PURPOSE: Selective tumor cell cytotoxicity can be achieved through a synthetic lethal strategy using poly(ADP)-ribose polymerase (PARP) inhibitor therapy in BRCA1/2 mutation carriers in whom tumor cells have defective homologous recombination (HR) DNA repair. Platinum-based chemotherapy responses correlate with HR DNA repair capacity. Olaparib is a potent, oral PARP inhibitor that is well tolerated, with antitumor activity in BRCA1/2 mutation carriers. PATIENTS AND METHODS: Patients with BRCA1/2-mutated ovarian cancer were treated with olaparib within a dose-escalation and single-stage expansion of a phase I trial. Antitumor activity was subsequently correlated with platinum sensitivity. RESULTS: Fifty patients were treated: 48 had germline BRCA1/2 mutations; one had a BRCA2 germline sequence change of unknown significance, and another had a strong family history of BRCA1/2-associated cancers who declined mutation testing. Of the 50 patients, 13 had platinum-sensitive disease, 24 had platinum-resistant disease, and 13 had platinum-refractory disease (according to platinum-free interval). Twenty (40%; 95% CI, 26% to 55%) achieved Response Evaluation Criteria in Solid Tumors (RECIST) complete or partial responses and/or tumor marker (CA125) responses, and three (6.0%) maintained RECIST disease stabilization for more than 4 months, giving an overall clinical benefit rate of 46% (95% CI, 32% to 61%). Median response duration was 28 weeks. There was a significant association between the clinical benefit rate and platinum-free interval across the platinum-sensitive, resistant, and refractory subgroups (69%, 45%, and 23%, respectively). Post hoc analyses indicated associations between platinum sensitivity and extent of olaparib response (radiologic change, P = .001; CA125 change, P = .002). CONCLUSION: Olaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.
PURPOSE: Selective tumor cell cytotoxicity can be achieved through a synthetic lethal strategy using poly(ADP)-ribose polymerase (PARP) inhibitor therapy in BRCA1/2 mutation carriers in whom tumor cells have defective homologous recombination (HR) DNA repair. Platinum-based chemotherapy responses correlate with HR DNA repair capacity. Olaparib is a potent, oral PARP inhibitor that is well tolerated, with antitumor activity in BRCA1/2 mutation carriers. PATIENTS AND METHODS: Patients with BRCA1/2-mutated ovarian cancer were treated with olaparib within a dose-escalation and single-stage expansion of a phase I trial. Antitumor activity was subsequently correlated with platinum sensitivity. RESULTS: Fifty patients were treated: 48 had germline BRCA1/2 mutations; one had a BRCA2 germline sequence change of unknown significance, and another had a strong family history of BRCA1/2-associated cancers who declined mutation testing. Of the 50 patients, 13 had platinum-sensitive disease, 24 had platinum-resistant disease, and 13 had platinum-refractory disease (according to platinum-free interval). Twenty (40%; 95% CI, 26% to 55%) achieved Response Evaluation Criteria in Solid Tumors (RECIST) complete or partial responses and/or tumor marker (CA125) responses, and three (6.0%) maintained RECIST disease stabilization for more than 4 months, giving an overall clinical benefit rate of 46% (95% CI, 32% to 61%). Median response duration was 28 weeks. There was a significant association between the clinical benefit rate and platinum-free interval across the platinum-sensitive, resistant, and refractory subgroups (69%, 45%, and 23%, respectively). Post hoc analyses indicated associations between platinum sensitivity and extent of olaparib response (radiologic change, P = .001; CA125 change, P = .002). CONCLUSION: Olaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.
Authors: 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 Journal: J Clin Oncol Date: 2014-11-03 Impact factor: 44.544
Authors: Kelly L Bolton; Georgia Chenevix-Trench; Cindy Goh; Siegal Sadetzki; Susan J Ramus; Beth Y Karlan; Diether Lambrechts; Evelyn Despierre; Daniel Barrowdale; Lesley McGuffog; Sue Healey; Douglas F Easton; Olga Sinilnikova; Javier Benítez; María J García; Susan Neuhausen; Mitchell H Gail; Patricia Hartge; Susan Peock; Debra Frost; D Gareth Evans; Rosalind Eeles; Andrew K Godwin; Mary B Daly; Ava Kwong; Edmond S K Ma; Conxi Lázaro; Ignacio Blanco; Marco Montagna; Emma D'Andrea; Maria Ornella Nicoletto; Sharon E Johnatty; Susanne Krüger Kjær; Allan Jensen; Estrid Høgdall; Ellen L Goode; Brooke L Fridley; Jennifer T Loud; Mark H Greene; Phuong L Mai; Angela Chetrit; Flora Lubin; Galit Hirsh-Yechezkel; Gord Glendon; Irene L Andrulis; Amanda E Toland; Leigha Senter; Martin E Gore; Charlie Gourley; Caroline O Michie; Honglin Song; Jonathan Tyrer; Alice S Whittemore; Valerie McGuire; Weiva Sieh; Ulf Kristoffersson; Håkan Olsson; Åke Borg; Douglas A Levine; Linda Steele; Mary S Beattie; Salina Chan; Robert L Nussbaum; Kirsten B Moysich; Jenny Gross; Ilana Cass; Christine Walsh; Andrew J Li; Ronald Leuchter; Ora Gordon; Montserrat Garcia-Closas; Simon A Gayther; Stephen J Chanock; Antonis C Antoniou; Paul D P Pharoah Journal: JAMA Date: 2012-01-25 Impact factor: 56.272
Authors: Joyce Liu; Mihaela C Cristea; Paul Frankel; Susan L Neuhausen; Linda Steele; Verena Engelstaedter; Ursula Matulonis; Sharon Sand; Nadine Tung; Judy E Garber; Jeffrey N Weitzel Journal: Cancer Genet Date: 2012 Jan-Feb