Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. Valuable tools for building a rewarding career in health care. There is a need to identify biomarkers to select patients for this therapy. 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). hW XqZkqF#eE7Ph A"l# -Ep5yY&5w^
7LSP Fong PC, Boss DS, Yap TA, et al. 0000036519 00000 n
0000054311 00000 n
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. 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. Clin Cancer Res 2010;16:2344-2351, 31. ]YQWYR},a'XBy+0v"v#Whv}3w{N
;: gD 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). 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 0000053040 00000 n
0000006974 00000 n
0000052922 00000 n
0000025289 00000 n
0000043244 00000 n
0000054647 00000 n
0000004905 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.) %%EOF
Cella DF, Tulsky DS, Gray G, et al. The identification of biomarkers for homologous-recombination deficiency may provide an opportunity to target PARP inhibitors to the appropriate population. 0000019998 00000 n
Semin Oncol 2006;33:Suppl:S12-S16, 5. The study was performed in accordance with the Declaration of Helsinki and the guidelines for Good Clinical Practice. Ledermann JA, Hackshaw A, Kaye S, et al. Konstantinopoulos PA, Spentzos D, Karlan BY, et al. All patients provided written informed consent. 0000054091 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. <<241AA167470147488D06DE51829A8373>]>>
Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. 0000053624 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
0000008331 00000 n
Panel B shows a subgroup analysis of progression-free survival in the randomized population. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. 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. Dose modifications were more common in the olaparib group; however, discontinuations due to adverse events were infrequent, and adherence to therapy was high. Treatment was interrupted for any event of CTCAE grade 3 or 4 that was considered to be related to treatment. 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. 0000054600 00000 n
0000049608 00000 n
0000004251 00000 n
0000055121 00000 n
J Clin Oncol 2006;24:4699-4707, 7. 0000003231 00000 n
0000052439 00000 n
All reported P values and confidence intervals are two-sided. Burger RA, Brady MF, Bookman MA, et al. Information and tools for librarians about site license offerings. }x0P: 0000045212 00000 n
0000053498 00000 n
BMC Cancer 2008;8:17-17, 15. 60 82
TxDgG%G`FoCoR4U(hwwT()H 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). 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). 0000055027 00000 n
Safety was assessed throughout the study by monitoring for adverse events, biochemical laboratory tests, assessment of vital signs, and physical examination. In addition, a blinded independent central review of tumor scans was performed retrospectively. 0l ?D0}*L)mZ [BBc01c\I7mrqE4{,0AEA?6QP)-ci[bB1DPD(TP 0000051012 00000 n
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). Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. April 12, 2012N Engl J Med 2012; 366:1382-1392
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. Fong PC, Yap TA, Boss DS, et al. Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. 0000055074 00000 n
), and Evangelisches Krankenhaus, Dsseldorf (W.M.) 0000024287 00000 n
J Clin Oncol 2008;26:3785-3790, 20. Int J Gynecol Cancer 2011;21:419-423, 29. Lancet 2003;361:2099-2106, 4. 0000002743 00000 n
0000053418 00000 n
0000054499 00000 n
Pfisterer J, Ledermann JA. 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). 0000030946 00000 n
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%). Tutt A, Robson M, Garber JE, et al. 0000007932 00000 n
Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. Y@bS*S$3OS_6kfYN L5oxBgr Synthetic lethality: general principles, utility and detection using genetic screens in human cells. Data collection and analysis were performed by the sponsor, and all the authors had full access to the data. 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. 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. 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. At the time of the data-cutoff point for progression-free survival, too few deaths had occurred for a survival analysis to be performed. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. Gynecol Oncol 2009;114:195-198, 8. Markman M, Liu PY, Moon J, et al. both in Israel; Indiana University School of Medicine, Indianapolis (D.M. Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks. 0000054874 00000 n
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. Objective response was not an informative end point because there were limited opportunities for further responses. The authorized source of trusted medical research and education for the Chinese-language medical community. J Clin Oncol 2010;28:3323-3329, 6. 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. 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). Prepare to become a physician, build your knowledge, lead a health care organization, and advance your career with NEJM Group information and services. The decision to submit the manuscript for publication was made by all the authors and the sponsor. The toxicity profile of olaparib in this population was consistent with that in previous studies. 0
0000003352 00000 n
0000037431 00000 n
startxref
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). 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). 0000052171 00000 n
0000054921 00000 n
1. The most trusted, influential source of new medical knowledge and clinical best practices in the world. 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). 0000048139 00000 n
0000038949 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). If the event did not resolve within 4 weeks after treatment or if two previous treatment interruptions had occurred, the patient was withdrawn from the study. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. 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). GCIG denotes Gynecologic Cancer InterGroup. Fung-Kee-Fung M, Oliver T, Elit L, Oza A, Hirte HW, Bryson P. Optimal chemotherapy treatment for women with recurrent ovarian cancer. 0000036849 00000 n
0000052880 00000 n
); Prince of Wales Hospital, Randwick, NSW (M.F. N Engl J Med 2011;365:2484-2496[Erratum, N Engl J Med 2012;366:284. 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). 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. Interim analysis showed no overall survival benefit. 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. Response rates were low in both study groups, and some patients in the placebo group had a reduction in tumor size. The most common adverse events that resulted in interruptions or reductions in the dose of olaparib were vomiting, nausea, and fatigue. 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. 0000013500 00000 n
K3=yg`D}\%-o00 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. 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). NEW! Rustin GJ, Vergote I, Eisenhauer E, et al. endstream
endobj
71 0 obj
<>
endobj
72 0 obj
<>stream
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. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. 0000046595 00000 n
Gelmon KA, Tischkowitz M, Mackay H, et al. 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. 0000000016 00000 n
0000053768 00000 n
0000054452 00000 n
0000052775 00000 n
Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. 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 New guidelines to evaluate the response to treatment in solid tumors. 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. 0000054358 00000 n
The primary end point was progression-free survival, as assessed by the site investigator and defined as the time from randomization (on completion of chemotherapy) until objective assessment of disease progression according to RECIST guidelines27 or death (from any cause in the absence of progression of disease). 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). ], 16. The study was designed by the first author, in collaboration with the last author and the study sponsor, AstraZeneca. The heterogeneity of the treatment effect among the subgroups was assessed with the use of statistical interaction tests and forest plots. 0000037237 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). N Engl J Med 2009;361:123-134, 24. 0000032584 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 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). 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. 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. 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). The final analysis of overall survival will be performed at 60% maturity (i.e., when 60% of the patients have died). -b`8HKs(|L8r98( V
0000014253 00000 n
Kaye SB, Fehrenbacher L, Holloway R, et al. 60 0 obj
<>
endobj
A phase 3 trial of bevacizumab in ovarian cancer. xb```b`Hd`c` @1v#@(!Gtm6Q>e 0000001936 00000 n
Only the 1000 most recent citing articles are listed here. 0000054214 00000 n
Lancet 2010;376:245-251, 26. The gray band represents 95% confidence intervals for the overall population. J Clin Oncol 2011;29:3798-3804. CA Cancer J Clin 2011;61:69-90[Erratum, CA Cancer J Clin 2011;61:134. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.). We thank Claire Routley, Ph.D. (Mudskipper Bioscience), for editorial assistance, funded by AstraZeneca. However, at the interim analysis, this did not translate into an overall survival benefit. 0000025214 00000 n
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. J Clin Oncol 1993;11:570-579, 30. There were no unexpected changes in biochemical laboratory measurements, vital signs, or findings on physical examination in either group. 141 0 obj
<>stream
0000033104 00000 n
Ann Oncol 2010;21:Suppl:LBA25-LBA25, 33. 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). ), and Royal Melbourne Hospital, Parkville, NSW (C.S.) 0000024625 00000 n
0000019390 00000 n
Weberpals JI, Clark-Knowles KV, Vanderhyden BC. 0000020900 00000 n
], 10. Nature 2005;434:917-921, 19. 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). 0000053816 00000 n
Between August 28, 2008, and February 9, 2010, we screened 326 patients at 82 investigational sites in 16 countries. 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. 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. 0000053955 00000 n
J Natl Cancer Inst 2006;98:1694-1706, 12. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. xref
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). 0000053672 00000 n
Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Patel AG, Sarkaria JN, Kaufmann SH. LQX#|w ~S`etECQ{n
UkuO`||ayc`lYnoyr]tdNUx]%EEJq
%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 Demographic and Baseline Characteristics of the Patients. Patients receiving placebo were not permitted to cross over to treatment with olaparib after disease progression. 0000053546 00000 n
0000043944 00000 n
NEW! 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. Curr Oncol 2007;14:195-208, 3. 0000025531 00000 n
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. 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). 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. The manuscript was written by the first author, with editorial assistance funded by the sponsor, and was reviewed by all authors and the sponsor. No predictive factors were identified (global treatment-by-subgroup interaction test, P=0.15). 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. J Clin Oncol 2010;28:3555-3561[Erratum, J Clin Oncol 2010;28:4868. Perren TJ, Swart AM, Pfisterer J, et al. All the authors vouch for the completeness and accuracy of the data and analyses and the fidelity of the study to the protocol. 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. J Clin Oncol 2010;28:2512-2519, 25. 0000025371 00000 n
Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Farmer H, McCabe N, Lord CJ, et al. M9C0. The majority of patients (246 of 264) had one or more adverse events, most of which were grade 1 or 2 (Table 2). 0000006077 00000 n
0000007501 00000 n
Mukhopadhyay A, Elattar A, Cerbinskaite A, et al. Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. An interim analysis of overall survival was performed after 101 deaths had been recorded. 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.
Sitemap 18