0000025214 00000 n
0000006974 00000 n
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. Data collection and analysis were performed by the sponsor, and all the authors had full access to the data. 0000053498 00000 n
Clin Cancer Res 2008;14:3916-3925, 22. 0000054499 00000 n
Dose modifications were more common in the olaparib group; however, discontinuations due to adverse events were infrequent, and adherence to therapy was high. 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). 0000000016 00000 n
Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. 0000054921 00000 n
-b`8HKs(|L8r98( V Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. The size of the circles is proportional to the number of events.
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. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. 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. J Natl Cancer Inst 2006;98:1694-1706, 12.
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). (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.). 0000053112 00000 n From University College London, London (J.L.
1. Pfisterer J, Plante M, Vergote I, et al. 0000007501 00000 n Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks.
0000020900 00000 n startxref 0000020418 00000 n 0000013899 00000 n
New guidelines to evaluate the response to treatment in solid tumors. ); and DanaFarber Cancer Institute, Boston (U.M.). Sz0|{{ZPCL.U(TY 0jA}oJ]fL#RZE At the time of the data-cutoff point for progression-free survival, too few deaths had occurred for a survival analysis to be performed. J Natl Cancer Inst 2000;92:205-216, 28. 0000025005 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. Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. CA Cancer J Clin 2011;61:69-90[Erratum, CA Cancer J Clin 2011;61:134.
DOI: 10.1056/NEJMoa1105535, Tap into groundbreaking research and clinically relevant insights. All patients provided written informed consent. Risch HA, McLaughlin JR, Cole DE, et al. 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). A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. 0000003231 00000 n Study treatment was blinded with the use of unique identifiers generated during randomization. 0000007932 00000 n 0l ?D0}*L)mZ [BBc01c\I7mrqE4{,0AEA?6QP)-ci[bB1DPD(TP ;`5*sko\6#mmXp?m9rv6;Enl4m'3Wp-9P2tS(U([PYS&ToR&UUEYpG;6EmVXA~ 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.
), and Evangelisches Krankenhaus, Dsseldorf (W.M.) Fung-Kee-Fung M, Oliver T, Elit L, Oza A, Hirte HW, Bryson P. Optimal chemotherapy treatment for women with recurrent ovarian cancer. 0000055027 00000 n 0000054091 00000 n Moynahan ME, Chiu JW, Koller BH, Jasin M. BRCA1 controls homology-directed DNA repair. 0000051012 00000 n Sporadic epithelial ovarian cancer: clinical relevance of BRCA1 inhibition in the DNA damage and repair pathway. 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. 0000052922 00000 n 0000041044 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. Prepare to become a physician, build your knowledge, lead a health care organization, and advance your career with NEJM Group information and services. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. 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 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). 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). Aghajanian C, Finkler NJ, Rutherford T, et al. O;I FBxLv{*g9PJ:/4(_h= Therasse P, Arbuck SG, Eisenhauer EA, et al. 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 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. 0000055121 00000 n 0000040403 00000 n 0000049608 00000 n In this population, maintenance therapy with olaparib, at a dose of 400 mg twice daily, significantly improved the duration of progression-free survival, as compared with placebo. However, at the interim analysis of overall survival (data-cutoff point, October 31, 2011), 101 patients (38%) had died: 52 in the olaparib group and 49 in the placebo group. The most advanced way to teach, practice, and assess clinical reasoning skills.
0000002584 00000 n 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
Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Pfisterer J, Ledermann JA. 0000013500 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). High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs.
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. Safety was assessed throughout the study by monitoring for adverse events, biochemical laboratory tests, assessment of vital signs, and physical examination. A phase 3 trial of bevacizumab in ovarian cancer. In both groups, nausea, fatigue, and vomiting were intermittent and did not require discontinuation of the study treatment. A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. Mol Cell 1999;4:511-518, 13. TxDgG%G`FoCoR4U(hwwT()H All reported P values and confidence intervals are two-sided.
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. `M'/n`W?-r}[tb&Pb00;4}@_z)W GpK.)44 C`OF- uL-~ Mukhopadhyay A, Elattar A, Cerbinskaite A, et al. Semin Oncol 2006;33:Suppl:S12-S16, 5.
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). J Clin Oncol 2010;28:3555-3561[Erratum, J Clin Oncol 2010;28:4868. 60 0 obj <> endobj Press JZ, De Luca A, Boyd N, et al.
Patients receiving placebo were not permitted to cross over to treatment with olaparib after disease progression. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. 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. 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 The content of this site is intended for health care professionals. This article (10.1056/NEJMoa1105535) was published on March 27, 2012, at NEJM.org. 0000054214 00000 n 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. Valuable tools for building a rewarding career in health care.
Burger RA, Brady MF, Bookman MA, et al. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Objective response was not an informative end point because there were limited opportunities for further responses.
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. endstream endobj 71 0 obj <> endobj 72 0 obj <>stream Clin Cancer Res 2010;16:2344-2351, 31. No predictive factors were identified (global treatment-by-subgroup interaction test, P=0.15).
Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. 0000054921 00000 n
-b`8HKs(|L8r98( V Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. The size of the circles is proportional to the number of events.
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. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. 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. J Natl Cancer Inst 2006;98:1694-1706, 12.
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). (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.). 0000053112 00000 n From University College London, London (J.L.
1. Pfisterer J, Plante M, Vergote I, et al. 0000007501 00000 n Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks.
0000020900 00000 n startxref 0000020418 00000 n 0000013899 00000 n
New guidelines to evaluate the response to treatment in solid tumors. ); and DanaFarber Cancer Institute, Boston (U.M.). Sz0|{{ZPCL.U(TY 0jA}oJ]fL#RZE At the time of the data-cutoff point for progression-free survival, too few deaths had occurred for a survival analysis to be performed. J Natl Cancer Inst 2000;92:205-216, 28. 0000025005 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. Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. CA Cancer J Clin 2011;61:69-90[Erratum, CA Cancer J Clin 2011;61:134.
DOI: 10.1056/NEJMoa1105535, Tap into groundbreaking research and clinically relevant insights. All patients provided written informed consent. Risch HA, McLaughlin JR, Cole DE, et al. 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). A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. 0000003231 00000 n Study treatment was blinded with the use of unique identifiers generated during randomization. 0000007932 00000 n 0l ?D0}*L)mZ [BBc01c\I7mrqE4{,0AEA?6QP)-ci[bB1DPD(TP ;`5*sko\6#mmXp?m9rv6;Enl4m'3Wp-9P2tS(U([PYS&ToR&UUEYpG;6EmVXA~ 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.
), and Evangelisches Krankenhaus, Dsseldorf (W.M.) Fung-Kee-Fung M, Oliver T, Elit L, Oza A, Hirte HW, Bryson P. Optimal chemotherapy treatment for women with recurrent ovarian cancer. 0000055027 00000 n 0000054091 00000 n Moynahan ME, Chiu JW, Koller BH, Jasin M. BRCA1 controls homology-directed DNA repair. 0000051012 00000 n Sporadic epithelial ovarian cancer: clinical relevance of BRCA1 inhibition in the DNA damage and repair pathway. 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. 0000052922 00000 n 0000041044 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. Prepare to become a physician, build your knowledge, lead a health care organization, and advance your career with NEJM Group information and services. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. 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 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). 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). Aghajanian C, Finkler NJ, Rutherford T, et al. O;I FBxLv{*g9PJ:/4(_h= Therasse P, Arbuck SG, Eisenhauer EA, et al. 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 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. 0000055121 00000 n 0000040403 00000 n 0000049608 00000 n In this population, maintenance therapy with olaparib, at a dose of 400 mg twice daily, significantly improved the duration of progression-free survival, as compared with placebo. However, at the interim analysis of overall survival (data-cutoff point, October 31, 2011), 101 patients (38%) had died: 52 in the olaparib group and 49 in the placebo group. The most advanced way to teach, practice, and assess clinical reasoning skills.
0000002584 00000 n 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
Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Pfisterer J, Ledermann JA. 0000013500 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). High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs.
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. Safety was assessed throughout the study by monitoring for adverse events, biochemical laboratory tests, assessment of vital signs, and physical examination. A phase 3 trial of bevacizumab in ovarian cancer. In both groups, nausea, fatigue, and vomiting were intermittent and did not require discontinuation of the study treatment. A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. Mol Cell 1999;4:511-518, 13. TxDgG%G`FoCoR4U(hwwT()H All reported P values and confidence intervals are two-sided.
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. `M'/n`W?-r}[tb&Pb00;4}@_z)W GpK.)44 C`OF- uL-~ Mukhopadhyay A, Elattar A, Cerbinskaite A, et al. Semin Oncol 2006;33:Suppl:S12-S16, 5.
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). J Clin Oncol 2010;28:3555-3561[Erratum, J Clin Oncol 2010;28:4868. 60 0 obj <> endobj Press JZ, De Luca A, Boyd N, et al.
Patients receiving placebo were not permitted to cross over to treatment with olaparib after disease progression. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. 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. 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 The content of this site is intended for health care professionals. This article (10.1056/NEJMoa1105535) was published on March 27, 2012, at NEJM.org. 0000054214 00000 n 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. Valuable tools for building a rewarding career in health care.
Burger RA, Brady MF, Bookman MA, et al. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Objective response was not an informative end point because there were limited opportunities for further responses.
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. endstream endobj 71 0 obj <> endobj 72 0 obj <>stream Clin Cancer Res 2010;16:2344-2351, 31. No predictive factors were identified (global treatment-by-subgroup interaction test, P=0.15).