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Journal ArticleDOI

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Robert L. Coleman1, Amit M. Oza2, Domenica Lorusso, Carol Aghajanian3, Ana Oaknin4, Andrew Dean, Nicoletta Colombo5, Johanne I Weberpals6, Andrew R Clamp7, Giovanni Scambia8, Alexandra Leary9, Robert W Holloway, Margarita Amenedo Gancedo, Peter C.C. Fong10, Jeffrey C. Goh11, David M. O'Malley12, Deborah K. Armstrong13, Jesus Garcia-Donas, Elizabeth M. Swisher14, Anne Floquet, Gottfried E. Konecny15, Iain A. McNeish16, Clare L. Scott17, Terri Cameron, Lara Maloney, Jeff Isaacson, Sandra Goble, Caroline Grace, Thomas Harding, Mitch Raponi, James Sun18, Kevin K. Lin, Heidi Giordano, Jonathan A. Ledermann19, Martin Buck, A Dean, Michael Friedlander, J C Goh11, Paul R. Harnett, G Kichenadasse20, C L Scott17, H Denys, Luc Dirix, Ignace Vergote, Laurie Elit, Prafull Ghatage, Amit M. Oza2, Marie Plante, Diane Provencher, J I Weberpals6, Stephen Welch, A Floquet, Laurence Gladieff, Florence Joly, A Leary9, Alain Lortholary, Jean-Pierre Lotz, J. Medioni, Olivier Tredan, Benoit You, A El-Balat, C Hänle, P Krabisch, T Neunhöffer, M Pölcher, Pauline Wimberger, Amnon Amit, S Kovel, M Leviov, Tamar Safra, Ronnie Shapira-Frommer, Salomon M. Stemmer, Alessandra Bologna, N Colombo5, Domenica Lorusso, Sandro Pignata, Roberto Sabbatini, G Scambia8, Stefano Tamberi, Claudio Zamagni, P C Fong10, A O'Donnell, M Amenedo Gancedo, A Casado Herraez, J Garcia-Donas, E M Guerra, A Oaknin4, I Palacio, Iris L. Romero, A Sanchez, Susana Banerjee, A Clamp7, Y Drew, Hani Gabra, D Jackson, Jonathan A. Ledermann19, I A McNeish16, Christine Parkinson, Melanie E Powell, C Aghajanian3, D K Armstrong13, Michael J. Birrer, Mary K. Buss, Setsuko K. Chambers, L-m Chen, Robert L. Coleman1, R W Holloway, G E Konecny15, L Ma, Mark A. Morgan, R T Morris, David G. Mutch, D M O'Malley12, B M Slomovitz, E M Swisher14, T Vanderkwaak, M Vulfovich 
28 Oct 2017-The Lancet (Elsevier)-Vol. 390, Iss: 10106, pp 1949-1961
TL;DR: This trial assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity.
About: This article is published in The Lancet.The article was published on 2017-10-28 and is currently open access. It has received 1139 citations till now. The article focuses on the topics: Rucaparib & Recurrent Ovarian Carcinoma.
Citations
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Journal ArticleDOI
TL;DR: The use of maintenance therapy with olaparib provided a substantial benefit with regard to progression‐free survival among women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation, with a 70% lower risk of disease progression or death with olAParib than with placebo.
Abstract: Background Most women with newly diagnosed advanced ovarian cancer have a relapse within 3 years after standard treatment with surgery and platinum-based chemotherapy. The benefit of the o...

1,552 citations


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Journal ArticleDOI
TL;DR: In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a BRCA mutation.
Abstract: Background Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. The effect of combining mainte...

962 citations

Journal ArticleDOI
TL;DR: Urgent progress is needed to develop evidence and consensus-based treatment guidelines for each subgroup, and requires close international cooperation in conducting clinical trials through academic research groups such as the Gynecologic Cancer Intergroup.

882 citations

Journal ArticleDOI
TL;DR: The authors review the progress made to date with PARP inhibitors, describe the expanding landscape of novel anticancer therapies targeting the DNA damage response and potential predictive biomarkers, mechanisms of resistance and combinatorial strategies are discussed.
Abstract: Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumour agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments (such as chemotherapeutics and radiation), novel molecularly targeted agents and immune-checkpoint inhibitors. In this Review, we discuss the current status of anticancer therapies targeting the DDR.

671 citations

Journal ArticleDOI
TL;DR: To improve survival in this aggressive disease, access to appropriate evidence‐based care is requisite and individualized precision medicine will require prioritizing clinical trials of innovative treatments and refining predictive biomarkers that will enable selection of patients who would benefit from chemotherapy, targeted agents, or immunotherapy.
Abstract: Ovarian cancer is the second most common cause of gynecologic cancer death in women around the world. The outcomes are complicated, because the disease is often diagnosed late and composed of several subtypes with distinct biological and molecular properties (even within the same histological subtype), and there is inconsistency in availability of and access to treatment. Upfront treatment largely relies on debulking surgery to no residual disease and platinum-based chemotherapy, with the addition of antiangiogenic agents in patients who have suboptimally debulked and stage IV disease. Major improvement in maintenance therapy has been seen by incorporating inhibitors against poly (ADP-ribose) polymerase (PARP) molecules involved in the DNA damage-repair process, which have been approved in a recurrent setting and recently in a first-line setting among women with BRCA1/BRCA2 mutations. In recognizing the challenges facing the treatment of ovarian cancer, current investigations are enlaced with deep molecular and cellular profiling. To improve survival in this aggressive disease, access to appropriate evidence-based care is requisite. In concert, realizing individualized precision medicine will require prioritizing clinical trials of innovative treatments and refining predictive biomarkers that will enable selection of patients who would benefit from chemotherapy, targeted agents, or immunotherapy. Together, a coordinated and structured approach will accelerate significant clinical and academic advancements in ovarian cancer and meaningfully change the paradigm of care.

663 citations

References
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Journal ArticleDOI
TL;DR: The revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions, and a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included.

20,760 citations

Journal ArticleDOI
TL;DR: Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer amongThose receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity.
Abstract: Tesaro; Amgen; Genentech; Roche; AstraZeneca; Myriad Genetics; Merck; Gradalis; Cerulean; Vermillion; ImmunoGen; Pfizer; Bayer; Nu-Cana BioMed; INSYS Therapeutics; GlaxoSmithKline; Verastem; Mateon Therapeutics; Pharmaceutical Product Development; Clovis Oncology; Janssen/Johnson Johnson; Eli Lilly; Merck Sharp Dohme

1,686 citations

Journal ArticleDOI
TL;DR: Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer and the toxicity profile of olaparIB in this population was consistent with that in previous studies.
Abstract: 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). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. 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. 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). CONCLUSIONS Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.)

1,490 citations

Journal ArticleDOI
Eric Pujade-Lauraine1, Jonathan A. Ledermann2, Frédéric Selle, Val Gebski3, Richard T Penson4, Amit M. Oza5, Jacob Korach6, Tomasz Huzarski7, Andres Poveda, Sandro Pignata, Michael Friedlander8, Nicoletta Colombo9, Philipp Harter, Keiichi Fujiwara10, Isabelle Ray-Coquard11, Susana Banerjee12, Joyce F. Liu4, Elizabeth S. Lowe13, Ralph Bloomfield13, Patricia Pautier14, Tomasz Byrski15, Giovanni Scambia, Maria Ornella Nicoletto, Fiona Nussey, Andrew R Clamp, Richard T. Penson4, Amit M. Oza5, Andrés Poveda Velasco, Manuel Rodrigues, Jean-Pierre Lotz, Diane Provencher, Aleix Prat Aparicio, Laura Vidal Boixader, Clare L. Scott, Kenji Tamura, Mayu Yunokawa, Alla Lisyanskaya16, Jacques Medioni, Nicolas Pécuchet, Coraline Dubot, Thibault De La Motte Rouge, Marie-Christine Kaminsky, Béatrice Weber, Alain Lortholary, Christine Parkinson, Jonathan A. Ledermann2, Sarah Williams, Jonathan Cosin, James Hoffman, Marie Plante, Allan Covens, Gabe S. Sonke17, Florence Joly, Anne Floquet, H. Hirte, Amnon Amit, Tjoung-Won Park-Simon18, Koji Matsumoto, Sergei Tjulandin, Jae Hoon Kim19, Jae Hoon Kim20, Laurence Gladieff, Roberto Sabbatini, David M. O'Malley, Patrick Timmins, Daniel Kredentser, Nuria Laínez Milagro, Maria Pilar Barretina Ginesta, Ariadna Tibau Martorell, Alfonso Gómez de Liaño Lista, Belén Ojeda González, Linda Mileshkin, Masaki Mandai, Ingrid A. Boere, Petronella B. Ottevanger, Joo-Hyun Nam, Elias Abdo Filho21, Salima Hamizi, Francesco Cognetti, David Warshal, Elizabeth Dickson-Michelson, Scott Kamelle, Nathalie McKenzie, Gustavo C. Rodriguez, Deborah K. Armstrong, Eva Chalas, Paul Celano, Kian Behbakht, Susan E Davidson, Stephen Welch, Limor Helpman, Ami Fishman, Ilan Bruchim, Magdalena Sikorska, Anna Słowińska, Wojciech Rogowski, Mariusz Bidziński, Beata Śpiewankiewicz, Antonio Casado Herraez, César Mendiola Fernández, Martina Gropp-Meier, Toshiaki Saito, Kazuhiro Takehara, Takayuki Enomoto, Hidemichi Watari, Chel Hun Choi, Byoung-Gie Kim, Jae Weon Kim19, Jae Weon Kim20, Roberto Hegg, Ignace Vergote15 
TL;DR: Olaparib tablet maintenance treatment provided a significant progression-free survival improvement with no detrimental effect on quality of life in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation.
Abstract: Summary Background Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has previously shown efficacy in a phase 2 study when given in capsule formulation to all-comer patients with platinum-sensitive, relapsed high-grade serous ovarian cancer. We aimed to confirm these findings in patients with a BRCA1 or BRCA2 (BRCA1/2 ) mutation using a tablet formulation of olaparib. Methods This international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial evaluated olaparib tablet maintenance treatment in platinum-sensitive, relapsed ovarian cancer patients with a BRCA1/2 mutation who had received at least two lines of previous chemotherapy. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status at baseline of 0–1 and histologically confirmed, relapsed, high-grade serous ovarian cancer or high-grade endometrioid cancer, including primary peritoneal or fallopian tube cancer. Patients were randomly assigned 2:1 to olaparib (300 mg in two 150 mg tablets, twice daily) or matching placebo tablets using an interactive voice and web response system. Randomisation was stratified by response to previous platinum chemotherapy (complete vs partial) and length of platinum-free interval (6–12 months vs ≥12 months) and treatment assignment was masked for patients, those giving the interventions, data collectors, and data analysers. The primary endpoint was investigator-assessed progression-free survival and we report the primary analysis from this ongoing study. The efficacy analyses were done on the intention-to-treat population; safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01874353, and is ongoing and no longer recruiting patients. Findings Between Sept 3, 2013, and Nov 21, 2014, we enrolled 295 eligible patients who were randomly assigned to receive olaparib (n=196) or placebo (n=99). One patient in the olaparib group was randomised in error and did not receive study treatment. Investigator-assessed median progression-free survival was significantly longer with olaparib (19·1 months [95% CI 16·3–25·7]) than with placebo (5·5 months [5·2–5·8]; hazard ratio [HR] 0·30 [95% CI 0·22–0·41], p vs two [2%] of 99 patients in the placebo group), fatigue or asthenia (eight [4%] vs two [2%]), and neutropenia (ten [5%] vs four [4%]). Serious adverse events were experienced by 35 (18%) patients in the olaparib group and eight (8%) patients in the placebo group. The most common in the olaparib group were anaemia (seven [4%] patients), abdominal pain (three [2%] patients), and intestinal obstruction (three [2%] patients). The most common in the placebo group were constipation (two [2%] patients) and intestinal obstruction (two [2%] patients). One (1%) patient in the olaparib group had a treatment-related adverse event (acute myeloid leukaemia) with an outcome of death. Interpretation Olaparib tablet maintenance treatment provided a significant progression-free survival improvement with no detrimental effect on quality of life in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Apart from anaemia, toxicities with olaparib were low grade and manageable. Funding AstraZeneca.

1,280 citations

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