Talazoparib

Talazoparib, sold under the brand name Talzenna, is an orally available poly ADP ribose polymerase (PARP) inhibitor developed by Pfizer for the treatment of advanced breast cancer with germline BRCA mutations.[4] Talazoparib is similar to the first in class PARP inhibitor, olaparib.[5][6] It was approved in October 2018, in the United States and June 2019, in the European Union for germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer.[5][7][8][9]

Talazoparib
Clinical data
Trade namesTalzenna
Other namesBMN-673
AHFS/Drugs.comMonograph
MedlinePlusa618070
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
Drug classPARP inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding74%
MetabolismMinimal metabolisation (<30%)
Elimination half-life90 (±58) hrs
Excretion69% in urine, 20% in feces
Identifiers
IUPAC name
  • (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one
CAS Number
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard100.249.319
Chemical and physical data
FormulaC19H14F2N6O
Molar mass380.359 g·mol−1
3D model (JSmol)
SMILES
  • Cn1c(ncn1)[C@H]2c3c4c(cc(cc4N[C@@H]2c5ccc(cc5)F)F)c(=O)[nH]n3
InChI
  • InChI=1S/C19H14F2N6O/c1-27-18(22-8-23-27)15-16(9-2-4-10(20)5-3-9)24-13-7-11(21)6-12-14(13)17(15)25-26-19(12)28/h2-8,15-16,24H,1H3,(H,26,28)/t15-,16-/m1/s1
  • Key:HWGQMRYQVZSGDQ-HZPDHXFCSA-N

Side effects

The most serious side effects in studies were related to the blood forming system and included anaemia (low red blood cell count), neutropenia (low neutrophil blood cell count) and thrombocytopenia (low platelet count). Serious forms of these conditions (grade 3 to 4) occurred in 39%, 21% and 15% of patients, respectively. Other adverse effects such as headache, nausea, hair loss and fatigue were mostly mild.[10]

Interactions

Combination with drugs that inhibit P-glycoprotein or BCRP may increase talazoparib concentrations in the body.[10]

Mechanism of action

Talazoparib acts as an inhibitor of poly ADP ribose polymerase (PARP) which aids in single strand DNA repair. Cells that have BRCA1/2 mutations are susceptible to the cytotoxic effects of PARP inhibitors because of an accumulation of DNA damage.[4] Talazoparib is theorized to have a higher potency than olaparib due to the additional mechanism of action called PARP trapping. PARP trapping is the mechanism of action where the PARP molecule is trapped on the DNA, which interferes with the cells ability to replicate. Talazoparib is found to be ~100 fold more efficient in PARP trapping than olaparib.[11] However, this increased potency may not translate directly to clinical effectiveness as many other factors must be considered.[6][11]

Commercialization

Talazoparib was originally developed by BioMarin Pharmaceutical Inc. However, Medivation Inc. acquired all worldwide rights to talazoparib in August 2015, to expand their global oncology franchise.[12] Medivation acquired talazoparib for $410 million with additional payments of up to $160 million in royalties and milestones. Under this agreement, Medivation assumed all financial responsibilities for the continued development, regulatory, and commercialization of talazoparib.[12][13]

References
  1. "Talzenna Product information". Health Canada. 25 April 2012. Retrieved 29 May 2022.
  2. "Summary Basis of Decision (SBD) for Talzenna". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  3. "Talzenna 0.25 mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). 1 June 2021. Retrieved 9 July 2021.
  4. Medivation Inc. "Talazoparib". Archived from the original on 8 June 2017. Retrieved 21 November 2016.
  5. "FDA approves Lynparza to treat advanced ovarian cancer". U.S. Food and Drug Administration (FDA) (Press release). 19 December 2014. Archived from the original on 19 December 2014. Retrieved 16 December 2019.
  6. Brown JS, Kaye SB, Yap TA (March 2016). "PARP inhibitors: the race is on". British Journal of Cancer. 114 (7): 713–5. doi:10.1038/bjc.2016.67. PMC 4984871. PMID 27022824.
  7. Pfizer Inc. "European Commission Approves TALZENNA (talazoparib) for Patients with Inherited (Germline) BRCA-Mutated Locally Advanced or Metastatic Breast Cancer".
  8. "Drug Approval Package: Talzenna (talazoparib)". U.S. Food and Drug Administration (FDA). 29 October 2018. Retrieved 10 March 2020.
  9. "Talzenna EPAR". European Medicines Agency (EMA). 8 July 2019. Retrieved 10 March 2020.
  10. Talzenna FDA Professional Drug Information
  11. Shen Y, Aoyagi-Scharber M, Wang B (June 2015). "Trapping Poly(ADP-Ribose) Polymerase". The Journal of Pharmacology and Experimental Therapeutics. 353 (3): 446–57. doi:10.1124/jpet.114.222448. PMID 25758918. S2CID 9810541.
  12. Biomarin (24 August 2015). "Medivation to Expand Global Oncology Franchise With the Acquisition of All Worldwide Rights to Talazoparib (BMN 673), a Potent PARP Inhibitor, From BioMarin".
  13. Inman S (25 August 2015). "Medivation Acquires BioMarin's PARP Inhibitor Talazoparib".
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