study 19 olaparib lancet

Panel A shows KaplanMeier curves for progression-free survival in the randomized population. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. A phase 3 trial of bevacizumab in ovarian cancer. trailer J Clin Oncol 2006;24:4699-4707, 7. 2hpp{@I]a`? Gynecol Oncol 2009;114:195-198, 8. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. ); Mount Vernon Hospital, Northwood (G.R. 0000046595 00000 n Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. Evers B, Drost R, Schut E, et al. 0000030946 00000 n Pfisterer J, Plante M, Vergote I, et al. 0000051012 00000 n ); and DanaFarber Cancer Institute, Boston (U.M.). 0000002793 00000 n 0 In conclusion, the results from this randomized, phase 2 study show that maintenance treatment with olaparib was associated with a significant improvement in progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Assuming that the true hazard ratio for progression or death with olaparib versus placebo was 0.75 (corresponding to a 33% increase in the median duration of progression-free survival, from 9 to 12 months after randomization) and that the overall type 1 error was 20% (one-sided test), we calculated that the analysis would have 80% power to show a significant difference in favor of olaparib (one-sided P<0.20). Synthetic lethality: general principles, utility and detection using genetic screens in human cells. BRCA1/2 mutation status was not required. 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). 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. The decision to submit the manuscript for publication was made by all the authors and the sponsor. However, at the interim analysis, this did not translate into an overall survival benefit. Patients could continue receiving olaparib or placebo until disease progression or as long as they were benefitting from the treatment and did not meet any criteria for discontinuation (i.e., the ongoing-treatment group). endstream endobj 61 0 obj <> endobj 62 0 obj <> endobj 63 0 obj <>/ProcSet[/PDF/Text]/ExtGState<>>>/Type/Page>> endobj 64 0 obj <> endobj 65 0 obj <> endobj 66 0 obj <> endobj 67 0 obj <> endobj 68 0 obj <> endobj 69 0 obj <> endobj 70 0 obj <>stream 0000000016 00000 n <<241AA167470147488D06DE51829A8373>]>> An interim analysis of overall survival was performed after 101 deaths had been recorded. ), and Royal Melbourne Hospital, Parkville, NSW (C.S.) startxref 1. p@l{[\Cp:&cS$Pn`j_i)I@d[=}^h4[I6.T?f/g]VN Y~b,9bwE5gMti2UuKAWFRs9o]~L]rr~*n/:G L &Ts&^]0@Cq2I@/Pny>37TP M39N All the authors vouch for the completeness and accuracy of the data and analyses and the fidelity of the study to the protocol. Data collection and analysis were performed by the sponsor, and all the authors had full access to the data. xb```b`Hd`c` @1v#@(!Gtm6Q>e 0000043552 00000 n 0000002584 00000 n 0000019998 00000 n The manuscript was written by the first author, with editorial assistance funded by the sponsor, and was reviewed by all authors and the sponsor. Progression events were observed in 60 patients (44.1%) in the olaparib group and 93 (72.1%) in the placebo group. The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. endstream endobj 71 0 obj <> endobj 72 0 obj <>stream 0000054311 00000 n `M'/n`W?-r}[tb&Pb00;4}@_z)W GpK.)44 C`OF- uL-~ The most trusted, influential source of new medical knowledge and clinical best practices in the world. 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. 0000053498 00000 n Pfisterer J, Ledermann JA. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Rottenberg S, Jaspers JE, Kersbergen A, et al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. 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. ), and AstraZeneca, Macclesfield (E.M., C.W., J.C.) both in the United Kingdom; Chaim Sheba Medical Center, Tel Hashomer (R.S.-F.), and Tel Aviv Sourasky Medical Center, Tel Aviv (T.S.)

Lancet 2010;376:235-244, 32. Demographic and baseline characteristics of the patients (Table 1) and any protocol deviations with the potential to affect the primary analysis (Table 1 in the Supplementary Appendix) were well balanced between the two study groups. 0000052880 00000 n both in Australia; University of Leuven, Leuven, Belgium (I.V. M9C0. 0000036849 00000 n Ann Oncol 2010;21:Suppl:LBA25-LBA25, 33. Information, resources, and support needed to approach rotations - and life as a resident.

DOI: 10.1056/NEJMoa1105535, Tap into groundbreaking research and clinically relevant insights. 0000054921 00000 n Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. GCIG denotes Gynecologic Cancer InterGroup.

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. 0000006974 00000 n Cella DF, Tulsky DS, Gray G, et al. ], 16. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. ); Prince of Wales Hospital, Randwick, NSW (M.F. 0000054647 00000 n

O;I FBxLv{*g9PJ:/4(_h= No predictive factors were identified (global treatment-by-subgroup interaction test, P=0.15). 0000008331 00000 n 0000053955 00000 n Secondary efficacy end points were time to progression, according to RECIST guidelines or CA-125 level, whichever showed earlier progression (with the CA-125 level assessed according to Gynecological Cancer InterGroup criteria; see the Supplementary Appendix)28; objective response rate, as determined according to RECIST guidelines or a combination of RECIST guidelines and CA-125 level; disease-control rate, according to RECIST guidelines (i.e., the percentage of patients who had confirmed complete response, partial response, stable disease, or no evidence of disease for at least 23 weeks); percentage change from baseline in the size of the target tumor lesion at weeks 12 and 24; and overall survival. The final analysis of overall survival will be performed at 60% maturity (i.e., when 60% of the patients have died). Patel AG, Sarkaria JN, Kaufmann SH. Press JZ, De Luca A, Boyd N, et al. Response rates were low in both study groups, and some patients in the placebo group had a reduction in tumor size. This randomized, phase 2 clinical trial involving patients with recurrent platinum-sensitive, high-grade serous ovarian cancer targeted a histologically and phenotypically defined subgroup of patients who have tumor cells that are highly enriched for homologous-recombination deficiency. 0000054499 00000 n A total of seven grade 4 events were reported in the olaparib group (in 5.1% of patients), and two were reported in the placebo group (in 1.6% of patients) (Table 3). Patients receiving placebo were not permitted to cross over to treatment with olaparib after disease progression. 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. Management of platinum-sensitive recurrent ovarian cancer. Fong PC, Boss DS, Yap TA, et al. However, the observed value of 4.8 months is consistent with recently published data from studies of maintenance treatment in similar patient populations (5.8 months and 2.8 months),32,33 suggesting that progression-free survival in the placebo group in our study was in line with that expected. J Natl Cancer Inst 2000;92:205-216, 28. 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. TxDgG%G`FoCoR4U(hwwT()H both in Israel; Indiana University School of Medicine, Indianapolis (D.M. ], 2. Only the 1000 most recent citing articles are listed here. Prepare to become a physician, build your knowledge, lead a health care organization, and advance your career with NEJM Group information and services. 0000053907 00000 n Markman M, Liu PY, Moon J, et al. A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. Adverse events with an incidence that was at least 10% higher in the olaparib group than in the placebo group, were nausea, fatigue, vomiting, and anemia. Mol Cell 2001;7:263-272, 14. 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. 0000003352 00000 n Y@bS*S$3OS_6kfYN L5oxBgr Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. Dose modifications were more common in the olaparib group; however, discontinuations due to adverse events were infrequent, and adherence to therapy was high. 0000045212 00000 n This article (10.1056/NEJMoa1105535) was published on March 27, 2012, at NEJM.org. NWV.*N"BIU'orH"WY'2$e40A=FKS A total enrollment of 250 patients was planned for the study, and the primary analysis was to be performed when at least 137 progression-free survival events had occurred. J Clin Oncol 1993;11:570-579, 30. 0000007501 00000 n Safety was assessed throughout the study by monitoring for adverse events, biochemical laboratory tests, assessment of vital signs, and physical examination. Weberpals JI, Clark-Knowles KV, Vanderhyden BC. Kaye SB, Fehrenbacher L, Holloway R, et al. J Clin Oncol 2008;26:3785-3790, 20. 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. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. 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. 0000055027 00000 n Clin Cancer Res 2008;14:3916-3925, 22. 0000025005 00000 n 0000054214 00000 n With the use of an interactive voice response system, patients were randomly assigned in a 1:1 ratio to receive olaparib capsules, at a dose of 400 mg twice daily (the monotherapy dose shown to be the maximum dose associated with acceptable adverse-event rates),23 or matching placebo within 8 weeks after completion of the last dose of platinum-based chemotherapy (Figure 1). Ashworth A. Nature 2005;434:917-921, 19. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. 0000054783 00000 n 0000025452 00000 n 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). 0000040403 00000 n

0000019390 00000 n Therasse P, Arbuck SG, Eisenhauer EA, et al. 0000025214 00000 n There were no unexpected changes in biochemical laboratory measurements, vital signs, or findings on physical examination in either group. Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. The content of this site is intended for health care professionals. The toxicity profile of olaparib in this patient population was consistent with that reported in previous clinical studies.24,25,31 The majority of adverse events were grade 1 or 2 and did not require interruptions of the treatment. hW XqZkqF#eE7Ph A"l# -Ep5yY&5w^ 7LSP 0000053040 00000 n Clin Cancer Res 2010;16:2344-2351, 31. Semin Oncol 2006;33:Suppl:S12-S16, 5. Proc Natl Acad Sci U S A 2008;105:17079-17084, 23. Study treatment was blinded with the use of unique identifiers generated during randomization. Aghajanian C, Finkler NJ, Rutherford T, et al. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75). NEW! ;`5*sko\6#mmXp?m9rv6;Enl4m'3Wp-9P2tS(U([PYS&ToR&UUEYpG;6EmVXA~ 0000024625 00000 n A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. Interim analysis showed no overall survival benefit. April 12, 2012N Engl J Med 2012; 366:1382-1392 ), and Evangelisches Krankenhaus, Dsseldorf (W.M.) 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. Demographic and Baseline Characteristics of the Patients. Ovarian cancer is the leading cause of death from gynecologic tumors in the Western world.1 Approximately 80% of patients with newly diagnosed ovarian cancer have a response to platinum-based chemotherapy. 0000052171 00000 n 0000032584 00000 n Curr Oncol 2007;14:195-208, 3. The secondary end point of time to progression according to the RECIST guidelines or CA-125 level, whichever showed earlier progression, was also significantly longer in the olaparib group than in the placebo group (median, 8.3 months vs. 3.7 months; hazard ratio for progression, 0.35; 95% CI, 0.25 to 0.47; P<0.001). 0000049608 00000 n A stratified log-rank test of progression-free survival supported the primary analysis (hazard ratio, 0.37; 95% CI, 0.26 to 0.51; P<0.001). A phase 2, randomized, placebo-controlled study of Hedgehog (Hh) pathway inhibitor GDC-0449 as maintenance therapy in patients with ovarian cancer in 2nd or 3rd complete remission (CR). Treatment was interrupted for any event of CTCAE grade 3 or 4 that was considered to be related to treatment. Ledermann JA, Hackshaw A, Kaye S, et al. The authorized source of trusted medical research and education for the Chinese-language medical community. 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. At the time of the data-cutoff point for progression-free survival, too few deaths had occurred for a survival analysis to be performed. Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. The most advanced way to teach, practice, and assess clinical reasoning skills. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. There were no significant differences between the study groups in the end points for symptoms or health-related quality of life. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Eligible patients had completed at least two courses of platinum-based chemotherapy, and their most recent regimen induced an objective response as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.0,27 or a cancer antigen 125 (CA-125) response, according to Gynecological Cancer InterGroup criteria28 (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Mol Cell 1999;4:511-518, 13. Tutt A, Robson M, Garber JE, et al. The gray band represents 95% confidence intervals for the overall population. 0000043944 00000 n 0000020418 00000 n No significant difference in overall survival was observed (hazard ratio for death in the olaparib group, 0.94; 95% CI, 0.63 to 1.39; P=0.75). ], 10. Lancet 2003;361:2099-2106, 4. Konstantinopoulos PA, Spentzos D, Karlan BY, et al. N Engl J Med 2009;361:123-134, 24. J Clin Oncol 2010;28:3323-3329, 6. Lancet 2010;376:245-251, 26. Valuable tools for building a rewarding career in health care.

Patients continued the assigned study treatment until objective disease progression, as defined by RECIST guidelines, provided that they did not meet any criteria for discontinuation (any grade 3 or 4 adverse event that did not resolve completely or to grade 1 within 28 days after onset, according to the National Cancer Institute's Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). K3=yg`D}\%-o00 Pujade-Lauraine E, Wagner U, Avall-Lundqvist E, et al. 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.

0000038949 00000 n Incorporation of bevacizumab in the primary treatment of ovarian cancer. CA Cancer J Clin 2011;61:69-90[Erratum, CA Cancer J Clin 2011;61:134. 0000036519 00000 n Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. 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%). 0000025531 00000 n 0000054452 00000 n Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. 0000033104 00000 n 0000025371 00000 n N Engl J Med 2011;365:2473-2483, 9. The study was performed in accordance with the Declaration of Helsinki and the guidelines for Good Clinical Practice.

0000054358 00000 n 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. The toxicity profile of olaparib in this population was consistent with that in previous studies. 0000054736 00000 n 0000054874 00000 n 6,> Dc,R.2B8:Rv-! 3B6k|]OVkRkI'Iji[AZ DN.x$3WZf2Vkz{[*xX+c9l~=cY KBvIg@hEl?_%J)}DwW(A((hll*,/((,- 5BCEPZZ ih(z]\E;\)H3}^'A&5'S:kq;X{)@T!AQgM0F,P-1g>0Y!{OJG53z]N}#)cVG Audeh MW, Carmichael J, Penson RT, et al. 0000020900 00000 n Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks. Median progression-free survival was 8.4 months in the olaparib group versus 4.8 months in the placebo group (hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001) (Figure 2A). 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). 0000041044 00000 n Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. Nijman SM. 0000053546 00000 n 0000053672 00000 n Fong PC, Yap TA, Boss DS, et al. 0000054043 00000 n

In both groups, nausea, fatigue, and vomiting were intermittent and did not require discontinuation of the study treatment. We evaluated the efficacy of olaparib monotherapy as maintenance treatment in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had had a response to their most recent platinum-based chemotherapy. 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.

Sitemap 28

study 19 olaparib lancet