Talazoparib

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Talazoparib
Talazoparib.svg
Clinical data
Trade namesTalzenna
ATC code
Legal status
Legal status
  • Investigational
Identifiers
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC19H14F2N6O
Molar mass380.35 g/mol
3D model (JSmol)

Talazoparib (trade name Talzenna, BMN-673) is an orally available poly ADP ribose polymerase (PARP) inhibitor currently in development by Pfizer for the treatment of advanced breast cancer patients with germline BRCA mutations.[1] Talazoparib is similar to the first in class PARP inhibitor, olaparib.[2][3] The U.S. FDA approved Talzenna (talazoparib) for patients with a germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer in october 2018.[2]

Mechanism of action[edit]

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.[1] 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.[4] However, this increased potency may not translate directly to clinical effectiveness as many other factors must be considered.[3][4]

Commercialization[edit]

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.[5] 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.[5][6]

Clinical trials[edit]

As of January 2016, talazoparib is in 14 active clinical trials [7] including a new arm of I-SPY 2.[8] These trials cover a variety of cancers types and combination therapies. The most notable clinical trials are the ABRAZO and EMBRACA studies.

ABRAZO[edit]

ABRAZO is a phase II study for the safety and efficacy of treatment of BRCA breast cancer patients with talazoparib monotherapy. This study is for patients who have failed at least two prior chemotherapy treatments for metastatic breast cancer or been previously treated with a platinum regimen.[6][9][10] The original target enrollment for the study was 70 patients but Biomarin expanded the trial to 140 patients.[9][10] The estimated completion date is December 2016.[10]

EMBRACA[edit]

EMBRACA is a phase III study for the treatment of BRCA breast cancer patients with talazoparib.[11][12][13] This trial is an open-label, randomized, parallel, 2-arm, multi-center comparison of talazaporib against physician’s preference for the treatment of patients with locally advanced or metastatic breast cancer. Patients must also have received prior chemotherapy regimens for metastatic breast cancer.[12][13] Patients participating in this study are randomly selected for either talazoparib or physician’s choice of chemotherapy at a 2:1 ratio to talazoparib.[6] The target enrollment for the study was 430 patients [12][13] and the estimated completion date is June 2017.[13] In the Phase 3 EMBRACA study, talazoparib was superior to physician’s choice chemotherapy in delaying disease progression in patients with gBRCA-mutated locally advanced or metastatic breast cancer who had received up to three prior lines of chemotherapy.

References[edit]

  1. ^ a b Medivation Inc. "Talazoparib".
  2. ^ a b FDA (19 December 2014). "FDA approves Lynparza to treat advanced ovarian cancer". FDA News Release.
  3. ^ a b Jessica Brown, Stan Kaye, Timothy Yap (29 March 2016). "PARP inhibitors: the race is on". British Journal of Cancer. 114: 713–5. doi:10.1038/bjc.2016.67. PMC 4984871. PMID 27022824.CS1 maint: Multiple names: authors list (link)
  4. ^ a b Yuqiao Shen, Mika Aoyagi-Scharber, Bing Wang (June 2015). "Trapping Poly(ADP-Ribose) Polymerase". Journal of Pharmacology and Experimental Therapeutics.CS1 maint: Multiple names: authors list (link)
  5. ^ a b 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".
  6. ^ a b c Silus Inman (25 August 2015). "Medivation Acquires BioMarin's PARP Inhibitor Talazoparib".
  7. ^ BMN 673 trials registered
  8. ^ I-SPY 2 TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2)
  9. ^ a b "BioMarin Provides Program Update for Talazoparib in Metastatic Breast Cancer". 20 July 2015.
  10. ^ a b c "A Phase 2, 2-Stage, 2-Cohort Study of Talazoparib (BMN 673), in Locally Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (ABRAZO Study)". ClinicalTrials.gov.
  11. ^ "EMBRACA CLINICAL STUDY IS NOW ENROLLING".
  12. ^ a b c "A Study Evaluating Talazoparib (BMN 673), a PARP Inhibitor, in Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (EMBRACA Study)". ClinicalTrials.gov.
  13. ^ a b c d "BioMarin Initiates Phase 3 BMN 673 Trial for Metastatic gBRCA Breast Cancer". Benzinga.