OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Rucaparib	283173-50-2	Not available

ANNOTATED BIBLIOGRAPHY

References updated: 01 June 2017

Abbreviations: PARP, poly adenine diphosphate ribose polymerase

• 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 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).
• Ledford H. Resurrected cancer drug faces regulators. Nature 2014; 510 (7506): 454. [PubMed: 24965630]

  (News report on olaparib, the initial PARP inhibitor, which in early clinical trials showed little effect on survival in women with ovarian carcinoma, but on reassessment limiting analysis of cases with BRCA mutations found evidence of an effect on cancer growth, reviving interest in pursuing olaparib as therapy of selected patients with ovarian cancer).
• Bao Z, Cao C, Geng X, Tian B, Wu Y, Zhang C, Chen Z, 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 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-i44. [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).
• Drew Y, Ledermann J, Hall G, Rea D, Glasspool R, Highley M, Jayson G, et al. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly (ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br J Cancer 2016; 114: 723-30. [PMC free article: PMC4882768] [PubMed: 27002934]

  (Among 78 patients with BRCA 1 or 2 mutations and advanced ovarian or breast cancer treated with rucaparib, the objective response rate was 7% and adverse events were common but usually manageable; no mention of ALT elevations or hepatotoxicity).
• Wilson RH, Evans TJ, Middleton MR, Molife LR, Spicer J, Dieras V, Roxburgh P, et al. A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours. Br J Cancer 2017; 116 (7): 884-92. [PMC free article: PMC5379148] [PubMed: 28222073]

  (Among 85 patients with advanced cancers treated with various chemotherapy regimens and rucaparib, 10 had at least a partial response and adverse events were common including fatigue, nausea, constipation and anemia; no mention of ALT elevations or hepatotoxicity).
• Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, Konecny GE, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017; 18: 75-87. [PubMed: 27908594]

  (Among 204 patients with relapsed, platinum-sensitive ovarian cancer treated with rucaparib [600 mg twice daily], the median progression free survival was longer in those with BRCA mutations [12.8 months] than in those with other tumor mutations [5.7 and 5.2 months], while common side effects included ALT or AST elevations in 43% of patients that were above 5 times ULN in 12%, although there were no treatment related deaths).