Rucaparib
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| Surname | Rucaparib | |||||||||||||||||||||
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| Molecular formula | C 19 H 18 FN 3 O | |||||||||||||||||||||
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PARP inhibitors |
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| Molar mass | 323.37 g mol −1 | |||||||||||||||||||||
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | ||||||||||||||||||||||
Rucaparib is an anti- tumor agent from the group of PARP inhibitors , which is used as Rubraca (manufacturer: Clovis Oncology ) for the oral treatment of advanced, relapsed ovarian cancer.
application areas
In December 2016, rucaparib was approved for the treatment of relapsed ovarian cancer with BRCA mutations (mutations in the BRCA1 or BRCA2 genes) by the US Food and Drug Administration in the United States. In May 2018, the European Commission granted approval in the European Union (EU) as monotherapy for the treatment of adult patients with platinum-sensitive, relapsed or progressive high-grade ovarian, fallopian tube or peritoneal carcinoma with BRCA mutations (germline and / or somatic) who have been treated with two or more previous platinum-based chemotherapy lines and who do not tolerate further platinum-based chemotherapy. This made rucaparib the first PARP inhibitor to be approved in the EU for the recurrence treatment of BRCA-mutated ovarian cancer.
In January 2019, the approval was extended in the EU as monotherapy for the treatment of adult patients with platinum-sensitive, relapsed or progressive high-grade ovarian, fallopian tube or primary peritoneal cancer who are in remission (complete or partial) after platinum-based chemotherapy. This indication is independent of the presence of a BRCA mutation. Rubraca has been available on the German market since March 2019.
In April 2018, the European Society for Medical Oncology (ESMO) and European Society of Gynecological Oncology (ESGO) included rucaparib in the treatment recommendations for ovarian cancer both as maintenance therapy after a response to platinum-based chemotherapy from the second line and from the third line of therapy, as well as monotherapy Patients with BRCA mutations included.
Type and duration of application
Rucaparib tablets come in three strengths: 300 mg, 250 mg and 200 mg. The initial dose according to the approval is 600 mg twice a day, which corresponds to a total daily dose of 1200 mg.
unwanted effects
The most common adverse reactions experienced in rucaparib-treated patients were nausea, fatigue / asthenia, vomiting, anemia, abdominal pain, dysgeusia , increased ALT , increased AST , decreased appetite, diarrhea , thrombocytopenia, and increased creatinine . The majority of the side effects were mild to moderate (1st or 2nd degree). The most common higher-grade side effects (Grade 3 or higher) included anemia (23%), elevated ALT levels (10%), fatigue / asthenia (10%), neutropenia (8%), thrombocytopenia (6%), and nausea (5 %). Moderate to severe side effects (i.e. 3rd or 4th degree according to CTCAE ), such as neutropenia, anemia and thrombocytopenia, can be mitigated with dose interruptions and / or dose reductions. Side effects that led to permanent discontinuation occurred in 10% of the patients.
Mechanism of action
Rucaparib blocks the activity of poly (ADP-ribose) polymerases (PARP) (PARP-1, -2 and -3), which are used to repair single-stranded DNA breaks . In cancer cells that have defects in the repair of DNA double-strand breaks , e.g. B. mediated by BRCA mutations or defects in other DNA repair pathways, the inhibition of PARP leads to the accumulation of DNA double-strand breaks, whereby the cells are driven into programmed cell death ( apoptosis ) (synthetic lethality).
Clinical studies
The approval of rucaparib as relapse maintenance therapy was based on the randomized double-blind phase III study ARIEL3, in which the efficacy and safety compared to placebo was examined in 564 patients with ovarian cancer who had a complete or partial response to at least two previous platinum-based patients Chemotherapy showed. ARIEL3 achieved both the primary endpoint - prolongation of investigator-determined progression-free survival (PFS) compared to placebo (median 10.8 vs. 5.4 months) - and the important secondary endpoint - prolongation of PFS through an independent radiological review (independent radiological review, IRR; median 13.7 vs. 5.4 months) - regardless of the BRCA status. Patients who showed a partial or complete response to chemotherapy at the start of the study benefited to the same extent.
The approval of rucaparib as third-line relapse monotherapy in patients with advanced epithelial ovarian, fallopian tube or primary peritoneal carcinoma with BRCA mutations is based on the results of the two single-arm phase II studies ARIEL2 and study 10.
Further studies are ongoing to investigate the effectiveness of rucaparib in ovarian cancer and in other indications, including prostate cancer. In January 2020, rucaparib was granted an extension of approval for BRCA-mutated, relapsed castration-resistant prostate cancer and received a "priority review designation".
Pharmacokinetic information
The mean absolute oral bioavailability after a single dose of 12-120 mg was 36%, maximum plasma levels averaged 1.9 hours. The metabolism takes place via various enzymes of the cytochrome P450 system; predominantly CYP2D6, to a lesser extent CYP1A2 and CYP3A4 . The mean half-life of rucaparib is 25.9 hours.
Individual evidence
- ↑ There is not yet a harmonized classification for this substance . A label for 8-fluoro-2- {4 - [(methylamino) methyl] phenyl} -1,3,4,5-tetrahydro-6H-pyrrolo [4,3,2-ef] is shown, which is derived from a self-classification by the distributor ] [2] benzazepin-6-one in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on July 12, 2020.
- ↑ Resources for Information, Approved Drugs: Rucaparib , FDA notification dated December 19, 2016, accessed May 7, 2020.
- ↑ a b c d e f European Medicines Agency : Summary of Product Characteristics: Rubraca film-coated tablets , as of May 2019 ( PDF ).
- ↑ a b EMA overview of Rucaparib and why it is authorized in the EU ( PDF )
- ↑ N. Colombo, et al .: ESMO – ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumors and recurrent disease . In: International Journal of Gynecological Cancer . tape 29 (2019) , pp. 728-760 , doi : 10.1136 / ijgc-2019-000308 .
- ^ LE Dockery, CC Gunderson, KN Moore: Rucaparib: the past, present, and future of a newly approved PARP inhibitor for ovarian cancer . In: OncoTargets and Therapy . Volume 10, June 2017, ISSN 1178-6930 , p. 3029-3037 , doi : 10.2147 / ott.s114714 .
- ↑ Coleman RL, et al. Lancet. 2017; 390 (10106): 1949-1961.
- ↑ Ledermann JA, et al. ESMO 2019, Abstract 1001P.
- ↑ Oza AM, et al. Gynecol Oncol. 2017; 147 (2): 267-275. doi: 10.1016 / j.ygyno.2017.08.022.
- ^ ClinicalTrial.gov. NCT02952534. A Study of Rucaparib in Patients With Metastatic Castration-Resistant Prostate Cancer and Homologous Recombination Gene Deficiency (TRITON2)
- ^ ClinicalTrial.gov. NCT02975934. A Study of Rucaparib Versus Physician's Choice of Therapy in Patients With Metastatic Castration-resistant Prostate Cancer and Homologous Recombination Gene Deficiency (TRITON3)
- ↑ Clovis Oncology's Rubraca (rucaparib) granted FDA priority review for advanced prostate cancer [news release]. Boulder, Colorado: Clovis Oncology; January 15, 2020. https://bit.ly/2RfG4da. Accessed: April 17, 2020.