TALZENNA Mechanism of Action

Normal Cells

PARP enzymes and BRCA1/2 proteins both have a role in DNA repair2,3

Preclinical studies have shown:
  • The role of PARP enzymes is to repair single-strand breaks (SSBs) in DNA generated during DNA replication or by DNA damage2
  • The role of BRCA1/2 proteins is to repair double-strand breaks (DSBs) in DNA via a repair mechanism called homologous recombination (HR)3  
 

Cancer Cells

Preclinical studies have shown:
  • In gBRCA-deficient cancer cells, HR, the mechanism that repairs harmful DSBs in DNA, is defective3,4
  • These cells become reliant on remaining intact repair mechanisms, like PARP enzymes, to maintain DNA repair and cell proliferation3,4
  • Cancer cell overreliance on these alternative repair mechanisms can lead to the accumulation of DNA damage, promoting the formation and survival of tumor cells4
 

TALZENNA Dual MOA

TALZENNA is a targeted treatment that leads to cancer cell death via 2 complementary mechanisms5*

PARP Enzyme Inhibition

Preclinical studies have shown:

  • PARP inhibition results in the accumulation of SSBs, which eventually convert to DSBs during DNA replication5
  • gBRCA-mutated cancer cells with defective HR repair mechanisms are unable to repair accumulated DSBs, leading to cancer cell death5
  • In vitro studies demonstrated that BRCA1/2-mutated HR-deficient cells are highly sensitive to cell death induced by PARP inhibition6,7†
 

PARP Enzyme Trapping

Preclinical studies have shown:
  • TALZENNA showed the capacity to trap PARP enzymes and form a complex with DNA to prevent DNA repair and replication, leading to cancer cell death3,5,7,8
  • TALZENNA demonstrated highly potent PARP trapping, which may be correlated with tumor cell death5,8

*Talazoparib can also affect healthy cells.

 

BRCA=breast cancer susceptibility gene; CI=confidence interval; gBRCA=germline breast cancer susceptibility gene; HER2-=human epidermal growth factor receptor 2 negative; HR=Homologous Recombination; MOA=mechanism of action; PARP=poly (ADP-ribose) polymerase; SSB=single-strand breaks; DSB=double-strand breaks.

 
REFERENCES
  1. TALZENNA Summary of Product Characteristics.
  2. Sonnenblick A, de Azambuja E, Azim HA Jr, Piccart M. An update on PARP inhibitors—moving to the adjuvant setting. Nat Rev Clin Oncol. 2015;12(1):27-41.
  3. Lee J-m, Ledermann JA, Kohn EC. PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies.  Ann Oncol. 2014;25(1):32-40.
  4. Lupo B, Trusolino L. Inhibition of poly(ADP-ribosyl)ation in cancer: old and new paradigms revisited. Biochim Biophys Acta. 2014;1846(1):201-215.
  5. Gavande NS, VanderVere-Carozza PS, Hinshaw HD, et al. DNA repair targeted therapy: the past or future of cancer treatment? Pharmacol Ther. 2016;160:65-83.
  6. Iglehart JD, Silver DP. Synthetic lethality—a new direction in cancer-drug development. N Eng J Med. 2009;361(2):189-191.
  7. van Wietmarschen N, Nussenzweig A. Mechanism for synthetic lethality in BRCA-deficient cancers: no longer lagging behind. Mol Cell. 2018;71(6):877-878.
  8. Murai J, Huang SY, Renaud A, et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther. 2014;13(2):433-443.
 

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of full SmPC for how to report adverse reactions.