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MJCA234/sandbox
Legal status
Legal status
  • Investigational
Identifiers
  • (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
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC19H14F2N6O
Molar mass380.35 g/mol g·mol−1
3D model (JSmol)
  • Cn1c(ncn1)[C@H]2c3c4c(cc(cc4N[C@@H]2c5ccc(cc5)F)F)c(=O)[nH]n3
  • 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

Talazoparib (BMN-673) is an orally available poly ADP ribose polymerase (PARP) inhibitor currently in development by Medivation 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] However, talazoparib is thought to be more potent than olaparib [3].


Mechanism of action

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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

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Talazoparib was originally developed by BioMarin Pharmaceutical Inc. However, Medivation Inc. acquired all worldwide rights to talazaporib 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

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As of January 2016, talazoparib is in 14 active clinical trials Cite error: The <ref> tag name cannot be a simple integer (see the help page). including a new arm of I-SPY 2.[7]. These trials cover a variety of cancers types and combination therapies. The most notable clinical trials are the ABRAZO and EMBRACA studies.

ABRAZO

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] [8].[9] The original target enrollment for the study was 70 patients but Biomarin expanded the trial to 140 patients [8] [9]. The estimated primary completion date is December 2016 [9].

EMBRACA

EMBRACA is a phase III study for the treatment of BRCA breast cancer patients with Talazoparib [10] [11].[12] 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 [11] [12]. 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 [11] [12] and the estimated primary completion date is June 2017 [12].


References

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  1. ^ a b Medivation Inc. "Talazoparib".
  2. ^ FDA (19 December 2014). "FDA approves Lynparza to treat advanced ovarian cancer". FDA News Release.
  3. ^ a b c Jessica Brown, Stan Kaye, Timothy Yap (29 March 2016). "PARP inhibitors: the race is on". British Journal of Cancer. 114 (7): 713–715. doi:10.1038/bjc.2016.67. PMC 4984871. PMID 27022824.{{cite journal}}: 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.{{cite web}}: 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. ^ I-SPY 2 TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2)
  8. ^ a b "BioMarin Provides Program Update for Talazoparib in Metastatic Breast Cancer". 20 July 2015.
  9. ^ 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.
  10. ^ "EMBRACA CLINICAL STUDY IS NOW ENROLLING".
  11. ^ 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.
  12. ^ a b c d "BioMarin Initiates Phase 3 BMN 673 Trial for Metastatic gBRCA Breast Cancer". Benzinga.
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Category:Experimental cancer drugs Category:Organofluorides Category:PARP inhibitors Category:Triazoles

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