Talazoparib

Last updated

Talazoparib
Talazoparib.svg
Clinical data
Trade names Talzenna
Other namesBMN-673
AHFS/Drugs.com Monograph
MedlinePlus a618070
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class PARP inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 74%
Metabolism Minimal metabolisation (<30%)
Elimination half-life 90 (±58) hrs
Excretion 69% in urine, 20% in feces
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
CAS Number
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.249.319 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H14F2N6O
Molar mass 380.359 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, sold under the brand name Talzenna, is an anti-cancer medication used for the treatment of breast cancer and prostate cancer. [5] It is an orally available poly ADP ribose polymerase PARP inhibitor marketed by Pfizer for the treatment of advanced breast cancer with germline BRCA mutations. [8] Talazoparib is similar to the first in class PARP inhibitor, olaparib. [9] [10]

Contents

The most common adverse reactions of any grade were fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, decreased appetite. [11]

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. [9] [12] [13] [7] In January 2024, the European Commission approved talazoparib in combination with enzalutamide for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in adults. [14]

Medical uses

Talazoparib is indicated for the treatment of breast cancer and prostate cancer. [5] [7] It is indicated for the treatment of people with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2‑negative locally advanced or metastatic breast cancer; [11] and, in combination with enzalutamide, for homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). [15]

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. [5]

The FDA label includes warnings and precautions for myelodysplastic syndrome/acute myeloid leukemia, myelosuppression, and embryo-fetal toxicity. [11]

Interactions

Combination with drugs that inhibit P-glycoprotein or BCRP may increase talazoparib concentrations in the body. [5]

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. [8] 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. [16] However, this increased potency may not translate directly to clinical effectiveness as many other factors must be considered. [10] [16]

History

The approval by the US Food and Drug Administration (FDA) for treating breast cancer was based on EMBRACA (NCT01945775), an open‑label trial randomizing 431 participants (2:1) with gBRCAm HER2‑negative locally advanced or metastatic breast cancer to receive talazoparib (1 mg) or physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). [11] All participants were required to have a known deleterious or suspected deleterious gBRCA mutation and must have received no more than three prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease. [11] Participants were required to have received treatment with an anthracycline and/or a taxane (unless contraindicated) in the neoadjuvant, adjuvant, and/or metastatic treatment setting. [11] The trial was conducted at 145 sites in the US, Europe, Brazil, South Korea, Taiwan, Israel, and Australia. [17]

The efficacy of talazoparib used to treat prostate cancer was evaluated in TALAPRO-2 (NCT03395197), a randomized, double-blind, placebo-controlled, multi-cohort trial enrolling 399 participants with HRR gene-mutated mCRPC. [15] Participants were randomized (1:1) to receive enzalutamide 160 mg daily plus either talazoparib 0.5 mg or placebo daily. [15] Participants were required to have a prior orchiectomy and, if not performed, received gonadotropin-releasing hormone (GnRH) analogs. [15] Participants with prior systemic therapy for mCRPC were excluded; however, prior CYP17 inhibitors or docetaxel for metastatic castration-sensitive prostate cancer (mCSPC) was permitted. [15] Randomization was stratified by previous treatment with a CYP17 inhibitor or docetaxel. [15] HRR genes (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) were assessed prospectively using tumor tissue and/or circulating tumor DNA (ctDNA)-based next generation sequencing assays. [15]

Society and culture

Economics

Talazoparib was developed by BioMarin Pharmaceutical Inc. and Medivation Inc. acquired all worldwide rights to talazoparib in August 2015. [18] Medivation acquired talazoparib for $410 million with additional payments of up to $160 million in royalties and milestones. [19] Pfizer acquired Medivation in 2016.

Related Research Articles

Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification. Triple-negative is sometimes used as a surrogate term for basal-like.

<span class="mw-page-title-main">Enzalutamide</span> Antiandrogen medication used in treatment of prostate cancer

Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC), nonmetastatic castration-resistant prostate cancer, and metastatic castration-sensitive prostate cancer (mCSPC). It is taken by mouth.

<span class="mw-page-title-main">Olaparib</span> Chemical compound (cancer therapy drug)

Olaparib, sold under the brand name Lynparza, is a medication for the maintenance treatment of BRCA-mutated advanced ovarian cancer in adults. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers.

<span class="mw-page-title-main">PARP inhibitor</span> Pharmacological enzyme inhibitors of poly (ADP-ribose) polymerases

PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP).

<span class="mw-page-title-main">Iniparib</span> Chemical compound

Iniparib was a drug candidate for cancer treatment. It was originally believed to act as an irreversible inhibitor of PARP1 and possibly other enzymes through covalent modification, but its effects against PARP were later disproven. It underwent clinical trials for treatment of some types of breast cancer, but was discontinued after disappointing phase III clinical trials.

<span class="mw-page-title-main">Veliparib</span> Chemical compound

Veliparib (ABT-888) is a potential anti-cancer drug acting as a PARP inhibitor. It kills cancer cells by blocking a protein called PARP, thereby preventing the repair of DNA or genetic damage in cancer cells and possibly making them more susceptible to anticancer treatments. Veliparib may make whole brain radiation treatment work more effectively against brain metastases from NSCLC. It has been shown to potentiate the effects of many chemotherapeutics, and as such has been part of many combination clinical trials.

<span class="mw-page-title-main">Rucaparib</span> Chemical compound

Rucaparib, sold under the brand name Rubraca, is a PARP inhibitor used as an anti-cancer agent. Rucaparib is a first-in-class pharmaceutical drug targeting the DNA repair enzyme poly-ADP ribose polymerase-1 (PARP-1). It is taken by mouth.

<span class="mw-page-title-main">Cabazitaxel</span> Chemical compound

Cabazitaxel, sold under the brand name Jevtana, is a semi-synthetic derivative of a natural taxoid. It is a microtubule inhibitor, and the fourth taxane to be approved as a cancer therapy.

Medivation was an American biopharmaceutical company focused on development of novel therapies to treat serious diseases for which there are limited treatment options. Medivation was headquartered in San Francisco, California, beginning operations in December 2004 with the acquisition of Medivation Neurology, Inc. Its final CEO was David Hung.

<span class="mw-page-title-main">Palbociclib</span> Medication for HR+ HER2− breast cancer

Palbociclib, sold under the brand name Ibrance among others, is a medication developed by Pfizer for the treatment of HR-positive and HER2-negative breast cancer. It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. Palbociclib was the first CDK4/6 inhibitor to be approved as a cancer therapy.

<span class="mw-page-title-main">Sacituzumab govitecan</span> Antibody-drug conjugate

Sacituzumab govitecan, sold under the brand name Trodelvy by Gilead Sciences, is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate used for the treatment of metastatic triple-negative breast cancer and metastatic urothelial cancer.

Darolutamide, sold under the brand name Nubeqa, is an antiandrogen medication which is used in the treatment of non-metastatic castration-resistant prostate cancer in men. It is specifically approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration. The medication is taken by mouth twice per day with food.

<span class="mw-page-title-main">Apalutamide</span> Chemical compound

Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication used for the treatment of prostate cancer. It is an androgen receptor inhibitor. It is taken by mouth.

<span class="mw-page-title-main">Abemaciclib</span> Anti-breast cancer medication

Abemaciclib, sold under the brand name Verzenio among others, is a medication for the treatment of advanced or metastatic breast cancers. It was developed by Eli Lilly and it acts as a CDK inhibitor selective for CDK4 and CDK6.

<span class="mw-page-title-main">Alpelisib</span> Chemical compound

Alpelisib, sold under the brand name Piqray among others, is a medication used to treat certain types of breast cancer. It is used together with fulvestrant. It is taken by mouth. It is marketed by Novartis.

<span class="mw-page-title-main">Niraparib</span> Anti-cancer medication

Niraparib, sold under the brand name Zejula, is an anti-cancer medication used for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is taken by mouth. It is a PARP inhibitor.

<span class="mw-page-title-main">Elacestrant</span> Chemical compound

Elacestrant, sold under the brand name Orserdu, is a selective estrogen receptor degrader (SERD) used in the treatment of breast cancer. It is taken by mouth.

<span class="mw-page-title-main">Trastuzumab deruxtecan</span> Medication

Trastuzumab deruxtecan, sold under the brand name Enhertu, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the topoisomerase I inhibitor deruxtecan. It is licensed for the treatment of breast cancer or gastric or gastroesophageal adenocarcinoma. Trastuzumab binds to and blocks signaling through epidermal growth factor receptor 2 (HER2/neu) on cancers that rely on it for growth. Additionally, once bound to HER2 receptors, the antibody is internalized by the cell, carrying the bound deruxtecan along with it, where it interferes with the cell's ability to make DNA structural changes and replicate its DNA during cell division, leading to DNA damage when the cell attempts to replicate itself, destroying the cell.

<span class="mw-page-title-main">HRDetect</span>

HRDetect is a whole-genome sequencing (WGS)-based classifier designed to predict BRCA1 and BRCA2 deficiency based on six mutational signatures. Additionally, the classifier is able to identify similarities in mutational profiles of tumors to that of tumors with BRCA1 and BRCA2 defects, also known as BRCAness. This classifier can be applied to assess the implementation of PARP inhibitors in patients with BRCA1/BRCA2 deficiency. The final output is a probability of BRCA1/2 mutation.

Niraparib/abiraterone acetate, sold under the brand name Akeega, is a fixed-dose combination anti-cancer medication used for the treatment of prostate cancer. It contains niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, and abiraterone acetate, a CYP17 inhibitor.

References

  1. 1 2 "Talzenna APMDS". Therapeutic Goods Administration (TGA). 26 May 2022. Retrieved 10 March 2024.
  2. ↑ "Talzenna Product information". Health Canada . 25 April 2012. Archived from the original on 30 May 2022. Retrieved 29 May 2022.
  3. ↑ "Summary Basis of Decision (SBD) for Talzenna". Health Canada . 23 October 2014. Archived from the original on 31 May 2022. Retrieved 29 May 2022.
  4. ↑ "Talzenna 0.25 mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). 1 June 2021. Archived from the original on 9 July 2021. Retrieved 9 July 2021.
  5. 1 2 3 4 5 "Talzenna- talazoparib capsule". DailyMed. 4 September 2023. Archived from the original on 30 July 2023. Retrieved 13 November 2023.
  6. ↑ "Talzenna- talazoparib capsule". DailyMed. 4 September 2023. Archived from the original on 29 May 2023. Retrieved 13 November 2023.
  7. 1 2 3 "Talzenna EPAR". European Medicines Agency (EMA). 8 July 2019. Archived from the original on 19 May 2020. Retrieved 10 March 2020.
  8. 1 2 Medivation Inc. "Talazoparib". Archived from the original on 8 June 2017. Retrieved 21 November 2016.
  9. 1 2 "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.
  10. 1 2 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.
  11. 1 2 3 4 5 6 "FDA approves talazoparib for gBRCAm HER2-negative locally advanced or". U.S. Food and Drug Administration. 16 October 2018. Retrieved 8 March 2024.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  12. ↑ "European Commission Approves Talzenna (talazoparib) for Patients with Inherited (Germline) BRCA-Mutated Locally Advanced or Metastatic Breast Cancer" (Press release). Pfizer Inc. Archived from the original on 22 September 2020. Retrieved 23 June 2019.
  13. ↑ "Drug Approval Package: Talzenna (talazoparib)". U.S. Food and Drug Administration (FDA). 29 October 2018. Archived from the original on 30 October 2020. Retrieved 10 March 2020.
  14. ↑ "Pfizer's Talzenna combination receives EC approval for metastatic prostate cancer". PMLive. 10 January 2024. Retrieved 11 January 2024.
  15. 1 2 3 4 5 6 7 "FDA approves talazoparib with enzalutamide for HRR gene-mutated metast". U.S. Food and Drug Administration. 20 June 2023. Retrieved 8 March 2024.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  16. 1 2 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.
  17. ↑ "Drug Trial Snapshot: Talzenna". U.S. Food and Drug Administration (FDA). 16 October 2018. Retrieved 9 March 2024.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  18. ↑ 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" (Press release). Archived from the original on 5 February 2017. Retrieved 21 November 2016.
  19. ↑ Inman S (25 August 2015). "Medivation Acquires BioMarin's PARP Inhibitor Talazoparib". Archived from the original on 21 November 2016. Retrieved 21 November 2016.
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