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). The majority of patients (246 of 264) had one or more adverse events, most of which were grade 1 or 2 (Table 2). There were no unexpected changes in biochemical laboratory measurements, vital signs, or findings on physical examination in either group.
Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. 0000054783 00000 n
The most advanced way to teach, practice, and assess clinical reasoning skills. ], 2. Of the 326 patients who were screened, 265 met the eligibility criteria and underwent randomization within 8 weeks after receiving their last dose of platinum-based chemotherapy. Perren TJ, Swart AM, Pfisterer J, et al. 0000024287 00000 n
0000014253 00000 n
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. 0000019390 00000 n
0000043552 00000 n
Ann Oncol 2010;21:Suppl:LBA25-LBA25, 33. The toxicity profile of olaparib in this population was consistent with that in previous studies. 0000003352 00000 n
Fong PC, Yap TA, Boss DS, et al. 3EQy|},
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0000030434 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. 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. Audeh MW, Carmichael J, Penson RT, et al. <<241AA167470147488D06DE51829A8373>]>> Therasse P, Arbuck SG, Eisenhauer EA, et al. The gray band represents 95% confidence intervals for the overall population. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. The content of this site is intended for health care professionals. 0000033104 00000 n Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. The final analysis of overall survival will be performed at 60% maturity (i.e., when 60% of the patients have died). Between August 28, 2008, and February 9, 2010, we screened 326 patients at 82 investigational sites in 16 countries. No predictive factors were identified (global treatment-by-subgroup interaction test, P=0.15). Fong PC, Boss DS, Yap TA, et al. Patients receiving placebo were not permitted to cross over to treatment with olaparib after disease progression. Mol Cell 2001;7:263-272, 14. Panel A shows KaplanMeier curves for progression-free survival in the randomized population. Kaye SB, Fehrenbacher L, Holloway R, et al. vKv8U,-Vgh'94G`Kh1g[j*[P2 dq"Z|:ab V*Fu\2*Ze,X4]}Pxg6!Tse[MZu3jQL`ToUImHh18Hk&2x.=>d f|Dse Lancet 2010;376:235-244, 32. Treatment was interrupted for any event of CTCAE grade 3 or 4 that was considered to be related to 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. Nijman SM. Development of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to poly(ADP-ribose) polymerase inhibitors. Evers B, Drost R, Schut E, et al. Lancet Oncol 2011;12:852-861, 27. 0000025531 00000 n 0000040403 00000 n 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 Incorporation of bevacizumab in the primary treatment of ovarian cancer. Only the 1000 most recent citing articles are listed here. 0000007932 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). Patients were eligible if they were 18 years of age or older and had recurrent ovarian or fallopian-tube cancer or primary peritoneal cancer with high-grade (grade 2 or 3) serous features or a serous component, which was platinum-sensitive (defined by an objective response to a previous platinum-based therapy for more than 6 months). 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.
BMC Cancer 2008;8:17-17, 15. Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. A supportive analysis of progression-free survival with the use of the log-rank test was performed (stratified by randomization factors). Microarray studies in serous epithelial ovarian cancer have identified a BRCAness gene-expression profile that appears to correlate with responsiveness to both platinum-based chemotherapy and poly(adenosine diphosphate [ADP]ribose) polymerase (PARP) inhibitors.15,16, PARP plays an essential part in the repair of single-stranded DNA breaks, through the base-excision-repair pathway, and it has been proposed that PARP keeps low-fidelity nonhomologous-end-joining DNA repair machinery in check.17 Thus, PARP inhibition leads to the formation of double-stranded DNA breaks that cannot be accurately repaired in tumors with homologous recombination deficiency,18,19 owing to aberrant activation of low-fidelity repair mediated by nonhomologous end joining,17 a concept known as synthetic lethality.20 Olaparib (AZD2281) is a potent oral PARP inhibitor that induces synthetic lethality in BRCA1/2-deficient tumor cells.21,22 Antitumor activity at doses that were not unacceptably toxic was observed in phase 1 and phase 2 monotherapy studies involving patients with ovarian cancer who had BRCA1/2 germline mutations.23-25 In addition, a phase 2 study of olaparib monotherapy in patients with high-grade serous ovarian cancer with or without BRCA1/2 mutations showed objective response rates of 41% for patients with BRCA1/2 mutations and 24% for those without such mutations.26. 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. 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). 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
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). From University College London, London (J.L.
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). A phase 3 trial of bevacizumab in ovarian cancer. Lancet 2010;376:245-251, 26. Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Dose modifications were more common in the olaparib group; however, discontinuations due to adverse events were infrequent, and adherence to therapy was high. Disease-related symptoms and health-related quality of life as reported by the patients were also measured (for details, see the Supplementary Appendix). Interim analysis showed no overall survival benefit. 0000024625 00000 n 0000054091 00000 n 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. Mol Cell 1999;4:511-518, 13. The decision to submit the manuscript for publication was made by all the authors and the sponsor. There is a need to identify biomarkers to select patients for this therapy. All the authors vouch for the completeness and accuracy of the data and analyses and the fidelity of the study to the protocol. 0000053907 00000 n 0000037237 00000 n Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. The identification of biomarkers for homologous-recombination deficiency may provide an opportunity to target PARP inhibitors to the appropriate population. A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. 0000054452 00000 n 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. trailer 0000013500 00000 n 0000002584 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. DOI: 10.1056/NEJMoa1105535, Tap into groundbreaking research and clinically relevant insights. 0000055027 00000 n 0000052922 00000 n The most trusted, influential source of new medical knowledge and clinical best practices in the world. Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. 0000054874 00000 n The authorized source of trusted medical research and education for the Chinese-language medical community. At the time of the data-cutoff point for progression-free survival, too few deaths had occurred for a survival analysis to be performed. Valuable tools for building a rewarding career in health care. 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. startxref 2hpp{@I]a`? 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). 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. Panel B shows a subgroup analysis of progression-free survival in the randomized population. Time-to-event variables (i.e., progression-free survival, overall survival, and time to worsening of disease-related symptoms and health-related quality of life) were analyzed with the use of a Cox proportional-hazards model that included covariates that were used as stratification factors at randomization. 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 ); Mount Vernon Hospital, Northwood (G.R. BRCA1/2 mutation status was not required. 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). Mukhopadhyay A, Elattar A, Cerbinskaite A, et al. 0000054214 00000 n Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. 0000043944 00000 n April 12, 2012N Engl J Med 2012; 366:1382-1392 However, at the interim analysis, this did not translate into an overall survival benefit. 0000054647 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). Nature 2005;434:917-921, 19. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. 0000003231 00000 n 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). 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. 0000054600 00000 n Weberpals JI, Clark-Knowles KV, Vanderhyden BC. 0000054736 00000 n hW XqZkqF#eE7Ph A"l# -Ep5yY&5w^ 7LSP 0000054043 00000 n 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). 0000025214 00000 n Demographic and Baseline Characteristics of the Patients. 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. Proc Natl Acad Sci U S A 2011;108:3406-3411, 18. The most common adverse events that resulted in interruptions or reductions in the dose of olaparib were vomiting, nausea, and fatigue. There were no significant differences between the study groups in the end points for symptoms or health-related quality of life. ), and Royal Melbourne Hospital, Parkville, NSW (C.S.) 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. A complete response (vs. partial response) to the final platinum-based therapy before study entry was a significant prognostic factor for longer progression-free survival, regardless of study group (hazard ratio, 0.46; P<0.001). NEW! 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. 0000053418 00000 n 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). 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. 0000013012 00000 n ), and Evangelisches Krankenhaus, Dsseldorf (W.M.) TxDgG%G`FoCoR4U(hwwT()H 0000025452 00000 n 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. 1. ;`5*sko\6#mmXp?m9rv6;Enl4m'3Wp-9P2tS(U([PYS&ToR&UUEYpG;6EmVXA~ Ashworth A. ); and DanaFarber Cancer Institute, Boston (U.M.). 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. endstream endobj 71 0 obj <> endobj 72 0 obj <>stream J Clin Oncol 2011;29:Suppl:LBA5007-LBA5007, 11. 0000025005 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). 0000037431 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). The study design is shown in Figure 1. The study was designed by the first author, in collaboration with the last author and the study sponsor, AstraZeneca.
Pfisterer J, Ledermann JA. 0000019998 00000 n 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. 0000052880 00000 n Clin Cancer Res 2010;16:2344-2351, 31.
Enrollment, Randomization, and Treatment. 0 FEBS Lett 2011;585:1-6, 21. Tutt A, Robson M, Garber JE, et al. GCIG denotes Gynecologic Cancer InterGroup. J Clin Oncol 1993;11:570-579, 30.
0000025371 00000 n 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). 0000053955 00000 n 0000052775 00000 n %PDF-1.7 % 0000001936 00000 n CA Cancer J Clin 2011;61:69-90[Erratum, CA Cancer J Clin 2011;61:134. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. Press JZ, De Luca A, Boyd N, et al. 0000053768 00000 n In addition, a blinded independent central review of tumor scans was performed retrospectively. M9C0. 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. 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. xb```b`Hd`c` @1v#@(!Gtm6Q>e 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.