Niraparib

Structural formula
General
Non-proprietary name	Niraparib
other names	2- {4 - [(3 S ) -3-piperidyl] phenyl} indazole-7-carboxamide
Molecular formula	C 19 H 20 N 4 O
External identifiers / databases
CAS number 1038915-60-4 EC number 685-112-3 ECHA InfoCard 100.210.548 PubChem 24958200 DrugBank DB11793 Wikidata Q25326660
Drug information
ATC code	L01 XX54
Drug class	PARP inhibitors
properties
Molar mass	320.39 g · mol -1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 302-400 P: 264-270-273-301 + 312-330-391-501
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Niraparib (trade name Zejula ; manufacturer Tesaro ) is a drug from the group of PARP inhibitors that is used in the treatment of ovarian carcinoma (ovarian cancer).

The European Commission (EC) approved Zejula (niraparib) in the European Union (EU) in November 2017 . Zejula is the first approved oral once-daily poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor in Europe that does not require BRCA mutation status testing or other biomarker testing . Niraparib was approved by the US Food and Drug Administration (FDA) for the United States in March 2017 .

Ovarian cancer in Europe

Europe has one of the highest incidences of ovarian cancer in the world , with around 45,000 women diagnosed annually . Ovarian cancer affects about 1.3 in 10,000 women in the European Union, where it is the sixth most common cancer in women and the fifth leading cause of cancer-related death in women. Despite the high initial response rates to platinum-based chemotherapy , around 85% of patients with advanced ovarian cancer have a relapse after first-line treatment. The effectiveness of chemotherapy also decreases with increasing therapy line.

Clinical information

application areas

Niraparib is used as a monotherapy for maintenance therapy in adult patients with relapse of a platinum-sensitive , poorly differentiated serous carcinoma of the ovaries (ovaries), tubes (fallopian tubes) or with primary peritoneal carcinoma who are in remission (complete or partial ) after platinum-based chemotherapy ) are applied.

Type and duration of application

The approved starting dose of Zejula is 300 milligrams once a day. A starting dose of 200 milligrams once a day may be considered for patients weighing less than 58 kilograms.

unwanted effects

The most common adverse effects are thrombocytopenia (34%), anemia (25%), neutropenia (20%) and hypertension (8%). After individual dose adjustments, the incidence of grade 3/4 thrombocytopenia was low and was 2.4% after three months. Most of the haematological side effects could be managed well through dose modifications. The rates of discontinuation due to thrombocytopenia, neutropenia, and anemia were 3%, 2% and 1%, respectively.

Mechanism of action

PARP inhibitors are inhibitors of the enzyme P oly- A DP R ibose- P Polymerase (PARP) and prevent cancer cells through a cytostatic drugs induced DNA damage repair. PARP inhibitors are therefore primarily an option as maintenance therapy after chemotherapy .

Other Information

Approval situation / orphan drug status

The FDA approved niraparib for the US in March 2017 and the EC for the EU in November 2017. Approval in the USA was preceded by an FDA Fast Track Designation , which significantly accelerated the approval process. In September 2017, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) gave a positive assessment of the application for approval of ZEJULA® (niraparib).

In April 2010 resp. in August 2010, Niraparib was approved by the FDA resp. the EC has been granted orphan drug status for the treatment of rare diseases .

Guidelines

The National Comprehensive Cancer Network (NCCN) has included niraparib in its ovarian cancer treatment guidelines Version 1.2017 (April 2017) as maintenance therapy for patients with platinum-sensitive disease who have a partial or complete response after completing two or more lines of platinum-based chemotherapy.

Studies

The EU approval of niraparib is based on data from the ENGOT-OV16 / NOVA clinical trial, a double-blind, placebo-controlled, international phase 3 study of niraparib in which 553 patients with relapsed ovarian cancer who were on their most recent platinum-based chemotherapy participated had fully or partially addressed. The primary study endpoint was progression-free survival (PFS). About two thirds of the patients did not have a germline BRCA mutation. Progression in the NOVA study was assessed by an independent central review of radiological or clinical progression.

Zejula significantly extended the PFS compared to the control arm in women with and without a BRCA germline mutation. Zejula reduced the risk of disease progression or death by 73% (HR 0.27) in women with a BRCA germline mutation and by 55% in women without a BRCA germline mutation (HR 0.45). After two years on niraparib, 42% of women with the BRCA germline mutation had no disease progression compared to 16% of women who received placebo. Patients with a partial or full response to chemotherapy at the start of the study benefited to the same extent.

The full results of the ENGOT-OV16 / NOVA study were presented at the European Society for Medical Oncology (ESMO) Congress in Copenhagen in October 2016. The data were simultaneously published in the New England Journal of Medicine .

Tesaro has set up an extensive niraparib study program by evaluating the activity of niraparib across multiple cancers. Several possible combinations of niraparib with other therapeutic agents are also being evaluated. The ongoing development program for niraparib includes a phase 3 study in patients who received first-line therapy for the treatment of ovarian cancer (PRIMA study) and a phase 2 registration study in patients who received multiple lines of treatment for ovarian cancer (QUADRA study) received. Several combination studies are ongoing; including studies with niraparib plus pembrolizumab (TOPACIO study) and niraparib plus bevacizumab (AVANOVA study).

Out-licensing

Janssen Biotech has licensed the rights to develop and commercialize niraparib specifically for prostate cancer patients worldwide, except in Japan.

literature

• Lotte van Andel et al .: Human mass balance study and metabolite profiling of 14C-niraparib, a novel poly (ADP-Ribose) polymerase (PARP) -1 and PARP-2 inhibitor, in patients with advanced cancer , Investigational New Drugs, March 2017, doi: 10.1007 / s10637-017-0451-2
• Susanne Heinzl: European Society for Medical Oncology (ESMO) 2016 - Recurrent Ovarian Cancer: Niraparib Extends Progression-Free Survival , Medscape - October 10, 2016.

Web links

• www.esmo.org
• www.tesarobio.com
• www.zejula.com

Individual evidence

1. ↑ New ATC / DDD classification; Implementation in the ATC / DDD (index: 2018) WHO Collaborating Center for Drug Statistics Methodology, accessed December 4, 2017.
2. ↑ ^{a b} selleck.cn: MSDS , accessed December 27, 2019.
3. ↑ European public assessment report (EPAR) for Zejula , WebSite EMA, accessed on December 5, 2017.
4. ↑ ^{a b} Mirza MR et al .: Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer . In: New England Journal of Medicine . No. 375, 2016, pp. 2154-2164. doi : 10.1056 / NEJMoa1611310 .
5. ↑ ^{a b c d e f g} TESARO Announces European Commission Approval of ZEJULA® for Women With Recurrent Ovarian Cancer ( Memento from December 1, 2017 in the Internet Archive ), PM TESARO from November 20, 2017, accessed on December 4, 2017.
6. ↑ ^{a b} Niraparib (ZEJULA) , PM FDA of March 27, 2017, accessed on December 4, 2017.
7. ↑ TESARO Announces Availability of Zejula ™ (Niraparib) for Patients With Recurrent Ovarian Cancer in the US , PM TESARO of April 19, 2017, accessed December 4, 2017.
8. ^ World Cancer Research Fund International , accessed December 4, 2017.
9. ↑ ^{a b} EUCAN (EU, EEA and Switzerland) ( Memento from December 5, 2017 in the Internet Archive ) Estimated incidence, mortality & prevalence, 2012, accessed on December 4, 2017.
10. ↑ CDC Ovarian Cancer Statistics, accessed December 4, 2017.
11. ↑ ^{a b} Zejula 100mg hard capsules , specialist information on www.fachinfo.de (access-protected, only for specialist groups), accessed on December 12, 2017.
12. ↑ Jones P et al .: Niraparib: A Poly (ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination . In: Journal of Medicinal Chemistry . No. 58, 2015, pp. 3302–3314. doi : 10.1021 / jm5018237 .
13. ↑ Niraparib Receives FDA Fast Track Designation for the Treatment of Recurrent Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer , PM ESMO, September 15, 2016, accessed December 4, 2017.
14. ↑ Zejula - Opinion , European Medicines Agency, accessed December 4, 2017.
15. ↑ Search Orphan Drug Designations and Approvals , Accessdata FDA, accessed December 3, 2017.
16. ↑ orphan designation , European Medicines Agency, accessed December 4, 2017.
17. ↑ NCCN Guidelines for Patients | Ovarian Cancer , accessed December 4, 2017.
18. ↑ Wang J et al. The Exposure-Response Relationship of Niraparib in Patients with gBRCAmut and Non-gBRCAmut: Results from the ENGOT-OV16 / NOVA Trial. ESMO; 2017 Sep 8-12; Madrid, Spain.
19. ↑ A Maintenance Study With Niraparib Versus Placebo in Patients With Platinum Sensitive Ovarian Cancer , clinicaltrials.gov, accessed December 4, 2017.
20. ↑ RESEARCH CENTER , TESARO website, accessed on December 4, 2017.

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