html5-img
1 / 20

1 Cedars-Sinai Cancer Center, Los Angeles, CA

Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. MW Audeh , 1 RT Penson, 2 M Friedlander, 3 B Powell, 4 KM Bell-McGuinn, 5 C Scott, 6 JN Weitzel, 7 J Carmichael 8 and A Tutt 9. 1 Cedars-Sinai Cancer Center, Los Angeles, CA

storm
Download Presentation

1 Cedars-Sinai Cancer Center, Los Angeles, CA

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer MW Audeh,1 RT Penson,2 M Friedlander,3 B Powell,4KM Bell-McGuinn,5 C Scott,6 JN Weitzel,7J Carmichael8 and A Tutt9 1Cedars-Sinai Cancer Center, Los Angeles, CA 22DF/HCC andMassachusetts General Hospital, Boston, MA, USA 3Prince of Wales Cancer Center, Randwick, Sydney, New South Wales, Australia 4University of California, San Francisco, CA, USA 5Memorial Sloan-Kettering Cancer Center, New York, NY, USA 6The Royal Melbourne Hospital, Victoria, Australia 7City of Hope Comprehensive Cancer Center, Duarte, California, USA 8AstraZeneca, Macclesfield, UK 9King’s College London School of Medicine, Guy's Hospital, London, UK Study ID: KU36-58; D0810C00009

  2. Poly(ADP-Ribose) Polymerase (PARP) A key regulator of DNA damage repair processes

  3. Normal cellwith functional HR pathway HR-deficient tumor cell (e.g. BRCA 1/2-/-) PARP inhibition and tumor-selective synthetic lethality DNA damage(SSBs) PARPinhibition PARP DNA replication(accumulation of DNA DSBs) HR-mediated DNA repair Impaired HR- mediated DNA repair Cell survival Cell death Tumor-selective cytotoxicity Farmer H et al.Nature 2005;434:917–921 Bryant HE et al. Nature 2005;434:913–917 McCabe N et al. Cancer Res 2006;66:8109–8115 DSB, double-strand break; HR, homologous recombinationSSB, single-strand break

  4. x x Lethality BRCA tumor-selective killing BRCA1 or BRCA2 Carrier Normal tissue BRCA1 or BRCA2 Carrier Tumor tissue DNA DAMAGE DNA DAMAGE HRNHEJ SSABERNER etc HRNHEJ SSABERNER etc x Tutt A et al.Cold Spring Harb Symp Quant Biol 2005;70:139–148; McCabe N et al. Cancer Res 2006;66:8109–8115

  5. OlaparibA novel, orally active PARP inhibitor • A Phase I trial identified olaparib (AZD2281; KU-0059436) 400 mg bid as the maximum tolerated dose1 with a 28% (13/46 pts) response rate (RECIST) in BRCA-mutated ovarian cancer2 • Most common toxicities: CTCAE grade 1 and 2 nausea and fatigue • Significant PARP inhibition and tumor response at olaparib doses 100–400 mg bid 1. Yap T et al.J Clin Oncol 2007;25(18S):abst 3529; 2. Fong P et al. J Clin Oncol 2008;26(15S):abst 5510

  6. Cohort 1 Olaparib 400 mg po bid (MTD)(28-day cycles)(n=33) Cohort 2 Olaparib 100 mg po bid(28-day cycles)(n=24) Study design An open-label, single-arm, multicenter Phase II study Recurrent (stage IIIB/IIIC/IV) ovarian cancer after failure of ≥1 prior platinum based chemotherapy Sequential cohorts • Patients • Confirmed germline BRCA1 or BRCA2 mutation • Measurable disease • ECOG performance status 0–2 MTD, maximum tolerated dose (determined during Phase I evaluation)

  7. Study endpoints Primary • Objective response rate (ORR) • Complete response (CR) + partial response (PR) by RECIST Secondary endpoints included: • Progression-free survival (PFS) • Response by either RECIST or GCIG (CA-125) criteria ( >50% reduction in CA125) • Safety and tolerability GCIG, Gynecologic Cancer Intergroup; RECIST, Response Evaluation Criteria in Solid Tumors

  8. Patient characteristics

  9. Patient characteristics

  10. Olaparib100 mg bid(n=24) 3 (13) 4 (17) 269 169–288 Efficacy Olaparib400 mg bid(n=33) RECIST response rate, n (%)* Responders by RECIST and/or GCIG criteria, n (%) Duration of response† Median (days) Range 11 (33) 20 (61) 290 126–513 ITT analysis *Confirmed responses; there were an additional 3 unconfirmed responders in the 400 mg cohort (unconfirmed ORR 42%) †Duration of response is underestimated as some patients are still responding

  11. Olaparib100 mg bid(n=24) 0 3 (13) 7 (29) 12 (50) 2 (8) Summary of best RECIST response 2 (6) 9 (27) 11 (33) 9 (27) 2 (6) ITT analysis* Confirmed responses; there were an additional 3 unconfirmed responders in the 400 mg cohort

  12. Best % change from baseline in target lesions 100 Olaparib 400 mg bid cohort 80 BRCA1 BRCA2 60 40 Increasing tumor shrinkage 20 Best % change from baseline 0 -20 -40 -60 -80 -100 Figure includes 3 unconfirmed responses. Data are not included for 2 patients as they had no RECIST data and subsequently died

  13. 100 80 60 40 20 0 -20 -40 -60 -80 -100 Changes in serum CA-125 Olaparib 400 mg bid cohort * * BRCA1 BRCA2 Best % change from baseline *Truncated values (% change >100%) Data are not included for 4 patients; 2 patients had no RECIST data and subsequently died, and there were no baseline CA-125 data for 2 patients

  14. Olaparib 100 mg bid Total Platinumsensitive Platinumresistant Evaluable patients Responders by RECIST 24 3 (13%) 8 2 (25%) 16 1 (6%) Response by platinum sensitivity Olaparib 400 mg bid Total Platinumsensitive Platinumresistant Evaluable patients Responders by RECIST 33 11 (33%) 7 1 (14%) 26 10 (38%)

  15. 100 90 80 Olaparib 100 mg: 1.9 (1.8–3.7) months 70 NB: Non-randomized sequential cohorts 60 Freedom from progression (%) 50 40 30 20 10 0 0 50 100 150 200 250 300 350 400 450 500 550 600 PFS (days) 100 mg: 24 19 8 5 4 3 2 1 1 0 0 0 0 400 mg: 33 31 20 17 15 13 11 8 6 4 4 3 0 Progression-free survival Median PFS (95% CI) Olaparib 400 mg: 5.8 (2.4–12) months No. of patients at risk

  16. Most frequently reported AEs* *≥25% reported in either cohortCTCAE, Common Terminology Criteria for Adverse Events

  17. Dose adjustments and discontinuations Olaparib 100 mg bid (n=24) Olaparib 400 mg bid (n=33) Discontinuations due to AEs, n (%) Dose interruption due to AEs, n (%) Dose reduction due to AEs, n (%) 4 (12) 12 (36) 9 (27) 1 (4) 4 (17) 0

  18. Overall summary • Olaparib 400 mg bid po has confirmed single-agent activity in advanced, heavily pre-treated BRCA1 or BRCA2 carriers with ovarian cancer • Objective response rate (RECIST): 33% and/or GCIG 61% • Median PFS: 5.8 months • Median duration of response: 9.6 months • Both doses were well tolerated in this patient population • Side effects predominantly CTCAE grade ≤2 • Tolerability in BRCA1/BRCA2 carriers was similar to that reported previously in non-carriers

  19. Conclusions • This study provides positive proof-of-concept of the activity and tolerability of genetically-defined targeted therapy with olaparib in BRCA1 or BRCA2 carriers with ovarian cancer • Olaparib is also active and well tolerated in advanced chemotherapy-refractory BRCA1 or BRCA2 carriers with breast cancer1 • Further studies are currently ongoing in this patient population 1. ASCO 2009 oral presentation: Tutt A et al (abst CRA501)

  20. Acknowledgements • The patients and their families • ICEBERG Trial Investigators • Judy Garber, Niklas Loman, Karen Lu, Anna Oaknin, Rita Schmutzler • with particular thanks to: • Ursula Matulonis, MD (Dana-Farber Cancer Institute) • Beth Y Karlan, MD (Cedars-Sinai Cancer Center) • BRCA carrier advocacy community • FORCE • Alan Ashworth’s Group, Breakthrough Breast Cancer • Chris Lord, Hannah Farmer, Nuala McCabe • KuDOS Pharmaceuticals/ AstraZeneca

More Related