Talazoparib

Identification

Summary

Talazoparib is a poly-ADP ribose polymerase inhibitor used to treat HER2-, BRCA mutated locally advanced or metastatic breast cancer and HRR gene-mutated metastatic castration-resistant prostate cancer.

Brand Names

Talzenna

Generic Name

Talazoparib

DrugBank Accession Number

DB11760

Background

Talazoparib is an inhibitor of mammalian polyadenosine 5’-diphosphoribose polymerases (PARPs), enzymes responsible for regulating essential cellular functions, such as DNA transcription and DNA repair.⁴

Developed by Pfizer, talazoparib was first approved by the FDA in October 2018 ² and by the EMA in June 2019.⁵ It was approved by Health Canada in September 2020.⁶ Talazoparib is currently used in the treatment of BRCA-mutated breast cancer and HRR-mutated prostate cancer.^4,6,7

Type

Small Molecule

Groups

Approved, Investigational

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Talazoparib (DB11760)

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Weight

Average: 380.359
Monoisotopic: 380.119715421

Chemical Formula

C₁₉H₁₄F₂N₆O

Synonyms

• Talazoparib

External IDs

• BMN 673
• BMN-673
• BMN673
• LT 006673
• LT-00673
• LT-673
• MDV-3800

Pharmacology

Indication

Talazoparib is indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer. This indication is approved by the FDA, EMA, and Health Canada.^4,6,7

In the US, talazoparib is also indicated in combination with enzalutamide for the treatment of adult patients with HRR gene-mutated metastatic castration-resistant prostate cancer (mCRPC).⁴

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Associated Conditions

• HRR gene-mutated (HRRm) metastatic castration-resistant prostate cancer (mCRPC)
• Locally Advanced Breast Cancer (LABC)
• Metastatic Breast Cancer

Contraindications & Blackbox Warnings

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Pharmacodynamics

Talazoparib is a cytotoxic and anti-tumour agent. In vitro, talazoparib caused cytotoxicity in cancer cell lines that harboured defects in DNA repair genes, including BRCA1 and BRCA2. Talazoparib mediated anti-tumour effects on patient-derived xenograft breast cancer models bearing mutated BRCA1 or mutated BRCA2 or wild type BRCA1 and BRCA2.^2,4

Mechanism of action

Poly(ADP-ribose) polymerases (PARPs) are multifunctional enzymes involved in essential cellular functions, such as DNA transcription and DNA repair. PARPs recognize and repair DNA single-strand breaks (SSBs) via the base excision repair (BER) pathway. DNA double-strand breaks (DSBs) are repaired via homologous recombination by tumour suppressor proteins encoded by BRCA1 and BRCA2.^3,2

Talazoparib is a potent inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1 and PARP2.⁴ In vitro, talazoparib binds to PARP-1 and -2 isoforms with similar affinity.² Inhibition of the BER pathway by talazoparib leads to the accumulation of unrepaired SSBs, which leads to the formation of DSBs, which is the most toxic form of DNA damage. While BRCA-dependent homologous recombination can repair DSBs in normal cells, this repair pathway is defective in cells with BRCA1/2 mutations, such as certain tumour cells.[A246015] Inhibition of PARP in cancer cells with BRCA mutations leads to genomic instability and apoptotic cell death. This end result is also referred to as synthetic lethality, a phenomenon where the combination of two defects - inhibition of PARP activity and loss of DSB repair by HR - that are otherwise benign when alone leads to detrimental results.^1,3 By inhibiting PARP, talazoparib increases the formation of PARP-DNA complexes resulting in DNA damage, decreased cell proliferation, and apoptosis.⁴

Target	Actions	Organism
APoly [ADP-ribose] polymerase 1	inhibitor	Humans
APoly [ADP-ribose] polymerase 2	inhibitor	Humans

Absorption

After administration of talazoparib 1 mg orally once daily, the mean [% coefficient of variation (CV%)] AUC and maximum observed plasma concentration (C_max) of talazoparib at steady-state was 208 (37%) ng x hr/mL and 16.4 (32%) ng/mL, respectively. The mean (CV%) steady-state C_trough was 3.53 (61%) ng/mL.⁴ Steady state was reached within two to three weeks of therapy.² The T_max ranges from one to two hours.⁴

A high-fat, high-calorie food increased the mean C_max by 46% and the median T_max from one to four hours, without affecting the AUC. ⁴

Volume of distribution

The mean apparent volume of distribution of talazoparib is 420 L.⁴

Protein binding

In vitro, the protein binding of talazoparib is 74% and is independent of talazoparib concentration.⁴

Metabolism

Talazoparib undergoes minimal hepatic metabolism. The metabolic pathways include mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluoro talazoparib, and glucuronide conjugation.⁴

Route of elimination

The major route of elimination is renal excretion. Approximately 68.7% of the total administered radiolabeled dose of talazoparib was recovered in urine, where 54.6% of that dose was in the form of an unchanged drug. About 19.7% of the drug was recovered in feces, with 13.6% of the dose is unchanged.⁴

Half-life

The mean terminal plasma half-life (±standard deviation) is 90 (±58) hours in patients with cancer.^2,4

Clearance

The mean apparent oral clearance is 6.45 L/h. The inter-subject variability is 31%.⁴

Adverse Effects

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Toxicity

There is no information available regarding the acute toxicity (LD₅₀) of talazoparib. There is no specific treatment in the event of talazoparib overdose, and symptoms of overdose have not been established. In the event of an overdose, discontinue treatment with talazoparib, consider gastric decontamination, follow general supportive measures, and treat symptomatically.⁴

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abemaciclib	The serum concentration of Talazoparib can be increased when it is combined with Abemaciclib.
Abrocitinib	The serum concentration of Talazoparib can be increased when it is combined with Abrocitinib.
Adagrasib	The serum concentration of Talazoparib can be increased when it is combined with Adagrasib.
Afatinib	The serum concentration of Talazoparib can be increased when it is combined with Afatinib.
Alectinib	The serum concentration of Talazoparib can be increased when it is combined with Alectinib.
Ambrisentan	The serum concentration of Talazoparib can be increased when it is combined with Ambrisentan.
Ambroxol	The risk or severity of methemoglobinemia can be increased when Talazoparib is combined with Ambroxol.
Amiodarone	The serum concentration of Talazoparib can be increased when it is combined with Amiodarone.
Apalutamide	The serum concentration of Talazoparib can be decreased when it is combined with Apalutamide.
Apixaban	The serum concentration of Talazoparib can be increased when it is combined with Apixaban.

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Food Interactions

• Take at the same time every day.
• Take with or without food. A high-fat, high-calorie meal decreases Cmax and delays Tmax, but not to a clinically significant extent.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Talazoparib tosylate	02WK9U5NZC	1373431-65-2	QUQKKHBYEFLEHK-QNBGGDODSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Talzenna	Capsule	0.25 mg	Oral	Pfizer Europe Ma Eeig	2021-02-11	Not applicable
Talzenna	Capsule	0.35 mg/1	Oral	Pfizer Laboratories Div Pfizer Inc	2023-06-21	Not applicable
Talzenna	Capsule	0.25 mg	Oral	Pfizer Canada Ulc	Not applicable	Not applicable
Talzenna	Capsule	1 mg/1	Oral	U.S. Pharmaceuticals	2018-12-10	Not applicable
Talzenna	Capsule	0.25 mg	Oral	Pfizer Europe Ma Eeig	2021-02-11	Not applicable
Talzenna	Capsule	1 mg/1	Oral	Pfizer Laboratories Div Pfizer Inc	2018-10-26	Not applicable
Talzenna	Capsule	0.25 mg	Oral	Pfizer Europe Ma Eeig	2021-02-11	Not applicable
Talzenna	Capsule	1 mg/1	Oral	Excella GmbH & Co. KG	2018-10-26	Not applicable
Talzenna	Capsule	0.1 mg/1	Oral	Pfizer Laboratories Div Pfizer Inc	2023-06-21	Not applicable
Talzenna	Capsule	1 mg	Oral	Pfizer Europe Ma Eeig	2021-02-11	Not applicable

Categories

ATC Codes

L01XK04 — Talazoparib

• L01XK — Poly (ADP-ribose) polymerase (PARP) inhibitors
• L01X — OTHER ANTINEOPLASTIC AGENTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• BCRP/ABCG2 Substrates
• Enzyme Inhibitors
• Narrow Therapeutic Index Drugs
• P-glycoprotein substrates
• P-glycoprotein substrates with a Narrow Therapeutic Index
• Poly (ADP-ribose) polymerase (PARP) inhibitors
• Poly(ADP-ribose) Polymerase Inhibitors
• Pyridazines

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as phenylquinolines. These are heterocyclic compounds containing a quinoline moiety substituted with a phenyl group.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Quinolines and derivatives

Sub Class

Phenylquinolines

Direct Parent

Phenylquinolines

Alternative Parents

Phthalazinones / Secondary alkylarylamines / Pyridazinones / Fluorobenzenes / Aralkylamines / Aryl fluorides / Triazoles / Heteroaromatic compounds / Lactams / Azacyclic compounds / Organooxygen compounds / Organofluorides / Organic oxides / Hydrocarbon derivatives

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Substituents

1,2,4-triazole / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzenoid / Fluorobenzene / Halobenzene / Heteroaromatic compound / Hydrocarbon derivative / Lactam / Monocyclic benzene moiety / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Phenylquinoline / Phthalazine / Phthalazinone / Pyridazine / Pyridazinone / Secondary aliphatic/aromatic amine / Secondary amine

show 19 more

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

9QHX048FRV

CAS number

1207456-01-6

InChI Key

HWGQMRYQVZSGDQ-HZPDHXFCSA-N

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

IUPAC Name

(11S,12R)-7-fluoro-11-(4-fluorophenyl)-12-(1-methyl-1H-1,2,4-triazol-5-yl)-2,3,10-triazatricyclo[7.3.1.0^{5,13}]trideca-1,5,7,9(13)-tetraen-4-one

SMILES

CN1N=CN=C1[C@@H]1[C@H](NC2=C3C1=NNC(=O)C3=CC(F)=C2)C1=CC=C(F)C=C1

References

Synthesis Reference

Wang B, Chu D, Feng Y, Shen Y, Aoyagi-scharber M, Post LE. Discovery and Characterization of (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 (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. J Med Chem. 2016;59(1):335-57.

General References

1. Javle M, Curtin NJ: The role of PARP in DNA repair and its therapeutic exploitation. Br J Cancer. 2011 Oct 11;105(8):1114-22. doi: 10.1038/bjc.2011.382. [Article]
2. Hoy SM: Talazoparib: First Global Approval. Drugs. 2018 Dec;78(18):1939-1946. doi: 10.1007/s40265-018-1026-z. [Article]
3. Bochum S, Berger S, Martens UM: Olaparib. Recent Results Cancer Res. 2018;211:217-233. doi: 10.1007/978-3-319-91442-8_15. [Article]
4. FDA Approved Drug Products: TALZENNA (talazoparib) capsules, for oral use (June 2023) [Link]
5. Pfizer Press Release: European Commission Approves TALZENNA® (talazoparib) for Patients with Inherited (Germline) BRCA-Mutated Locally Advanced or Metastatic Breast Cancer [Link]
6. Health Canada Approved Drug Products: TALZENNA (Talazoparib) Oral Capsules [Link]
7. EMA Approved Drug Products: TALZENNA (talazoparib) Oral Capsules [Link]

External Links

PubChem Compound

44819241

PubChem Substance

347828114

ChemSpider

28637772

BindingDB

50084621

RxNav

2099704

ChEMBL

CHEMBL3137320

ZINC

ZINC000072318110

PDBe Ligand

2YQ

Wikipedia

Talazoparib

PDB Entries

4pjt / 4pjv / 4und / 7kk3 / 7kkn

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	MCRPC	1
3	Active Not Recruiting	Treatment	Prostate Cancer	1
3	Completed	Treatment	BRCA 1 Gene Mutation / BRCA 2 Gene Mutation / Breast Neoplasms	1
3	Recruiting	Treatment	Advanced Malignant Neoplasm / Non-Small Cell Lung Cancer (NSCLC) / Ovarian Cancer / Solid Tumors / Urothelial Cancer	1
3	Terminated	Treatment	Ovarian Cancer	1
2	Active Not Recruiting	Treatment	Advanced Lung Non-Squamous Non-Small Cell Carcinoma / Recurrent Non-Squamous Non-Small Cell Lung Carcinoma / Stage IV Lung Cancer AJCC v8 / Stage IVA Lung Cancer AJCC v8 / Stage IVB Lung Cancer AJCC v8	1
2	Active Not Recruiting	Treatment	Advanced Malignant Neoplasm / ATM Gene Mutation / BRCA 1 Gene Mutation / BRCA 2 Gene Mutation / Metastatic Cancer / PALB2 Gene Mutation / Recurrent Malignant Neoplasm / Refractory Malignant Neoplasm	1
2	Active Not Recruiting	Treatment	Breast Cancer / Triple-Negative Breast Cancer	1
2	Active Not Recruiting	Treatment	Extensive-stage Small Cell Lung Cancer (SCLC)	1
2	Active Not Recruiting	Treatment	Fumarate Hydratase Deficient Renal Cell Carcinoma / Metastatic Renal Cell Carcinoma ( mRCC) / Succinate Dehydrogenase Deficient Renal Cell Carcinoma	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	0.1 mg/1
Capsule	Oral	0.25 mg/1
Capsule	Oral	0.35 mg/1
Capsule	Oral	0.5 mg/1
Capsule	Oral	0.75 mg/1
Capsule	Oral	1 mg/1
Capsule	Oral	1.453 mg
Capsule	Oral	0.25 mg
Capsule	Oral	1 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9820985	No	2017-11-21	2029-07-27
US8012976	No	2011-09-06	2029-10-19
US8735392	No	2014-05-27	2031-10-20
US8420650	No	2013-04-16	2029-07-27
US10189837	No	2019-01-29	2031-10-20
US10780088	No	2009-07-27	2029-07-27

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.101 mg/mL	ALOGPS
logP	2.93	ALOGPS
logP	2.11	Chemaxon
logS	-3.6	ALOGPS
pKa (Strongest Acidic)	9.48	Chemaxon
pKa (Strongest Basic)	1.66	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	5	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	84.2 Å2	Chemaxon
Rotatable Bond Count	2	Chemaxon
Refractivity	111.27 m3·mol-1	Chemaxon
Polarizability	35.82 Å3	Chemaxon
Number of Rings	5	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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Details1. Poly [ADP-ribose] polymerase 1

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Zinc ion binding

Specific Function

Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This ...

Gene Name

PARP1

Uniprot ID

P09874

Uniprot Name

Poly [ADP-ribose] polymerase 1

Molecular Weight

113082.945 Da

References

1. Wang B, Chu D, Feng Y, Shen Y, Aoyagi-Scharber M, Post LE: Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-te trahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. J Med Chem. 2016 Jan 14;59(1):335-57. doi: 10.1021/acs.jmedchem.5b01498. Epub 2015 Dec 23. [Article]
2. FDA Approved Drug Products: TALZENNA (talazoparib) capsules, for oral use (June 2023) [Link]

Details2. Poly [ADP-ribose] polymerase 2

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Nad+ adp-ribosyltransferase activity

Specific Function

Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This ...

Gene Name

PARP2

Uniprot ID

Q9UGN5

Uniprot Name

Poly [ADP-ribose] polymerase 2

Molecular Weight

66205.31 Da

References

1. Wang B, Chu D, Feng Y, Shen Y, Aoyagi-Scharber M, Post LE: Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-te trahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. J Med Chem. 2016 Jan 14;59(1):335-57. doi: 10.1021/acs.jmedchem.5b01498. Epub 2015 Dec 23. [Article]
2. FDA Approved Drug Products: TALZENNA (talazoparib) capsules, for oral use (June 2023) [Link]

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Drug created at October 20, 2016 20:45 / Updated at July 18, 2023 22:56