Perren TJ, Swart AM, Pfisterer J, et al. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. 0000054736 00000 n
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Mol Cell 1999;4:511-518, 13. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. Treatment was interrupted for any event of CTCAE grade 3 or 4 that was considered to be related to treatment. The median overall survival was similar in the two study groups (29.7 months in the olaparib group and 29.9 months in the placebo group). The secondary end points of change in tumor size, combined response rate according to RECIST guidelines and CA-125 measurement (Table 2 in the Supplementary Appendix), and disease-control rate are reported in the Supplementary Appendix. 0000052171 00000 n
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7LSP Lancet 2003;361:2099-2106, 4. Aghajanian C, Finkler NJ, Rutherford T, et al. From University College London, London (J.L. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. OCEANS: a randomized, double-blinded, placebo-controlled phase III trial of chemotherapy with or without bevacizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC). 0000001936 00000 n
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Progression-free survival was assessed with the use of computed tomographic scans obtained every 12 weeks and was calculated on the basis of measurements of target and nontarget lesions and assessment for new lesions that were recorded by the investigators. Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. 0000002793 00000 n
Safety was assessed throughout the study by monitoring for adverse events, biochemical laboratory tests, assessment of vital signs, and physical examination. Other key inclusion criteria were CA-125 measurements before treatment that were below the upper limit of the normal range (in the case of values above this limit, any increase in a second sample, obtained more than 7 days later, had to be less than a 15% increase from the first sample). Predictive and prognostic factors for progression-free survival were explored with the use of preplanned subgroup analyses, including status with respect to BRCA1/2 germline mutation, age, Jewish or non-Jewish ancestry, response status at baseline, and time to progression from the start of the penultimate platinum-based regimen. In this randomized, double-blind, phase 2 study, eligible patients were stratified according to the interval between disease progression and completion of their penultimate platinum-based regimen (from 6 to 12 months vs. more than 12 months), objective response to their most recent regimen (complete response vs. partial response), and ancestry (Jewish vs. non-Jewish), to help balance the distribution of BRCA1/2 germline mutations (which are found more frequently in Jewish populations). 0000037237 00000 n
The content of this site is intended for health care professionals. We conducted a randomized, double-blind, placebo-controlled, phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen. Impact on survival of 12 versus 3 monthly cycles of paclitaxel (175 mg/m2) administered to patients with advanced ovarian cancer who attained a complete response to primary platinum-paclitaxel: follow-up of a Southwest Oncology Group and Gynecologic Oncology Group phase 3 trial. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Weberpals JI, Clark-Knowles KV, Vanderhyden BC.
); Mount Vernon Hospital, Northwood (G.R. Information and tools for librarians about site license offerings. More patients in the olaparib group had dose interruptions or reductions (27.9% and 22.8%, respectively) as a result of adverse events, as compared with the placebo group (8.6% and 4.7%). ], 16. The subgroups of patients who did not have the BRCA mutation or who were Jewish were not included in the subgroup analysis because there were fewer than 20 events in those subgroups. 0000055074 00000 n
The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. Ann Oncol 2010;21:Suppl:LBA25-LBA25, 33. However, at the interim analysis of overall survival (data-cutoff point, October 31, 2011), 101 patients (38%) had died: 52 in the olaparib group and 49 in the placebo group. No predictive factors were identified (global treatment-by-subgroup interaction test, P=0.15). Farmer H, McCabe N, Lord CJ, et al. The identical hazard ratios for the primary end point of progression-free survival, according to RECIST guidelines, and for the secondary progression end point that also incorporated objective CA-125 measurements further support the validity of the significant improvement in progression-free survival. Lancet 2010;376:245-251, 26. 0000000016 00000 n
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The study protocol was approved by the institutional review board or independent ethics committee at each investigational site; the protocol and the statistical analysis plan are available at NEJM.org. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.). Sporadic epithelial ovarian cancer: clinical relevance of BRCA1 inhibition in the DNA damage and repair pathway. Patel AG, Sarkaria JN, Kaufmann SH. Lancet 2010;376:235-244, 32. We followed patients until progression of disease, regardless of whether the treatment was discontinued or delayed or whether there were deviations from the protocol (i.e., the ongoing study group). A recent study showed that the formation of Rad51 foci correlated with an in vitro response to PARP inhibition in primary epithelial ovarian-cancer cells.30 Rad51 is involved in homologous recombination repair; it is relocalized to the nucleus in response to DNA damage to form distinct foci that are thought to be assemblages of proteins required for homologous recombination repair. Progression-free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). 0000054499 00000 n
A supportive analysis of progression-free survival with the use of the log-rank test was performed (stratified by randomization factors). 0000033104 00000 n
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BRCA1/2 mutation status was not required. Panel A shows KaplanMeier curves for progression-free survival in the randomized population. Patients receiving placebo were not permitted to cross over to treatment with olaparib after disease progression. LQX#|w ~S`etECQ{n
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J Clin Oncol 2006;24:4699-4707, 7. J Clin Oncol 2010;28:3555-3561[Erratum, J Clin Oncol 2010;28:4868. Parmar MK, Ledermann JA, Colombo N, et al. 0000008331 00000 n
Moynahan ME, Chiu JW, Koller BH, Jasin M. BRCA1 controls homology-directed DNA repair. Women with germline mutations in BRCA1, BRCA2, or both (BRCA1/2) have an increased risk of ovarian cancer, particularly the most common type, invasive high-grade serous carcinoma.11 About 15% of epithelial ovarian cancers are deficient in homologous recombination repair, owing to mutations in BRCA1/2.12,13 In up to 50% of patients with high-grade serous tumors, the tumor cells may be deficient in homologous recombination as a result of germline or somatically acquired BRCA1/2 mutations, epigenetic inactivation of BRCA1, or defects in the homologous recombination pathway that are independent of BRCA1/2.14 The silencing or dysfunction of genes in BRCA1/2-related pathways gives rise to a BRCAness phenotype similar to that resulting from inherent mutations in BRCA1/2. Valuable tools for building a rewarding career in health care. Data collection and analysis were performed by the sponsor, and all the authors had full access to the data. A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. Of the 265 patients who met the eligibility criteria, 136 were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, and 129 to receive placebo (Figure 1). 0000025531 00000 n
TxDgG%G`FoCoR4U(hwwT()H The gray band represents 95% confidence intervals for the overall population. The median progression-free survival of 4.8 months from randomization in the placebo group was shorter than the expected progression-free survival specified in the protocol (9 months). Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. Evers B, Drost R, Schut E, et al. Ashworth A. 0000006974 00000 n
Information, resources, and support needed to approach rotations - and life as a resident. A blinded, independent, central review of the data also showed consistent results (hazard ratio, 0.39; 95% CI, 0.27 to 0.55; P<0.001). Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. An interim analysis of overall survival was performed after 101 deaths had been recorded. Rottenberg S, Jaspers JE, Kersbergen A, et al. J Clin Oncol 1993;11:570-579, 30. Enrollment, Randomization, and Treatment. At the time of the data-cutoff point, the median duration of exposure to the treatment was 206.5 days (range, 3 to 469) for olaparib and 141 days (range, 34 to 413) for placebo, and the mean rate of adherence to the assigned study treatment was 85% and 96%, respectively. The most trusted, influential source of new medical knowledge and clinical best practices in the world. endstream
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Olaparib (AZD2281) is an oral poly(adenosine diphosphate [ADP]ribose) polymerase inhibitor that has shown antitumor activity in patients with high-grade serous ovarian cancer with or without BRCA1 or BRCA2 germline mutations. At the time of the data-cutoff point for progression-free survival, too few deaths had occurred for a survival analysis to be performed. J Clin Oncol 2011;29:3798-3804. N Engl J Med 2011;365:2473-2483, 9. GCIG denotes Gynecologic Cancer InterGroup. Gelmon KA, Tischkowitz M, Mackay H, et al. BMC Cancer 2008;8:17-17, 15. `M'/n`W?-r}[tb&Pb00;4}@_z)W GpK.)44
C`OF- uL-~ Konstantinopoulos PA, Spentzos D, Karlan BY, et al. There were no significant differences between the study groups in the end points for symptoms or health-related quality of life. 0000054311 00000 n
April 12, 2012N Engl J Med 2012; 366:1382-1392
J Clin Oncol 2010;28:2512-2519, 25. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. The most advanced way to teach, practice, and assess clinical reasoning skills. 0000020418 00000 n
Our data cannot address differences that might exist between patients with BRCA germline mutations and those with a BRCAness phenotype; it will be important to address these questions at the final analysis of overall survival. 0000043244 00000 n
Only the 1000 most recent citing articles are listed here. Fong PC, Yap TA, Boss DS, et al. Synthetic lethality: general principles, utility and detection using genetic screens in human cells. A significant benefit in the secondary end points of time to progression, as assessed by means of RECIST guidelines or CA-125 level, whichever showed earlier progression, and change in tumor size at 24 weeks was also observed in patients receiving olaparib. both in Israel; Indiana University School of Medicine, Indianapolis (D.M. There were no significant between-group differences in disease-related symptoms or rates of improvement in health-related quality of life, as measured by scores on the Functional Assessment of Cancer Therapy (FACT)Ovarian questionnaire, the FACTNational Comprehensive Cancer Network Ovarian Symptom Index, and the Trial Outcome Index (Table 3 in the Supplementary Appendix).29 The time to worsening of each of these end points was shorter with olaparib than with placebo; however, the difference was not significant (Table 4 in the Supplementary Appendix). ); Prince of Wales Hospital, Randwick, NSW (M.F. A phase 3 trial of bevacizumab in ovarian cancer. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. 0000054214 00000 n
both in Germany; University of Edinburgh Cancer Research U.K. Centre, Edinburgh (C.G. J Natl Cancer Inst 2006;98:1694-1706, 12. N Engl J Med 2011;365:2484-2496[Erratum, N Engl J Med 2012;366:284. 141 0 obj
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We thank Claire Routley, Ph.D. (Mudskipper Bioscience), for editorial assistance, funded by AstraZeneca. Because only patients with a response to chemotherapy were enrolled in the study, just 40% had measurable disease at entry. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Response rates and rates of improvement in patient-reported outcomes were analyzed with the use of logistic regression, and the percentage change in tumor size was assessed with the use of analysis of covariance; both these analyses were adjusted for the stratification factors at randomization. The heterogeneity of the treatment effect among the subgroups was assessed with the use of statistical interaction tests and forest plots. 0000036519 00000 n
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At the data-cutoff point (June 30, 2010), 68 patients (50%) in the olaparib group and 21 (16%) in the placebo group were still receiving the study treatment. If the toxicity resolved entirely or to a grade 1 level, treatment was restarted with a reduction in the dose to 200 mg or 100 mg twice daily. At the time that the study was designed, there were no reported data from trials of maintenance treatment in patients with a relapse of platinum-responsive ovarian cancer, which would have provided a basis for estimating progression-free survival in the placebo group. NEW! Adverse events that led to the permanent discontinuation of treatment occurred in three patients receiving olaparib (one each with palpitations and myalgia, erythematous rash, and nausea and obstruction in the small intestine) and in one patient receiving placebo (nausea); all these adverse events were grade 2 and were considered by the investigator to be related to treatment, except for the grade 4 obstruction in the small intestine. The size of the circles is proportional to the number of events.