OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Niraparib	1038915-60-4	C19-H20-N4-O

ANNOTATED BIBLIOGRAPHY

References updated: 20 July 2017

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of protein kinase or PARP inhibitors such as niraparib, olaparib and rucaparib).
• DeLeve LD. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents discusses several tyrosine kinase inhibitors including imatinib, gefitinib, erlotinib and crizotinib, but not olaparib or rucaparib).
• Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.

  (Textbook of pharmacology and therapeutics).
• Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, Greninger P, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 2012; 483 (7391): 570-5. [PMC free article: PMC3349233] [PubMed: 22460902]

  (Correlation of mutated cancer genes identified in cancer cell lines with their sensitivity to growth inhibition by antineoplastic agents revealed the possible role of PARP inhibition in several tumors including Ewing sarcoma).
• Plummer R, Lorigan P, Steven N, Scott L, Middleton MR, Wilson RH, Mulligan E, et al. A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation. Cancer Chemother Pharmacol 2013; 71: 1191-9. [PubMed: 23423489]

  (Among 46 patients with metastatic melanoma treated with the combination of temozolomide and rucaparib [12 mg/m² intravenously for 5 days of 28-day cycles], found objective response rates of 17%, side effects including myelosuppression were common and one patient died of “hepatorenal failure”).
• Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf 2013; 36: 491-503. [PubMed: 23620168]

  (Review of the hepatotoxicity of 18 tyrosine kinase inhibitors approved for use in cancer in the US as of 2013, discusses imatinib and sunitinib, but not olaparib or rucaparib).
• Bao Z, Cao C, Geng X, Tian B, Wu Y, Zhang C, Chen Z, Li W, et al. Effectiveness and safety of poly (ADP-ribose) polymerase inhibitors in cancer therapy: A systematic review and meta-analysis. Oncotarget 2016; 7: 7629-39 . [PMC free article: PMC4884943] [PubMed: 26399274]

  (Systematic review of the efficacy and safety of PARP inhibitors in cancer chemotherapy mentioned that in 5 placebo controlled trials, ALT elevations were no more frequent with the PARP inhibitors than in “controls”, but neither were there any other adverse events).
• Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Br J Cancer 2016; 115: 1157-73. [PMC free article: PMC5104889] [PubMed: 27736844]

  (Review of role of BRCA 1 and 2 mutations in tumorigenesis and the mechanism of action of PARP inhibitors).
• Ledermann JA. PARP inhibitors in ovarian cancer. Ann Oncol 2016; 27 Suppl 1: i40-4. [PubMed: 27141070]

  (Review of possible role of PARP inhibitors in ovarian cancer mentions that cells with defective BRCA proteins are deficient in repair of double-stranded breaks in DNA by homologous recombination and rely on other pathways, notably PARP that detects single DNA strand breaks and activates effector proteins to initiate repair).
• Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD, Miranda S, Hylands L, et al. The poly (ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol 2013; 14: 882-92. [PubMed: 23810788]

  (Among 100 patients with advanced or metastatic cancers refractory to chemotherapy who received escalating doses of niraparib, common side effects were anemia [48%], nausea [42%], fatigue [42%], thrombocytopenia [35%], anorexia [26%], neutropenia [24%], and constipation [23%]; severe side effects included neutropenia, prolongation of the QTc interval and severe fatigue; no mention of ALT elevations or hepatotoxicity).
• Infante JR, Burris HA 3rd. PARP inhibitors: pitfalls and promises. Lancet Oncol 2013; 14: 798-9. [PubMed: 23810789]

  (Commentary in response to Sandhu [2013]).
• Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, et al.; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016; 375: 2154-64. [PubMed: 27717299]

  (Among 553 patients with recurrent ovarian cancer after platinum-based chemotherapy treated with niraparib or placebo, progression-free survival was improved by niraparib, particularly in patients with germline BRCA mutations while adverse events were mostly hematologic and manageable; no mention of ALT elevations or hepatotoxicity).
• Scott LJ. Niraparib: First Global Approval. Drugs 2017; 77: 1029-34. [PubMed: 28474297]

  (Review of the mechanism of action, pharmacology, clinical efficacy and safety of niraparib shortly after its initial approval in the US; no mention of ALT elevations or hepatotoxicity).