FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline <i>BRCA</i>-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy

Kim, Geoffrey; Ison, Gwynn; McKee, Amy E.; Zhang, Hui; Tang, Shenghui; Gwise, Thomas; Sridhara, Rajeshwari; Lee, Eunice; Tzou, Abraham; Philip, Reena; Chiu, Haw-Jyh; Ricks, Tiffany K.; Palmby, Todd R.; Russell, Anne Marie; Ladouceur, Gaétan; Pfuma, Elimika; Li, Hongshan; Zhao, Liang; Liu, Qi; Venugopal, Rajesh; Ibrahim, Amna; Pazdur, Richard

doi:10.1158/1078-0432.ccr-15-0887

Cited by 444 publications

(323 citation statements)

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“…PARP inhibition is 1000 times more potent in In BRCA-deficient cells in comparison to BRCA wild-type cells [37,39]. Olaparib is the most extensively investigated PARPi and is approved by the US FDA for use in pretreated advanced germline BRCA mutated ovarian cancer [40]. As already indicated, SCLC exhibits high levels of PARP1 expression and there are preclinical data to support PARP1 inhibition for clinical evaluation as a monotherapy and in combination with DNA damaging agents [36,41,42].…”

Section: Parp Inhibitorsmentioning

confidence: 99%

Targeting DNA damage in SCLC

et al. 2017

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A B S T R A C TSCLC accounts for 15% of lung cancer worldwide. Characterised by early dissemination and rapid development of chemo-resistant disease, less than 5% of patients survive 5 years. Despite 3 decades of clinical trials there has been no change to the standard platinum and etoposide regimen for first line treatment developed in the 1970's.The exceptionally high number of genomic aberrations observed in SCLC combined with the characteristic rapid cellular proliferation results in accumulation of DNA damage and genomic instability. To flourish in this precarious genomic context, SCLC cells are reliant on functional DNA damage repair pathways and cell cycle checkpoints.Current cytotoxic drugs and radiotherapy treatments for SCLC have long been known to act by induction of DNA damage and the response of cancer cells to such damage determines treatment efficacy. Recent years have witnessed improved understanding of strategies to exploit DNA damage and repair mechanisms in order to increase treatment efficacy.This review will summarise the rationale to target DNA damage response in SCLC, the progress made in evaluating novel DDR inhibitors and highlight various ongoing challenges for their clinical development in this disease.

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Section: Parp Inhibitorsmentioning

confidence: 99%

Targeting DNA damage in SCLC

et al. 2017

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“…Single-agent olaparib is approved in the United States for the treatment of patients with advanced germline BRCA1/2-mutated ovarian cancer who have received three or more lines of chemotherapy (27,28). Rucaparib (CO-338; formerly known as AG-014447 and PF-01367338) is a potent small-molecule inhibitor of PARP-1, -2, and -3 (29,30), and was approved in the United States in December 2016 for the treatment of patients with advanced ovarian cancer associated with deleterious germline or somatic BRCA mutations who have received two or more chemotherapies (31).…”

Section: Introductionmentioning

confidence: 99%

A Phase I–II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors

Kristeleit

Shapiro

Burris

et al. 2017

Clinical Cancer Research

214

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Purpose: Rucaparib is a potent, oral, small-molecule PARP inhibitor. This phase I-II study was the first to evaluate singleagent oral rucaparib at multiple doses.Experimental Design: Part 1 (phase I) sought to determine the MTD, recommended phase II dose (RP2D), and pharmacokinetics of oral rucaparib administered in 21-day continuous cycles in patients with advanced solid tumors. Part 2A (phase II) enrolled patients with platinum-sensitive, high-grade ovarian carcinoma (HGOC) associated with a germline BRCA1/2 mutation who received two to four prior regimens and had a progression-free interval of 6 months or more following their most recent platinum therapy. The primary endpoint was investigator-assessed objective response rate (ORR) by RECIST version 1.1.Results: In part 1, 56 patients received oral rucaparib (40 to 500 mg once daily and 240 to 840 mg twice daily). No MTD was identified per protocol-defined criteria; 600 mg twice daily was selected as the RP2D based on manageable toxicity and clinical activity. Pharmacokinetics were approximately doseproportional across all dose levels. In part 2A, 42 patients with germline BRCA1/2-mutated HGOC received rucaparib 600 mg twice daily. Investigator-assessed ORR was 59.5%. The most common treatment-emergent adverse events (all grades) were asthenia/fatigue (85.7%; 36/42), nausea (83.3%; 35/42), anemia (71.4%; 30/42), alanine transaminase and/or aspartate transaminase elevations (57.1%; 24/42), and vomiting (54.8%; 23/42). Among 98 patients, 5 (5.1%) discontinued because of an adverse event (excluding disease progression).Conclusions: Rucaparib was tolerable and had activity in patients with platinum-sensitive germline BRCA1/2-mutated HGOC. Clin Cancer Res; 23(15); 4095-106. Ó2017 AACR.

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“…Synthetic lethality, commonly based on tumor suppressor loss, emerges as an alternative approach. Indeed, PARP inhibitors were recently approved for the treatment of a subset of ovarian cancer patients who harbor BRCA mutations (16,17).…”

Section: Introductionmentioning

confidence: 99%