Rucaparib Explained

Tradename:Rubraca
Dailymedid:Rucaparib
Pregnancy Category:Not recommended
Routes Of Administration:By mouth
Atc Prefix:L01
Atc Suffix:XK03
Legal Uk:POM
Legal Uk Comment:[1]
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Status:Rx-only
Bioavailability:30–45% (Tmax = 1.9 hours)
Protein Bound:70% (in vitro)
Metabolism:Liver (primarily CYP2D6; 1A2 and 3A4 to a lesser extent)
Elimination Half-Life:17–19 hours[2]
Index2 Label:as salt
Cas Number:283173-50-2
Cas Number2:1859053-21-6
Pubchem:9931954
Pubchem2:121490161
Iuphar Ligand:7736
Drugbank:DB12332
Drugbank2:DBSALT001982
Chemspiderid:8107584
Chemspiderid2:57643660
Unii:8237F3U7EH
Unii2:41AX9SJ8KO
Kegg:D10079
Kegg2:D10982
Chebi:134689
Chebi2:134692
Chembl:1173055
Chembl2:3833368
Pdb Ligand:RPB
Synonyms:CO-338, AG-014699, PF-0136738, PF-01367338
Iupac Name:8-Fluoro-2--1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one
C:19
H:18
F:1
N:3
O:1
Smiles:CNCc1ccc(cc1)c2[nH]c3cc(F)cc4C(=O)NCCc2c34
Stdinchi:1S/C19H18FN3O/c1-21-10-11-2-4-12(5-3-11)18-14-6-7-22-19(24)15-8-13(20)9-16(23-18)17(14)15/h2-5,8-9,21,23H,6-7,10H2,1H3,(H,22,24)
Stdinchikey:HMABYWSNWIZPAG-UHFFFAOYSA-N

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.[3]

The most common side effects include tiredness or weakness, nausea (feeling sick), increased levels of creatinine (which may indicate kidney problems) and liver enzymes in the blood (which may indicate liver damage), vomiting, anaemia (low red blood cell counts), decreased appetite, dysgeusia (taste disturbances), diarrhoea, thrombocytopenia (low levels of platelets) and abdominal pain (belly ache).

Medical uses

Rucaparib is indicated as monotherapy for the maintenance treatment of adults with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.[4]

In the United States, rucaparib is also indicated for the treatment of prostate cancer.

Pharmacology

Mechanism of action

Rucaparib inhibits "the contraction of isolated vascular smooth muscle, including that from the tumours of cancer patients. It also reduces the migration of some cancer and normal cells in culture."[5]

As a PARP inhibitor, rucaparib is expected to be more effective in the 9% of pancreatic cancers with a BRCA mutation (BRCA1 or BRCA2).[6]

History

It was discovered as part of a collaboration between scientists working at the Northern Institute of Cancer Research and Medical School of Newcastle University and Agouron Pharmaceuticals in San Diego, California.[7] It was being developed by Clovis Oncology until it was sold to Pharmaand GmbH (Pharma&) as part of Clovis's bankruptcy proceedings.[8]

Society and culture

Legal status

In December 2016, the US Food and Drug Administration (FDA) granted an accelerated approval for use in cases of pretreated advanced ovarian cancer.[9] [10]

It was designated an orphan medicinal product in the European Union in October 2012.[11] In March 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a conditional marketing authorization, intended for the treatment of relapsed or progressive ovarian cancer.[12] It was approved for medical use in the European Union in May 2018.[13]

Research

Clinical trials

After the FDA approval, TRITON2 and TRITON3 mCRPC studies were initiated in order to determine how patients with prostate cancer will respond to the rucaparib drug. The studies for these two trials are still going on and the estimated dates for the first results are range between 2019 and 2022.[14]

The ARIEL3 and ARIEL4 are two randomized, double-blind phase III studies. The ARIEL3 study was designed to evaluate the effect of the investigational agent as a maintenance treatment for the advanced platinum-sensitive ovarian cancer patients compared placebo after their response to at least two prior chemotherapies. The top-line results from the study were presented at the ESMO 2017 congress and right after that, it was published in the Lancet journal in September 2017. The findings showed significant improvement in progression-free survival (PFS) in patients treated with Rubraca than placebo. Recently, in October 2017, a supplemental sNDA for the rucaparib ARIEL3 maintenance treatment has been submitted to the FDA.[15]

Interim results from the ARIEL4 study to evaluate how patients will best respond to treatment with rucaparib compared with chemotherapy show a decrease in overall survival compared to standard of care.[16] [17] A detrimental effect in terms of overall survival (OS) has been observed for rucaparib compared to the chemotherapy-containing control arm (19.6 months and 27.1 months respectively with a Hazard Ratio (HR) of 1.550 (95% CI: 1.085, 2.214), p=0.0161) following a planned interim analysis (IA) in the post-approval randomized controlled study CO-338-043 (ARIEL4).

External links

Notes and References

  1. Web site: Rubraca 200mg film-coated tablets - Summary of Product Characteristics (SmPC) . (emc) . 19 June 2019 . 17 May 2020 . 29 August 2021 . https://web.archive.org/web/20210829165635/https://www.medicines.org.uk/emc/product/10026/smpc . live .
  2. Web site: Rubraca- rucaparib tablet, film coated . DailyMed . 6 April 2018 . 17 May 2020 . 9 May 2020 . https://web.archive.org/web/20200509213711/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a6d46c03-bb1d-417b-b8e5-3bffe352fe29 . live .
  3. Web site: Cancer Research Launches New Drug Trial. netdoctor.co.uk. Hearst Magazines UK. 20 December 2016. 10 January 2012. 26 December 2017. https://web.archive.org/web/20171226182244/http://www.netdoctor.co.uk/healthy-living/news/a21930/cancer-research-launches-new-drug-trial/. live.
  4. FDA approves rucaparib . U.S. Food and Drug Administration (FDA) . 6 April 2018 . 17 May 2020 . 17 May 2020 . https://web.archive.org/web/20200517181341/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-rucaparib-maintenance-treatment-recurrent-ovarian-fallopian-tube-or-primary-peritoneal . live .
  5. Web site: Does the PARP inhibitor AG014699 act via the nucleotide P2 receptor? . School of Pharmacy - PhD Projects 2009 . 17 November 2009 . dead . https://web.archive.org/web/20110613171138/http://www.qub.ac.uk/schools/SchoolofPharmacy/Filestore/Filetoupload,121186,en.pdf . 13 June 2011 .
  6. Web site: Rucaparib shows clinical benefit in pancreatic cancer patients with BRCA mutation. sciencedaily.com. 12 June 2016. 17 August 2019. https://web.archive.org/web/20190817092414/https://www.sciencedaily.com/releases/2016/06/160604131908.htm. live.
  7. White AW, Almassy R, Calvert AH, Curtin NJ, Griffin RJ, Hostomsky Z, Maegley K, Newell DR, Srinivasan S, Golding BT . 6 . Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase . Journal of Medicinal Chemistry . 43 . 22 . 4084–97 . November 2000 . 11063605 . 10.1021/jm000950v .
  8. Web site: Bell . Jacob . Navigating bankruptcy, Clovis reaches deal to sell cancer drug Rubraca . BioPharma Dive . 2023-04-07 . 2023-10-04.
  9. News: Bankhead C . PARP Inhibitor Gets FDA Nod for Ovarian Cancer . 20 December 2016 . MedPage Today, LLC. . 19 December 2016 . 20 December 2016 . https://web.archive.org/web/20161220093042/http://www.medpagetoday.com/HematologyOncology/OvarianCancer/62165 . live .
  10. Web site: Rubraca (rucaparib) Tablets . U.S. Food and Drug Administration (FDA) . 30 January 2017 . 17 May 2020 . 1 April 2021 . https://web.archive.org/web/20210401022155/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000TOC.cfm . live .
  11. Web site: EU/3/12/1049: Orphan designation for the treatment of ovarian cancer . European Medicines Agency (EMA) . 17 September 2018 . 8 August 2022 . 21 January 2021 . https://web.archive.org/web/20210121001607/https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3121049 . live .
  12. Web site: Rubraca . European Medical Agency . 22 March 2018 . https://web.archive.org/web/20180529202957/http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004272/smops/Positive/human_smop_001275.jsp&mid=WC0b01ac058001d127 . 29 May 2018 .
  13. Web site: Rubraca EPAR . European Medicines Agency (EMA) . 17 September 2018 . 17 May 2020 . 6 August 2020 . https://web.archive.org/web/20200806172356/https://www.ema.europa.eu/en/medicines/human/EPAR/rubraca . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  14. "Web site: Rucaparib Clinical Overview . Clovis Oncology . https://web.archive.org/web/20180413211112/http://clovisoncology.com/files/Clovis_Oncology_Clinical_Trial_Fact_Sheet_FINAL_1.pdf . 13 April 2018 .
  15. Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, Colombo N, Weberpals JI, Clamp A, Scambia G, Leary A, Holloway RW, Gancedo MA, Fong PC, Goh JC, O'Malley DM, Armstrong DK, Garcia-Donas J, Swisher EM, Floquet A, Konecny GE, McNeish IA, Scott CL, Cameron T, Maloney L, Isaacson J, Goble S, Grace C, Harding TC, Raponi M, Sun J, Lin KK, Giordano H, Ledermann JA . 6 . Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial . Lancet . 390 . 10106 . 1949–1961 . October 2017 . 28916367 . 5901715 . 10.1016/S0140-6736(17)32440-6 .
  16. Web site: Rucaparib (Rubraca): interim data from Study CO-338-043 (ARIEL4) show a decrease in overall survival compared to standard of care . European Medicines Agency (EMA) . 6 May 2022 . 8 May 2022 . 9 May 2022 . https://web.archive.org/web/20220509234140/https://www.ema.europa.eu/en/medicines/dhpc/rucaparib-rubracar-interim-data-study-co-338-043-ariel4-show-decrease-overall-survival-compared . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  17. "Web site: Ledermann J, Oza AM, Lorusso D . ARIEL3: a phase 3, randomised, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma (OC) . November 2017 . 28 . 23 February 2020 . 26 July 2019 . https://web.archive.org/web/20190726144435/https://clovisoncology.com/media/1046/rucaparib_jledermann_oral_esgo2017.pdf . live .

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