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man SM. An interim analysis of o

Nijman SM. 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). Ashworth A. N Engl J Med 2011;365:2473-2483, 9. Farmer H, McCabe N, Lord CJ, et al. 0000054091 00000 n 0000036519 00000 n In this population, maintenance therapy with olaparib, at a dose of 400 mg twice daily, significantly improved the duration of progression-free survival, as compared with placebo. An analysis performed after 153 progression events had occurred (in 57.7% of patients) showed that progression-free survival was significantly longer in the olaparib group than in the placebo group. 60 0 obj <> endobj 0000004905 00000 n -b`8HKs(|L8r98( V 0000054647 00000 n The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. 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. Mol Cell 1999;4:511-518, 13.

All patients provided written informed consent. Fung-Kee-Fung M, Oliver T, Elit L, Oza A, Hirte HW, Bryson P. Optimal chemotherapy treatment for women with recurrent ovarian cancer. 0000054214 00000 n 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). Information and tools for librarians about site license offerings. 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. However, the observed benefit with respect to progression-free survival did not translate into an overall survival benefit at the time of the interim analysis of overall survival. Aghajanian C, Finkler NJ, Rutherford T, et al. 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).

Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Pfisterer J, Plante M, Vergote I, et al. However, at the interim analysis, this did not translate into an overall survival benefit. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. Burger RA, Brady MF, Bookman MA, et al. Sz0|{{ZPCL.U(TY 0jA}oJ]fL#RZE Mol Cell 2001;7:263-272, 14. DOI: 10.1056/NEJMoa1105535, Tap into groundbreaking research and clinically relevant insights. 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. The size of the circles is proportional to the number of events. 0000055074 00000 n CA Cancer J Clin 2011;61:69-90[Erratum, CA Cancer J Clin 2011;61:134. 0000037431 00000 n 0000014253 00000 n Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression than those in the placebo group (Figure 2B). The most common adverse events that resulted in interruptions or reductions in the dose of olaparib were vomiting, nausea, and fatigue. 0000007932 00000 n Fong PC, Boss DS, Yap TA, et al. 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). 0000037237 00000 n Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. ), and Evangelisches Krankenhaus, Dsseldorf (W.M.) In addition, a blinded independent central review of tumor scans was performed retrospectively. Weberpals JI, Clark-Knowles KV, Vanderhyden BC. 0l ?D0}*L)mZ [BBc01c\I7mrqE4{,0AEA?6QP)-ci[bB1DPD(TP Y@bS*S$3OS_6kfYN L5oxBgr As of this writing, 21% of the patients were still receiving olaparib (and 3% were still receiving placebo), which indicates that the disease is controlled for a prolonged period in some patients. 2hpp{@I]a`?

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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 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. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Data collection and analysis were performed by the sponsor, and all the authors had full access to the data. The manuscript was written by the first author, with editorial assistance funded by the sponsor, and was reviewed by all authors and the sponsor. All the authors vouch for the completeness and accuracy of the data and analyses and the fidelity of the study to the protocol. 0000001936 00000 n 0000038949 00000 n endstream endobj 71 0 obj <> endobj 72 0 obj <>stream Semin Oncol 2006;33:Suppl:S12-S16, 5. At study entry, 40% of the overall study population had measurable disease and could be assessed for an objective response according to RECIST guidelines; the response rate was 12% (7 of 57 patients with measurable disease at study entry) in the olaparib group, as compared with 4% (2 of 48) in the placebo group (odds ratio, 3.36; 95% CI, 0.75 to 23.72; P=0.12). ), 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.) ], 2.

0000052439 00000 n 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). Therasse P, Arbuck SG, Eisenhauer EA, et al. 0000054736 00000 n Rottenberg S, Jaspers JE, Kersbergen A, et al. NWV.*N"BIU'orH"WY'2$e40A=FKS The authorized source of trusted medical research and education for the Chinese-language medical community. 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.

A phase 3 trial of bevacizumab in ovarian cancer. A supportive analysis of progression-free survival with the use of the log-rank test was performed (stratified by randomization factors). Lancet 2003;361:2099-2106, 4. Safety was assessed throughout the study by monitoring for adverse events, biochemical laboratory tests, assessment of vital signs, and physical examination. BMC Cancer 2008;8:17-17, 15. 0000055121 00000 n Audeh MW, Carmichael J, Penson RT, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. 0000054452 00000 n 0000030434 00000 n vKv8U,-Vgh'94G`Kh1g[j*[P2 dq"Z|:ab V*Fu\2*Ze,X4]}Pxg6!Tse[MZu3jQL`ToUImHh18Hk&2x.=>d f|Dse (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.). The study design is shown in Figure 1.

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. 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). K3=yg`D}\%-o00 Kaye SB, Fehrenbacher L, Holloway R, et al. 0000003352 00000 n 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). Management of platinum-sensitive recurrent ovarian cancer. 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). J Clin Oncol 1993;11:570-579, 30. However, most patients have relapses, and responses to subsequent therapies are generally short-lived.2-6 Maintenance chemotherapy as part of first-line treatment has been shown to prolong control of ovarian cancer,7 and disease control has also been prolonged with the combination of bevacizumab and chemotherapy in patients receiving first-line treatment8,9 and in those with platinum-sensitive relapsed ovarian cancer.10 However, new treatments are needed because most patients eventually have a relapse. The study was performed in accordance with the Declaration of Helsinki and the guidelines for Good Clinical Practice. 0000054783 00000 n 0000002584 00000 n 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). 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. 0000033104 00000 n Information, resources, and support needed to approach rotations - and life as a resident.

A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. Between August 28, 2008, and February 9, 2010, we screened 326 patients at 82 investigational sites in 16 countries. Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Lancet 2010;376:235-244, 32. FEBS Lett 2011;585:1-6, 21. KaplanMeier Estimates and Subgroup Analysis of Progression-free Survival. Synthetic lethality: general principles, utility and detection using genetic screens in human cells. 0000054600 00000 n The study was designed by the first author, in collaboration with the last author and the study sponsor, AstraZeneca. 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. `M'/n`W?-r}[tb&Pb00;4}@_z)W GpK.)44 C`OF- uL-~ ;`5*sko\6#mmXp?m9rv6;Enl4m'3Wp-9P2tS(U([PYS&ToR&UUEYpG;6EmVXA~

There were no significant differences between the study groups in the end points for symptoms or health-related quality of life. 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). Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. 0000054311 00000 n Because only patients with a response to chemotherapy were enrolled in the study, just 40% had measurable disease at entry. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. 0000044133 00000 n 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. 0000032584 00000 n

N Engl J Med 2009;361:123-134, 24. Valuable tools for building a rewarding career in health care.

both in Israel; Indiana University School of Medicine, Indianapolis (D.M. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. 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). 0000053672 00000 n No predictive factors were identified (global treatment-by-subgroup interaction test, P=0.15).

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The majority of patients (246 of 264) had one or more adverse events, most of which were grade 1 or 2 (Table 2). 0000041044 00000 n Fong PC, Yap TA, Boss DS, et al. 0000043552 00000 n 141 0 obj <>stream 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.

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man SM. An interim analysis of o