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Showing content from https://www.ncbi.nlm.nih.gov/pubmed/31157963 below:

Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer

Clinical Trial

. 2019 Jul 25;381(4):317-327. doi: 10.1056/NEJMoa1903387. Epub 2019 Jun 2. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer Pascal Hammel¹, Michele Reni¹, Eric Van Cutsem¹, Teresa Macarulla¹, Michael J Hall¹, Joon-Oh Park¹, Daniel Hochhauser¹, Dirk Arnold¹, Do-Youn Oh¹, Anke Reinacher-Schick¹, Giampaolo Tortora¹, Hana Algül¹, Eileen M O'Reilly¹, David McGuinness¹, Karen Y Cui¹, Katia Schlienger¹, Gershon Y Locker¹, Hedy L Kindler¹

Affiliations

Affiliation

¹ From the Oncology Institute, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel (T.G.); Hôpital Beaujon (Assistance Publique-Hôpitaux de Paris), Clichy, and University Paris VII, Paris (P.H.); IRCCS Ospedale San Raffaele Scientific Institute, Milan (M.R.), Azienda Ospedaliera Universitaria Integrata Verona, Verona (G.T.), and Fondazione Policlinico Universitario Gemelli IRCCS, Rome (G.T.) - all in Italy; University Hospitals Gasthuisberg and KU Leuven, Leuven, Belgium (E.V.C.); Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona (T.M.); Fox Chase Cancer Center, Philadelphia (M.J.H.); Samsung Medical Center, Sungkyunkwan University School of Medicine (J.-O.P.), and Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine (D.-Y.O.) - both in Seoul, South Korea; University College London Cancer Institute, London (D.H.), and AstraZeneca, Cambridge (D.M.) - both in the United Kingdom; Asklepios Tumorzentrum Hamburg Asklepios Klinik Altona, Hamburg (D.A.), St. Josef-Hospital, Ruhr University Bochum, Bochum (A.R.-S.), and Klinikum rechts der Isar, Department of Internal Medicine II, Technische Universität München, Munich (H.A.) - all in Germany; Memorial Sloan Kettering Cancer Center, New York (E.M.O.); AstraZeneca, Gaithersburg, MD (K.Y.C., G.Y.L.); Merck, Kenilworth, NJ (K.S.); and the University of Chicago, Chicago (H.L.K.).

PMID: 31157963
PMCID: PMC6810605
DOI: 10.1056/NEJMoa1903387

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Clinical Trial

Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer

Talia Golan et al. N Engl J Med. 2019.

. 2019 Jul 25;381(4):317-327. doi: 10.1056/NEJMoa1903387. Epub 2019 Jun 2. Authors Talia Golan¹, Pascal Hammel¹, Michele Reni¹, Eric Van Cutsem¹, Teresa Macarulla¹, Michael J Hall¹, Joon-Oh Park¹, Daniel Hochhauser¹, Dirk Arnold¹, Do-Youn Oh¹, Anke Reinacher-Schick¹, Giampaolo Tortora¹, Hana Algül¹, Eileen M O'Reilly¹, David McGuinness¹, Karen Y Cui¹, Katia Schlienger¹, Gershon Y Locker¹, Hedy L Kindler¹ Affiliation

¹ From the Oncology Institute, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel (T.G.); Hôpital Beaujon (Assistance Publique-Hôpitaux de Paris), Clichy, and University Paris VII, Paris (P.H.); IRCCS Ospedale San Raffaele Scientific Institute, Milan (M.R.), Azienda Ospedaliera Universitaria Integrata Verona, Verona (G.T.), and Fondazione Policlinico Universitario Gemelli IRCCS, Rome (G.T.) - all in Italy; University Hospitals Gasthuisberg and KU Leuven, Leuven, Belgium (E.V.C.); Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona (T.M.); Fox Chase Cancer Center, Philadelphia (M.J.H.); Samsung Medical Center, Sungkyunkwan University School of Medicine (J.-O.P.), and Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine (D.-Y.O.) - both in Seoul, South Korea; University College London Cancer Institute, London (D.H.), and AstraZeneca, Cambridge (D.M.) - both in the United Kingdom; Asklepios Tumorzentrum Hamburg Asklepios Klinik Altona, Hamburg (D.A.), St. Josef-Hospital, Ruhr University Bochum, Bochum (A.R.-S.), and Klinikum rechts der Isar, Department of Internal Medicine II, Technische Universität München, Munich (H.A.) - all in Germany; Memorial Sloan Kettering Cancer Center, New York (E.M.O.); AstraZeneca, Gaithersburg, MD (K.Y.C., G.Y.L.); Merck, Kenilworth, NJ (K.S.); and the University of Chicago, Chicago (H.L.K.).

PMID: 31157963
PMCID: PMC6810605
DOI: 10.1056/NEJMoa1903387

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Abstract

Background: Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population.

Methods: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review.

Results: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event.

Conclusions: Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. (Funded by AstraZeneca and others; POLO ClinicalTrials.gov number, NCT02184195.).

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Figures
Figure 1.. Screening, Enrollment, Randomization, and Intervention.

Figure 1.. Screening, Enrollment, Randomization, and Intervention.

One patient in the placebo group incorrectly received…

Figure 1.. Screening, Enrollment, Randomization, and Intervention.

One patient in the placebo group incorrectly received olaparib and was included in the olaparib group for the safety analyses. After initiation of the trial intervention, another patient in the placebo group was found not to have met the eligibility criteria, and the intervention was discontinued on day 3 at the decision of the trial sponsor. In addition to this patient, one patient in each trial group was found, after randomization, not to have met the eligibility criteria. Both were included in the intention-to-treat efficacy analyses. Neither patient received a trial intervention, and so neither was included in the safety analyses.

Figure 2.. Kaplan–Meier Estimates of Progression-free Survival…

Figure 2.. Kaplan–Meier Estimates of Progression-free Survival and Overall Survival.

Panel A shows Kaplan–Meier estimates…

Figure 2.. Kaplan–Meier Estimates of Progression-free Survival and Overall Survival.

Panel A shows Kaplan–Meier estimates of progression‑free survival (based on blinded independent central review), and Panel B shows Kaplan–Meier estimates of overall survival in the olaparib group and the placebo group.

Figure 3.. Subgroup Analysis of Progression-free Survival.

Figure 3.. Subgroup Analysis of Progression-free Survival.

Subgroups in which fewer than five progression‑free survival…

Figure 3.. Subgroup Analysis of Progression-free Survival.

Subgroups in which fewer than five progression‑free survival events occurred per group were not included in the analysis. The sizes of the circles are proportional to the number of events. The dashed line indicates the point of no effect (hazard ratio = 1). The prespecified gemcitabine–cisplatin subgroup included two patients in the olaparib group and three patients in the placebo group; this subgroup did not meet the threshold for inclusion in the subgroup analysis. Patients who received gemcitabine–cisplatin were not included in the “other” subcategory of the “previous chemotherapy” subgroup but are included in the “doublet chemotherapy” subgroup. Race was determined from patient records.