0000013012 00000 n
In addition, a blinded independent central review of tumor scans was performed retrospectively. Interim analysis showed no overall survival benefit. hTRn0{LH$Cj,)R1C,mxw'i]q"TxiDNl $6N]C-`/F0|any56A{*CYoRqJtLjZ-dP*'VqDpB3!i \~V 2W-HK!4 'a3aVo8e,ck"HJdaDg9;A"DLTBi*).(3Hhs~Wkk>S F 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. 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. 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). 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). Data collection and analysis were performed by the sponsor, and all the authors had full access to the data. 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. Valuable tools for building a rewarding career in health care. Clin Cancer Res 2010;16:2344-2351, 31. The toxicity profile of olaparib in this population was consistent with that in previous studies. Dose modifications were more common in the olaparib group; however, discontinuations due to adverse events were infrequent, and adherence to therapy was high. both in Israel; Indiana University School of Medicine, Indianapolis (D.M. hW XqZkqF#eE7Ph A"l# -Ep5yY&5w^
7LSP 0000054452 00000 n
J Natl Cancer Inst 2000;92:205-216, 28. However, at the interim analysis, this did not translate into an overall survival benefit. Information and tools for librarians about site license offerings. 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. CA Cancer J Clin 2011;61:69-90[Erratum, CA Cancer J Clin 2011;61:134. 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). 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. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.). K3=yg`D}\%-o00 Kaye SB, Fehrenbacher L, Holloway R, et al. Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. At the time of the interim analysis of overall survival, 29 patients were still receiving olaparib after a period of at least 21 months, and 4 patients were still receiving placebo. 0000036519 00000 n
Mol Cell 1999;4:511-518, 13. 0000003352 00000 n
Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. 0000054874 00000 n
), and Royal Melbourne Hospital, Parkville, NSW (C.S.) 0000006077 00000 n
6,>
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5BCEPZZ ih(z]\E;\)H3}^'A&5'S:kq;X{)@T!AQgM0F,P-1g>0Y!{OJG53z]N}#)cVG 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). ]YQWYR},a'XBy+0v"v#Whv}3w{N
;: gD Weberpals JI, Clark-Knowles KV, Vanderhyden BC. LQX#|w ~S`etECQ{n
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%uI]T=XJqC69Z'@@w`&?SIzF@OQ0b$slvv]!%PHL}f}__J c1UDdt^Jd&4s}mQX:-V |avlwA[-
iPa8GOk1MIRJ`oP@D\c0iFi15%'j*p40"G9[9"oRm/Pz`{]P,PAWn| -l0KMyddLTJWS 2hpp{@I]a`? The size of the circles is proportional to the number of events. J Clin Oncol 2010;28:3555-3561[Erratum, J Clin Oncol 2010;28:4868. FEBS Lett 2011;585:1-6, 21. Lancet Oncol 2011;12:852-861, 27. ;`5*sko\6#mmXp?m9rv6;Enl4m'3Wp-9P2tS(U([PYS&ToR&UUEYpG;6EmVXA~ TxDgG%G`FoCoR4U(hwwT()H Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. Mol Cell 2001;7:263-272, 14. 0000046595 00000 n
Rottenberg S, Jaspers JE, Kersbergen A, et al. 0
Information, resources, and support needed to approach rotations - and life as a resident. 0000008331 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. 0000053418 00000 n
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. There were no unexpected changes in biochemical laboratory measurements, vital signs, or findings on physical examination in either group. 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). Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. 0000043552 00000 n
0000052880 00000 n
Tutt A, Robson M, Garber JE, et al. 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. 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. 0000054647 00000 n
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. Safety was assessed throughout the study by monitoring for adverse events, biochemical laboratory tests, assessment of vital signs, and physical examination. The study design is shown in Figure 1. 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). 0000004905 00000 n
0000013899 00000 n
J Clin Oncol 2008;26:3259-3267, 17. Press JZ, De Luca A, Boyd N, et al. 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. All patients provided written informed consent. Semin Oncol 2006;33:Suppl:S12-S16, 5. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. 0000025289 00000 n
0000025214 00000 n
-b`8HKs(|L8r98( V
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. 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. Sz0|{{ZPCL.U(TY 0jA}oJ]fL#RZE ), and Evangelisches Krankenhaus, Dsseldorf (W.M.) Proc Natl Acad Sci U S A 2008;105:17079-17084, 23. Aghajanian C, Finkler NJ, Rutherford T, et al. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. At the time of the data-cutoff point for progression-free survival, too few deaths had occurred for a survival analysis to be performed. The most trusted, influential source of new medical knowledge and clinical best practices in the world. The incidence of grade 3 or 4 adverse events was 35.3% in the olaparib group and 20.3% in the placebo group (Table 2). High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. 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). 0000024625 00000 n
0000054043 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. 0000002743 00000 n
Because only patients with a response to chemotherapy were enrolled in the study, just 40% had measurable disease at entry. Fong PC, Yap TA, Boss DS, et al. 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. BRCA1/2 mutation status was not required. Incorporation of bevacizumab in the primary treatment of ovarian cancer. 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 supportive analysis of progression-free survival with the use of the log-rank test was performed (stratified by randomization factors). Patel AG, Sarkaria JN, Kaufmann SH. 0000041044 00000 n
Lancet 2010;376:235-244, 32. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. <<241AA167470147488D06DE51829A8373>]>>
0000054499 00000 n
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. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. Therasse P, Arbuck SG, Eisenhauer EA, et al. A phase 3 trial of bevacizumab in ovarian cancer. 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. 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). Fong PC, Boss DS, Yap TA, et al. Between August 28, 2008, and February 9, 2010, we screened 326 patients at 82 investigational sites in 16 countries. 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 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). 0000055027 00000 n
This article (10.1056/NEJMoa1105535) was published on March 27, 2012, at NEJM.org. 0000013500 00000 n
J Clin Oncol 2011;29:Suppl:LBA5007-LBA5007, 11. 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). Mukhopadhyay A, Elattar A, Cerbinskaite A, et al. 0000054311 00000 n
Enrollment, Randomization, and Treatment. Nature 2005;434:917-921, 19. N Engl J Med 2011;365:2473-2483, 9. 0000019998 00000 n
A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. The most advanced way to teach, practice, and assess clinical reasoning skills. The final analysis of overall survival will be performed at 60% maturity (i.e., when 60% of the patients have died).
J Clin Oncol 2008;26:3785-3790, 20. 0000053955 00000 n
Gelmon KA, Tischkowitz M, Mackay H, et al.
Markman M, Liu PY, Moon J, et al. The study was performed in accordance with the Declaration of Helsinki and the guidelines for Good Clinical Practice. 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. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. 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). Furthermore, the lower risk of disease progression associated with olaparib treatment was consistent across all the subgroups analyzed (Figure 2B). Risch HA, McLaughlin JR, Cole DE, et al. The identification of biomarkers for homologous-recombination deficiency may provide an opportunity to target PARP inhibitors to the appropriate population. 0000053498 00000 n
Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks. 0000002584 00000 n
0000053907 00000 n
J Natl Cancer Inst 2006;98:1694-1706, 12. The heterogeneity of the treatment effect among the subgroups was assessed with the use of statistical interaction tests and forest plots. %%EOF
New guidelines to evaluate the response to treatment in solid tumors. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. 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. 1. O;I FBxLv{*g9PJ:/4(_h= Prepare to become a physician, build your knowledge, lead a health care organization, and advance your career with NEJM Group information and services. 0000000016 00000 n
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Panel B shows a subgroup analysis of progression-free survival in the randomized population. We thank Claire Routley, Ph.D. (Mudskipper Bioscience), for editorial assistance, funded by AstraZeneca. 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. xref
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. 0000020418 00000 n
DOI: 10.1056/NEJMoa1105535, Tap into groundbreaking research and clinically relevant insights. Disease-related symptoms and health-related quality of life as reported by the patients were also measured (for details, see the Supplementary Appendix). 0000054358 00000 n
The most common adverse events that resulted in interruptions or reductions in the dose of olaparib were vomiting, nausea, and fatigue. Evers B, Drost R, Schut E, et al. Response rates were low in both study groups, and some patients in the placebo group had a reduction in tumor size. 141 0 obj
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Proc Natl Acad Sci U S A 2011;108:3406-3411, 18. Perren TJ, Swart AM, Pfisterer J, et al. 0000054736 00000 n
), 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.) Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. The majority of patients (246 of 264) had one or more adverse events, most of which were grade 1 or 2 (Table 2). 0000053768 00000 n
Only the 1000 most recent citing articles are listed here. Analyses of efficacy and patient-reported outcomes included all patients who were randomly assigned to a study group, and safety analyses included all patients who received at least one dose of the assigned study medication. A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. 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. 0000054783 00000 n
0000040403 00000 n
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All the authors vouch for the completeness and accuracy of the data and analyses and the fidelity of the study to the protocol. An interim analysis of overall survival was performed after 101 deaths had been recorded. 0000030946 00000 n
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0000048139 00000 n
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0000053672 00000 n
J Clin Oncol 2011;29:3798-3804. 0000049608 00000 n
0000053546 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). 60 82
0000007932 00000 n
Panel A shows KaplanMeier curves for progression-free survival in the randomized population. 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. Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer.
Farmer H, McCabe N, Lord CJ, et al. 0000054091 00000 n
0000037431 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. 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. Konstantinopoulos PA, Spentzos D, Karlan BY, et al. Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Cella DF, Tulsky DS, Gray G, et al. 0000033104 00000 n
Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. Objective response was not an informative end point because there were limited opportunities for further responses. 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. 0000007501 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). 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. 0000053816 00000 n
The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. 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). 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). 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. `M'/n`W?-r}[tb&Pb00;4}@_z)W GpK.)44
C`OF- uL-~ 0000054600 00000 n
0000052171 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. Audeh MW, Carmichael J, Penson RT, et al. 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). 0000025005 00000 n
0000043244 00000 n
Nijman SM. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge.
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