARP inhibitors in breast cancer. Breast Cancer Res Treat 200, 15–22 (2023). https://doi.org/10.1007/s10549-023-06940-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-023-06940-0

Keywords