Journal ArticleDOI
The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial
Shahneen Sandhu,Shahneen Sandhu,William R. Schelman,George Wilding,Victor Moreno,Richard D. Baird,Susana Miranda,Lucy Hylands,Ruth Riisnaes,Martin Forster,Aurelius Omlin,Nathan Kreischer,Khin Thway,Heidrun Gevensleben,L. Sun,John W. Loughney,Manash Shankar Chatterjee,Carlo Toniatti,Carlo Toniatti,Christopher L. Carpenter,Robert Iannone,Stan B. Kaye,Johann S. de Bono,Robert M Wenham +23 more
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Niraparib (MK4827) as mentioned in this paper is an oral potent, selective PARP-1/PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function.Abstract:
Summary Background Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. Methods In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov, NCT00749502. Findings Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8–46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% [95% CI 19–64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7–93]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. Interpretation A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. Funding Merck Sharp and Dohme.read more
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DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.
Joaquin Mateo,Suzanne Carreira,Shahneen Sandhu,Susana Miranda,Helen Mossop,Raquel Perez-Lopez,Daniel Nava Rodrigues,Dan R. Robinson,Aurelius Omlin,Nina Tunariu,Gunther Boysen,Nuria Porta,Penny Flohr,Alexa Gillman,Ines Figueiredo,Claire Paulding,George Seed,Suneil Jain,Christy Ralph,Andrew Protheroe,Syed A. Hussain,Robert Jones,Tony Elliott,Ursula McGovern,Diletta Bianchini,Jane C. Goodall,Zafeiris Zafeiriou,Chris T. Williamson,Roberta Ferraldeschi,Ruth Riisnaes,Bernardette Ebbs,Gemma Fowler,Desamparados Roda,Wei Yuan,Yi-Mi Wu,Xuhong Cao,Rachel Brough,Helen Pemberton,Roger A'Hern,Amanda Swain,Lakshmi P. Kunju,Rosalind A. Eeles,Gerhardt Attard,Christopher J. Lord,Alan Ashworth,Mark A. Rubin,Karen E. Knudsen,Felix Y. Feng,Arul M. Chinnaiyan,Emma Hall,Johann S. de Bono +50 more
TL;DR: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate.
Journal ArticleDOI
Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer
Mansoor Raza Mirza,Bradley J. Monk,Jørn Herrstedt,Amit M. Oza,Sven Mahner,Sven Mahner,Andrés Redondo,Michel Fabbro,Jonathan A. Ledermann,Domenica Lorusso,Ignace Vergote,Noa Ben-Baruch,Christian Marth,Radosław Mądry,René dePont Christensen,Jonathan S. Berek,Anne Dørum,Anne Dørum,Anna V. Tinker,Andreas du Bois,Antonio González-Martín,Philippe Follana,Benedict B. Benigno,Per Rosenberg,Lucy Gilbert,Bobbie J. Rimel,Joseph Buscema,John Balser,Shefali Agarwal,Ursula A. Matulonis,Ursula A. Matulonis +30 more
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.
Journal ArticleDOI
Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation
Bella Kaufman,Ronnie Shapira-Frommer,Rita K. Schmutzler,M. William Audeh,Michael Friedlander,Judith Balmaña,Gillian Mitchell,Georgeta Fried,Salomon M. Stemmer,Ayala Hubert,Ora Rosengarten,Mariana Steiner,Niklas Loman,Karin Bowen,Anitra Fielding,Susan M. Domchek +15 more
TL;DR: Responses to olaparib were observed across different tumor types associated with germline BRCA1/2 mutations, and warrants further investigation in confirmatory studies.
Journal ArticleDOI
Emerging Mechanisms of Resistance to Androgen Receptor Inhibitors in Prostate Cancer
TL;DR: This Review highlights emerging mechanisms of acquired resistance to contemporary therapies targeting the AR pathway, which fall into the three broad categories of restored AR signalling, AR bypass signalling and complete AR independence.
Journal ArticleDOI
State-of-the-art strategies for targeting the DNA damage response in cancer
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.
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TL;DR: It is reported that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1,BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes.
Journal ArticleDOI
Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers
Peter C.C. Fong,D. S. Boss,Timothy A. Yap,Andrew Tutt,Peijun Wu,Marja Mergui-Roelvink,Peter S. Mortimer,Helen Swaisland,Alan Lau,Mark J. O'Connor,Alan Ashworth,James Carmichael,Stan B. Kaye,Jan H.M. Schellens,Jan H.M. Schellens,Johann S. de Bono +15 more
TL;DR: Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCa2 mutation.
Journal ArticleDOI
The mutational landscape of lethal castration-resistant prostate cancer
Catherine S. Grasso,Yi-Mi Wu,Dan R. Robinson,Xuhong Cao,Saravana M. Dhanasekaran,Amjad Khan,Michael J. Quist,Xiaojun Jing,Robert J. Lonigro,J. Chad Brenner,Irfan A. Asangani,Bushra Ateeq,Sang Y. Chun,Javed Siddiqui,Lee Sam,Matt Anstett,Rohit Mehra,John R. Prensner,Nallasivam Palanisamy,Gregory A. Ryslik,Fabio Vandin,Benjamin J. Raphael,Lakshmi P. Kunju,Daniel R. Rhodes,Kenneth J. Pienta,Arul M. Chinnaiyan,Scott A. Tomlins +26 more
TL;DR: The mutational landscape of a heavily treated metastatic cancer is described, novel mechanisms of AR signalling deregulated in prostate cancer are identified, and candidates for future study are prioritize.
Journal ArticleDOI
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial
Andrew Tutt,Mark E. Robson,Judy Garber,Susan M. Domchek,M. William Audeh,Jeffrey N. Weitzel,Michael Friedlander,Banu Arun,Niklas Loman,Rita K. Schmutzler,Andrew M Wardley,Gillian Mitchell,H. M. Earl,Mark Wickens,James Carmichael +14 more
TL;DR: Findings from this phase 2 study provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA-mutated advanced ovarian cancer.