There is a need to identify biomarkers to select patients for this therapy. 1.
Management of platinum-sensitive recurrent 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). Information, resources, and support needed to approach rotations - and life as a resident. The study was designed by the first author, in collaboration with the last author and the study sponsor, AstraZeneca. 0000030946 00000 n NEW!
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). Int J Gynecol Cancer 2011;21:419-423, 29. Proc Natl Acad Sci U S A 2008;105:17079-17084, 23.
Case Records of the Massachusetts General Hospital, Monkeypox Virus Infection in Humans across 16 Countries AprilJune 2022, Protection Associated with Previous SARS-CoV-2 Infection in Nicaragua, Nirmatrelvir for Nonhospitalized Adults with Covid-19, Efficacy of Antibodies and Antiviral Drugs against Omicron BA.2.12.1, BA.4, and BA.5 Subvariants, Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults, Case 23-2022: A 49-Year-Old Man with Hypoglycemia, http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf, Trial of Anti-BDCA2 Antibody Litifilimab for Cutaneous Lupus Erythematosus, Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkins Lymphoma, NEJM Catalyst Innovations in Care Delivery.
Response rates were low in both study groups, and some patients in the placebo group had a reduction in tumor size.
Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. Therasse P, Arbuck SG, Eisenhauer EA, 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.
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.
Patel AG, Sarkaria JN, Kaufmann SH. 0000054214 00000 n Burger RA, Brady MF, Bookman MA, et al.
0000032584 00000 n Tutt A, Robson M, Garber JE, et al.
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. Kaye SB, Fehrenbacher L, Holloway R, et al. Objective response was not an informative end point because there were limited opportunities for further responses. 141 0 obj <>stream
Lancet Oncol 2011;12:852-861, 27. J Clin Oncol 2011;29:Suppl:LBA5007-LBA5007, 11.
Women with germline mutations in BRCA1, BRCA2, or both (BRCA1/2) have an increased risk of ovarian cancer, particularly the most common type, invasive high-grade serous carcinoma.11 About 15% of epithelial ovarian cancers are deficient in homologous recombination repair, owing to mutations in BRCA1/2.12,13 In up to 50% of patients with high-grade serous tumors, the tumor cells may be deficient in homologous recombination as a result of germline or somatically acquired BRCA1/2 mutations, epigenetic inactivation of BRCA1, or defects in the homologous recombination pathway that are independent of BRCA1/2.14 The silencing or dysfunction of genes in BRCA1/2-related pathways gives rise to a BRCAness phenotype similar to that resulting from inherent mutations in BRCA1/2.
0000036519 00000 n J Clin Oncol 2010;28:2512-2519, 25. 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. 0000055121 00000 n 0000053768 00000 n New guidelines to evaluate the response to treatment in solid tumors.
Demographic and Baseline Characteristics of the Patients.
J Clin Oncol 2010;28:3555-3561[Erratum, J Clin Oncol 2010;28:4868. Curr Oncol 2007;14:195-208, 3. 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 most advanced way to teach, practice, and assess clinical reasoning skills.
O;I FBxLv{*g9PJ:/4(_h= Patients receiving placebo were not permitted to cross over to treatment with olaparib after disease progression.
J Clin Oncol 2010;28:3323-3329, 6.
0000049608 00000 n
The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines. 0000000016 00000 n The study design is shown in Figure 1. Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group.
(Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.). 0000054311 00000 n 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.
However, at the interim analysis, this did not translate into an overall survival benefit. 0000025214 00000 n xref endstream endobj 71 0 obj <> endobj 72 0 obj <>stream Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. 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).
`M'/n`W?-r}[tb&Pb00;4}@_z)W GpK.)44 C`OF- uL-~ Between August 28, 2008, and February 9, 2010, we screened 326 patients at 82 investigational sites in 16 countries.
-b`8HKs(|L8r98( V
An interim analysis of overall survival was performed after 101 deaths had been recorded. Weberpals JI, Clark-Knowles KV, Vanderhyden BC.
Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer.
0000004905 00000 n 0000054091 00000 n
Cella DF, Tulsky DS, Gray G, et al.
], 16. 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. 0000006077 00000 n
0000013899 00000 n
60 0 obj <> endobj 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.
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.
0000037431 00000 n 0000025005 00000 n 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
Address reprint requests to Dr. Ledermann at the University College London (UCL) Cancer Institute, UCL & UCL Hospitals Comprehensive Biomedical Research Centre, 90 Tottenham Court Rd., London W1T 4TJ, United Kingdom, or at [emailprotected]. Progression events were observed in 60 patients (44.1%) in the olaparib group and 93 (72.1%) in the placebo group.
Aghajanian C, Finkler NJ, Rutherford T, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. ), and Royal Melbourne Hospital, Parkville, NSW (C.S.)
The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams.
0000054921 00000 n
Valuable tools for building a rewarding career in health care. 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.
0000043552 00000 n Mukhopadhyay A, Elattar A, Cerbinskaite A, et al. This article (10.1056/NEJMoa1105535) was published on March 27, 2012, at NEJM.org. 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. 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. 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). A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making.
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. Evers B, Drost R, Schut E, et al. 0000053418 00000 n %PDF-1.7 % 0000052439 00000 n 0000053907 00000 n
hW XqZkqF#eE7Ph A"l# -Ep5yY&5w^ 7LSP 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. 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. 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.
vKv8U,-Vgh'94G`Kh1g[j*[P2 dq"Z|:ab V*Fu\2*Ze,X4]}Pxg6!Tse[MZu3jQL`ToUImHh18Hk&2x.=>d f|Dse
N Engl J Med 2011;365:2473-2483, 9. 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).
The authorized source of trusted medical research and education for the Chinese-language medical community.
0000053546 00000 n Lancet 2010;376:245-251, 26. K3=yg`D}\%-o00 Markman M, Liu PY, Moon J, et al.
The majority of patients (246 of 264) had one or more adverse events, most of which were grade 1 or 2 (Table 2).
From University College London, London (J.L. Panel B shows a subgroup analysis of progression-free survival in the randomized population. Rustin GJ, Vergote I, Eisenhauer E, et al.
A supportive analysis of progression-free survival with the use of the log-rank test was performed (stratified by randomization factors). 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. 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). 0000054600 00000 n 0000048139 00000 n
0000030434 00000 n The size of the circles is proportional to the number of events. both in Germany; University of Edinburgh Cancer Research U.K. Centre, Edinburgh (C.G.
60 82 Fong PC, Yap TA, Boss DS, et al. 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).
Mol Cell 1999;4:511-518, 13. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.
0000003352 00000 n
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. Moynahan ME, Chiu JW, Koller BH, Jasin M. BRCA1 controls homology-directed DNA repair.
Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. There were no significant differences between the study groups in the end points for symptoms or health-related quality of life.
Rottenberg S, Jaspers JE, Kersbergen A, et al.
0000055027 00000 n 0 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).
0000052922 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. 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. 0000024287 00000 n
Furthermore, the lower risk of disease progression associated with olaparib treatment was consistent across all the subgroups analyzed (Figure 2B).
;`5*sko\6#mmXp?m9rv6;Enl4m'3Wp-9P2tS(U([PYS&ToR&UUEYpG;6EmVXA~ 2hpp{@I]a`?
<<241AA167470147488D06DE51829A8373>]>> J Natl Cancer Inst 2006;98:1694-1706, 12. ], 2. Farmer H, McCabe N, Lord CJ, et al.
0000013500 00000 n 0000052880 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). Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. 0000025452 00000 n
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. Press JZ, De Luca A, Boyd N, et al. The final analysis of overall survival will be performed at 60% maturity (i.e., when 60% of the patients have died). Information and tools for librarians about site license offerings. Because only patients with a response to chemotherapy were enrolled in the study, just 40% had measurable disease at entry. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. CA Cancer J Clin 2011;61:69-90[Erratum, CA Cancer J Clin 2011;61:134.
Safety was assessed throughout the study by monitoring for adverse events, biochemical laboratory tests, assessment of vital signs, and physical examination. both in Australia; University of Leuven, Leuven, Belgium (I.V. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. 0000051012 00000 n
Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse.
0000007501 00000 n
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.
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). 0l ?D0}*L)mZ [BBc01c\I7mrqE4{,0AEA?6QP)-ci[bB1DPD(TP At the time of the data-cutoff point for progression-free survival, too few deaths had occurred for a survival analysis to be performed. 3EQy|}, ; 2(8vG&( 4LjKp Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo.
Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin.
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).
0000006974 00000 n
Ann Oncol 2010;21:Suppl:LBA25-LBA25, 33.
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).
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
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). 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. 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. Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. 0000014253 00000 n J Clin Oncol 1993;11:570-579, 30. 0000020900 00000 n BMC Cancer 2008;8:17-17, 15. Lancet 2003;361:2099-2106, 4. 0000053672 00000 n GCIG denotes Gynecologic Cancer InterGroup. The content of this site is intended for health care professionals.
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). 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).
Perren TJ, Swart AM, Pfisterer J, et al.
The manuscript was written by the first author, with editorial assistance funded by the sponsor, and was reviewed by all authors and the sponsor.
Nijman SM. There were no unexpected changes in biochemical laboratory measurements, vital signs, or findings on physical examination in either group. Mol Cell 2001;7:263-272, 14.
}x0P: 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 0000002584 00000 n Nature 2005;434:917-921, 19. 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.
Data collection and analysis were performed by the sponsor, and all the authors had full access to the data. KaplanMeier Estimates and Subgroup Analysis of Progression-free Survival.
The heterogeneity of the treatment effect among the subgroups was assessed with the use of statistical interaction tests and forest plots. The identification of biomarkers for homologous-recombination deficiency may provide an opportunity to target PARP inhibitors to the appropriate population. 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. 0000046595 00000 n The study was performed in accordance with the Declaration of Helsinki and the guidelines for Good Clinical Practice. 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. 0000001936 00000 n 0000040403 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. 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%).
Gynecol Oncol 2009;114:195-198, 8. Only the 1000 most recent citing articles are listed here. Interim analysis showed no overall survival benefit.
0000053040 00000 n Prepare to become a physician, build your knowledge, lead a health care organization, and advance your career with NEJM Group information and services.
0000025531 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).
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.
Panel A shows KaplanMeier curves for progression-free survival in the randomized population. Dose modifications were more common in the olaparib group; however, discontinuations due to adverse events were infrequent, and adherence to therapy was high. Risch HA, McLaughlin JR, Cole DE, et al. 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). 0000043944 00000 n
Study treatment was blinded with the use of unique identifiers generated during randomization.
N Engl J Med 2011;365:2484-2496[Erratum, N Engl J Med 2012;366:284.
All reported P values and confidence intervals are two-sided.
Sporadic epithelial ovarian cancer: clinical relevance of BRCA1 inhibition in the DNA damage and repair pathway. 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).
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.
The most trusted, influential source of new medical knowledge and clinical best practices in the world. 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). A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. 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
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. 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. 0000054043 00000 n ); Mount Vernon Hospital, Northwood (G.R. ), and Evangelisches Krankenhaus, Dsseldorf (W.M.)
]YQWYR},a'XBy+0v"v#Whv}3w{N ;: gD
Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery.
Semin Oncol 2006;33:Suppl:S12-S16, 5. both in Israel; Indiana University School of Medicine, Indianapolis (D.M.
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. 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. xb```b`Hd`c` @1v#@(!Gtm6Q>e
0000054647 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).
0000002743 00000 n 0000038949 00000 n %%EOF Ashworth A. J Clin Oncol 2011;29:3798-3804. 0000045212 00000 n 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.