BASES RACIONALES DEL USO DE TRATAMIENTOS SISTÉMICOS EN CÁNCER DE OVARIO CON BRCA MUTADOS Dr. Gonzalo H Giornelli 20 de abril, 2018.

Transcripción

1 BASES RACIONALES DEL USO DE TRATAMIENTOS SISTÉMICOS EN CÁNCER DE OVARIO CON BRCA MUTADOS Dr. Gonzalo H Giornelli 20 de abril, Códoba, Argentina.

2 DEFICIENCIA EN RECOMBINACIÓN HOMÓLOGA EN QUÉ ES DEFICIENTE EL CÁNCER DE OVARIO BRCA MUT?

3 Cáncer de ovario: neoplasia heterogénea

4 Ovarian cancer: caos genético X X

5 DEFICIENCIA EN LA RECOMBINACIÓN HOMÓLOGA EN CÁNCER DE OVARIO 50% OF HGSOC HAVE SOME MUTATION RESULTING IN HOMOLOGOUS RECOMBINATION DEFFICIENT (HRd) PHENOTYPE.

6 MECANISMOS DE REPARACIÓN DEL ADN EN CÉLULAS NORMALES

7 HOMOLOGOUS RECOMBINATION H2AX H2AX P P P 5 3 G T RAD51A CRAD51 T RAD51 A G A C G G T G T MRN C A T G A T C RAD51 T RAD51 G CRAD51 C A C A 3 5 P P P CHK 1 CHK 2 G C T AP Cdc 25 A T p21 CHECK POINT ACTIVATION CELL-CYCLE ARREST C G p53 T A P A A T BAX T APOPTOSIS G G C C FA FA A FA C T G T Complex senses damage Recruitmaint/activation ATM G C G C T T A A G G C C T T A A Dr Juan Pablo Sade

8 NHEJ en HRd luego de daño por CARBOPLATINO al DNA

9 NHEJ en HRd luego de daño por CARBOPLATINO al DNA

10 NHEJ en HRd luego de daño por CARBOPLATINO al DNA

11 HRD EN CO BRCAmut. Consecuencias: LSST, NHEJ, TAI DSB BRCA defficient cell HRd creates LSST BRCA defficient cell KU DNA PK NHEJ-loss of genetic material genetic instability Apoptosis Dr Juan Pablo Sade

12 OC: genetic chaos X X

13 Por qué es importante conocer el status de BRCA? Consejo genético. Las mutaciones de BRCA 1 & 2 son pronósticas Comprensión de la biología de la enfermedad. Impacto en el tratamiento.respuesta a platino y otros agentes Sensibilidad a PARPii.

14 Por qué es importante conocer el status de BRCA? Consejo genético. Las mutaciones de BRCA 1 & 2 son pronósticas Comprensión de la biología de la enfermedad. Impacto en el tratamiento.respuesta a platino y otros agentes Sensibilidad a PARPii.

15 HEREDITARY OVARIAN CANCER BRCA 1 & 2 ASSOCIATED OVARIAN CANCER

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21 Por qué es importante conocer el status de BRCA? Consejo genético. Las mutaciones de BRCA 1 & 2 son pronósticas Comprensión de la biología de la enfermedad. Impacto en el tratamiento.respuesta a platino y otros agentes Sensibilidad a PARPi.

22 Germline BRCA ½ mutations are prognostic

23 Por qué es importante conocer el status de BRCA? Consejo genético. Las mutaciones de BRCA 1 & 2 son pronósticas Comprensión de la biología de la enfermedad. Impacto en el tratamiento.respuesta a platino y otros agentes Sensibilidad a PARPii.

24 Por qué es importante conocer el status de BRCA? Consejo genético. Las mutaciones de BRCA 1 & 2 son pronósticas Comprensión de la biología de la enfermedad. Impacto en el tratamiento.respuesta a platino y otros agentes Sensibilidad a PARPi.

25 Prediction/ comprehension on disease behaviour.

26 Por qué es importante conocer el status de BRCA? Consejo genético. Las mutaciones de BRCA 1 & 2 son pronósticas Comprensión de la biología de la enfermedad. Impacto en el tratamiento.respuesta a platino y otros agentes Sensibilidad a PARPi.

27 Por qué es importante conocer el status de BRCA? Consejo genético. Las mutaciones de BRCA 1 & 2 son pronósticas Comprensión de la biología de la enfermedad. Impacto en el tratamiento.respuesta a platino y otros agentes Sensibilidad a PARPi.

28 Respuesta a platino y otros agentes Effect of platinum-based cemotherapy in BMOC

29 ORR a QT basada en platino BRCAmut vs BRCAwt

30 Respuesta a Trabectidina/ PLD

31 Respuesta a PLD (doxorrubicina liposomal) PFS 7,1 m PFS Safra et al N=40 ORR PFS ORR Adams et al N=23 BRCA wt BRCA m

32 Por qué es importante conocer el status de BRCA? Consejo genético. Las mutaciones de BRCA 1 & 2 son pronósticas Comprensión de la biología de la enfermedad. Impacto en el tratamiento. Respuesta a platino y otros agentes Sensibilidad a PARPii.

33 Por qué es importante conocer el status de BRCA? Consejo genético. Las mutaciones de BRCA 1 & 2 son pronósticas Comprensión de la biología de la enfermedad. Impacto en el tratamiento. Respuesta a platino y otros agentes Sensibilidad a PARPii.

34 PARP INHIBITORS OLAPARIB-NIRAPARIB-RUCAPARIB

35 Clasificación de PARPi

36 PARP y BER SSB PARP Dr Juan Pablo Sade

37 PARPi.Mecanismo de acción DSB SSB PARP PARPi Dr Juan Pablo Sade

38 PARP Inhibitors and Homologous Recombination repair of DNA damage DNA SSBs occur all the time in cells and PARP detects and repairs them PARP During the replication process unrepaired SSBs are converted into DSBs Replicating cells Normal cell Cancer cell with HRD Repair by Homologous Recombination No effective repair (No HR pathway) Survival Tumour specific killing by PARP inhibitor Cell death

39 OC: genetic chaos X X

40 INHIBIDORES DEL PARP Poly(ADP-ribose) polymerase y reparación de DNA PARP is a key regulator of DNA damage repair processes Involved in DNA base-excision repair (BER) Binds directly to DNA damage Produces large branched chains of poly(adp-ribose) Attracts and assists BER repair effectors Farmer et al Nature 2005 DNA Repair Defect Homologous Recombination Deficiency

41 Olaparib (AZD2281)Phase I/II trials 1. Fong et al. N Engl J Med Fong et al. J Clin Oncol Audeh et al. Lancet 2010

42 Best change from baseline in size of target lesion (%) Best change from baseline in size of target lesion (%) Olaparib en CO BRCA mutado y no-brca mutado Ovarian BRCA Ovarian non-brca BRCA, platinum resistant or refractory BRCA, platinum sensitive Non-BRCA, platinum resistant or refractory Non-BRCA, platinum sensitive Olaparib activity in BRCA mut and BRCA wt Activity greater in platinumsensitive compared with platinum-resistant relapse Gelmon KA, et al. Lancet Oncol 2011;12:852 61

43 Mutaciones germinales y somáticas de BRCA en HGSOC Other 34% MMR Germline 2% CCNE1 Amplification 15% BRCA1 Germline 8% BRCA2 Germline 6% BRCA1 Somatic 3% BRCA2 Somatic 3% BRCA1 Methylation 11% EMSY Amplification 6% PTEN Loss 5% Other HRD 7% gbrca-mutated 14% sbrca-mutated 6% HR-deficient 30% Not HR-deficient HR-deficient gbrca, germline BRCA; HR, homologous recombination; sbrca, somatic BRCA. Levine, D. Personal communication;

44 PARP I Y SENSIBILIDAD A PLATINO

45 STUDY 9 N Plat sens 13 Plat resist 24 Plat refr 13 TOTAL 50

46 STUDY 9

47 PARP I EN LA FASE DE MANTENIMIENTO

48 Qué es la fase de mantenimiento?

49 ESTUDIO 19 Fase II Randomisado de mantenimiento con olaparib en CO seroso de alto grado, recaída platinosensible. Aim: to assess the efficacy and safety of olaparib as a maintenance treatment Design: randomized, double-blind, placebo-controlled phase II maintenance study 265 patients in 82 investigational sites in 16 countries Patients: Platinum-sensitive high-grade serous ovarian cancer 2 previous platinum regimens Last chemotherapy was platinum-based, to which they had a maintained PR or CR prior to enrolment Stable CA-125 Olaparib 400 mg po bid Randomised 1:1 Placebo po bid Treatment until disease progression Sept 2008 Feb 2010 bid, twice daily; CA-125, Cancer Antigen 125; CR, complete response; po, orally; PR, partial response. Primary end point: PFS Ledermann J et al. N Engl J Med 2012;366:

50 Proportion of patients progression free PFS - Study 19 olaparib mantenimiento At risk (n) Olaparib Placebo Randomised treatment Placebo Olaparib 400 mg bid Events/total patients (%) Median PFS, months Time from randomisation (months) Olaparib (n=74) Placebo (n=62) 60/136 (44.1) 93/129 (72.1) HR= % CI: 0.25, 0.49; P<0.001 After 153 progression events (57.7% of patients) the study met its primary endpoint of a statistically significant PFS benefit in the overall study population CI, confidence interval; HR, hazard ratio. Ledermann J et al. N Engl J Med 2012;366:

51 Proportion of patients progression-free Number at risk Olaparib BRCAm Placebo BRCAm PFS - Study 19 olaparib maintenance en pacientes con BRCAm: Olaparib BRCAm Placebo BRCAm Events/total patients (%) Median PFS, months (95% CI) Time from randomisation (months) BRCAm subgroup (n=136) Placebo Olaparib (n=74) (n=62) 26/74 (35%) 46/62 (74%) 11.2 (8.3, NC) 4.3 (3.0, 5.4) HR= % CI: 0.10, 0.31; P< NC, not calculable. Ledermann J et al. Lancet Oncol 2014;15:

52 Study 19 subgroupo BRCAm segundo análisis interino de sobrevida 14 patients (23%) from the placebo arm received post-discontinuation PARP inhibitor treatment

53 Nuevos end-points TFST (time from randomisation to first subsequent therapy or death) TSST (time from randomisation to second subsequent therapy or death) PFS2 (time from randomisation to second objective disease progression or death)* Progression Intermediate clinical endpoints Olaparib maintenance monotherapy PFS TFST PFS2 TSST OS Chemo Chemo All patients who received treatment were included in exploratory endpoint analyses First subsequent treatment response Progression Progression *TSST is a surrogate for PFS2 Ledermann J et al. Lancet Oncol 2014;15:

54 Not on first subsequent therapy (%) Study 19 olaparib mantenimiento: pacientes BRCAm TFST TFST events, n (%) BRCAm subgroup (n=136) Olaparib (n=74) Placebo (n=62) 53 (72) 59 (95) Median TFST, months HR= % CI P< Olaparib Placebo Number of patients at risk: Time from randomisation (months) Olaparib Placebo Maturity: 82% Updated exploratory analysis Ledermann J et al. J Clin Oncol 34, 2016 (suppl; abstr 5501). Slides presented at ASCO 2016

55 Not on second subsequent therapy (%) Study 19 olaparib mantenimiento: pacientes BRCAm TSST TSST events, n (%) BRCAm subgroup (n=136) Olaparib (n=74) Placebo (n=62) 52 (70) 56 (90) Median TSST, months HR= % CI P= Olaparib Placebo Number of patients at risk: Time from randomisation (months) Olaparib Placebo Updated Maturity: exploratory 79% analysis Updated exploratory analysis Ledermann J et al. J Clin Oncol 34, 2016 (suppl; abstr 5501). Slides presented at ASCO 2016 Ledermann J et al. Lancet Oncol 2014;15:

56 STUDY 19 ANÁLISIS DE SOBREVIDA GLOBAL 28 Aug Oct Nov Sep 2015 FSI DCO DCO DCO OS data maturity: 38% Alpha (two-sided) = 0.1% HR= % CI , P=0.75 OS data maturity: 58% Alpha (two-sided) = 3% HR= % CI , P=0.44 OS data maturity: 77% Alpha (two-sided) = 0.95% Additional follow-up since previous analysis = 3 years CI, confidence interval; DCO, data cut-off; FSI, first subject in Ledermann J et al. J Clin Oncol 34, 2016 (suppl; abstr 5501). Slides presented at ASCO 2016 Ledermann J et al. New Engl J Med 2012;366: Ledermann J et al. Lancet Oncol 2014;15:

57 Sobrevida global actualizada de Study 19- olaparib mantenimiento BRCAm subgroup Maturity 77 % Whole study population Ledermann et al ASCO 2016; Lancet Oncol 2016 Maturity 70%

58 PATIENTS ON OLAPARIB (%) EXPOSICIÓN PROLONGADA EN BRCA mut y wt en Estudio 19 OLAPARIB COMO MANTENIMIENTO Median follow-up of 5.9 years: 15 patients (11%) still receiving olaparib (8 BRCAm, 7 BRCAwt); one patient (<1%) still receiving placebo (BRCAm) % % 18% 15% 13% Overall study population BRCAm subgroup BRCAwt subgroup % TIME ON OLAPARIB (YEARS) Ledermann et al ASCO 2016

59 PATIENTS ON OLAPARIB (%) EXPOSICIÓN PROLONGADA EN BRCA mut y wt en Estudio 19 OLAPARIB COMO MANTENIMIENTO Median follow-up of 5.9 years: 15 patients (11%) still receiving olaparib (8 BRCAm, 7 BRCAwt); one patient (<1%) still receiving placebo (BRCAm) % % 22% 16% 15% Overall study population BRCAm subgroup BRCAwt subgroup % TIME ON OLAPARIB (YEARS) Ledermann et al ASCO 2016

60 PATIENTS ON OLAPARIB (%) EXPOSICIÓN PROLONGADA EN BRCA mut y wt en Estudio 19 OLAPARIB COMO MANTENIMIENTO Median follow-up of 5.9 years: 15 patients (11%) still receiving olaparib (8 BRCAm, 7 BRCAwt); one patient (<1%) still receiving placebo (BRCAm) % Overall study population % 14% 14% 12% BRCAm subgroup BRCAwt subgroup % TIME ON OLAPARIB (YEARS) Ledermann et al ASCO 2016

61 Resúmen de END POINTS del ESTUDIO 19. Olaparib como mantenimiento Months Chemo Maintenance Primary endpoint PFS months 11.2 HR: 0.18 (95% CI ), p< Secondary endpoints OS months 34.9 HR: 0.62 (95% CI ), p= ; NS Key exploratory endpoints TFST TSST months HR: 0.32 (95% CI ), nominal p< Placebo Olaparib 400 mg bid 6.7 months Difference between arms 22 HR: 0.41 (95% CI ), nominal p= Months (median) AstraZeneca. Data on file LYN/002/JUN16

62 Olaparib Study 19 Progression-free survival in BRCA wt (excludes gbrca & sbrca) BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance) Ledermann et al Lancet Oncol 2014

63 Eviencia FASE III OLAPARIB MANTENIMIENTO EN BRCA MUT SOLO 2

64 SOLO 2

65 SOLO 2 PFS mpfs 19,1 meses

66 PARPi como tratamiento de mantenimiento STUDY 19 SOLO 2

67 OLAPARIB APROBAFO POR ANMAT Como mantenimiento en pacientes BRCA mut somáticas o germnales, luego de respuesta completa o parcial a quimioterapia basada en platino, en recaída platino-sensible.

68 NOVA trial N Engl J Med 2016;375:

69 NOVA: Niraparib maintenance en HGSOC recaído platino sensible Phase III, multicenter, randomized, double-blind, placebo-controlled study Relapsed high-grade serous histology or known gbrca mut 2 prior regimens of platinum-based chemotherapy Responded to last platinum regimen; remains in response and enrolled within 8 weeks of completion of last platinum regimen No measurable lesion 2cm N=553 Non-gBRCA mut gbrca mut 2:1 Randomization 2:1 Randomization Niraparib 300 mg QD Placebo Niraparib 300 mg QD Placebo n=234 n=116 n=138 n=65 Primary Endpoint PFS; >90% power to detect 4.8-month improvement (HR 0.50) Non-gBRCA mut cohort endpoint assessed hierarchically to control type 1 error: HRD+ population first, followed by entire population

70 NOVA: Niraparib maintenance en HGSOC recaído platino sensible Progression-free Survival: gbrcamut Treatm ent Nirapa rib (N=138 ) Placeb o (N=65) PFS Median (95% CI) (Month s) 21.0 (12.9, NE) 5.5 (3.8, 7.2) Hazard Ratio (95% CI) p-value 0.27 (0.173, 0.410) p< % of Patients without Progressi on or Death 12 mo 62 % 16 % 18 mo 50 % 16 % Mirza et al ESMO 2016

71 NOVA: Niraparib maintenance en HGSOC recaído platino sensible Progression-free Survival: Non-gBRCAmut Treatm ent Nirapar ib (N=234 ) Placeb o (N=116 ) PFS Media n (95% CI) (Mont hs) 9.3 (7.2, 11.2) 3.9 (3.7, 5.5) Hazard Ratio (95% CI) p-value 0.45 (0.338, 0.607) p< % of Patients without Progressi on or Death 12 mo 41 % 14 % 18 mo 30 % 12 % Mirza et al ESMO 2016

72 Testeo de HRD o Loss of Heterozygosity, o Large-scale State Transitions, o Telomeric Imbalance Courtesy of Tesaro/Myriad Genetics

73 NOVA: análisis exploratorio: PFS en Subgrupos no-gbrcamut Treatme nt Nirapari b (N=35) Placebo (N=12) sbrcamut PFS Media n (95% CI) (Month s) 20.9 (9.7, NR) 11.0 (2.0, NR) Hazard Ratio (95% CI) p- value 0.27 (0.081, 0.903) p= % of Patients without Progressio n or Death 12 mo 62 % 19 % HRD-positive 18 mo 52 % 19 % Treatme nt Nirapari b (N=71) Placebo (N=44) BRCAwt PFS Media n (95% CI) (Mont hs) 9.3 (5.8, 15.4) 3.7 (3.3, 5.6) Hazard Ratio (95% CI) p- value 0.38 (0.231, 0.628) p= % of Patients without Progressio n or Death 12 mo 45 % 11 % 18 mo 27 % 6% Treatme nt Nirapari b (N=92) Placebo (N=42) HRD-negative PFS Median (95% CI) (Month s) 6.9 (5.6, 9.6) 3.8 (3.7, 5.6) Hazard Ratio (95% CI) p- value 0.58 (0.361, 0.922) p= % of Patients without Progressio n or Death 12 mo 27 % 18 mo 19 % 7% 7% Mirza et al ESMO 2016 NR=Not reached

74 NOVA: análisis exploratorio: PFS en Subgrupos no-gbrcamut Treatme nt Nirapari b (N=35) Placebo (N=12) sbrcamut PFS Media n (95% CI) (Month s) 20.9 (9.7, NR) 11.0 (2.0, NR) Hazard Ratio (95% CI) p- value 0.27 (0.081, 0.903) p= % of Patients without Progressio n or Death 12 mo 62 % 19 % HRD-positive 18 mo 52 % 19 % Treatme nt Nirapari b (N=71) Placebo (N=44) BRCAwt PFS Media n (95% CI) (Mont hs) 9.3 (5.8, 15.4) 3.7 (3.3, 5.6) Hazard Ratio (95% CI) p- value 0.38 (0.231, 0.628) p= % of Patients without Progressio n or Death 12 mo 45 % 11 % 18 mo 27 % 6% Treatme nt Nirapari b (N=92) Placebo (N=42) HRD-negative PFS Median (95% CI) (Month s) 6.9 (5.6, 9.6) 3.8 (3.7, 5.6) Hazard Ratio (95% CI) p- value 0.58 (0.361, 0.922) p= % of Patients without Progressio n or Death 12 mo 27 % 18 mo 19 % 7% 7% Mirza et al ESMO 2016 NR=Not reached

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76 TRIALS CON RUCAPARIB

77 Rucaparib: eficacia y tolerabilidad Study 10 and ARIEL2 parts 1 & 2 Study 10 (NCT ) ARIEL2 (NCT ) Safety Population (n=377) Criteria - Diagnosis of ovarian cancer (inclusive of primary peritoneal and fallopian tube cancer) - Enrolled at 600 mg BID dosing level and received 1 dose of rucaparib 600 mg n=62 n=315 Efficacy Population (n=106) Criteria - Received 2 prior chemotherapies, including 2 platinum-based regimens - Had a deleterious germline BRCA or somatic BRCA mutation - Enrolled at 600 mg BID dosing level and received 1 dose of rucaparib 600 mg n=42 n=64 Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016). Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). Kristeliet et al ESMO 2016

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79 RUCAPARIB. ARIEL 2

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81 Rucaparib: PFS en ARIEL 2 (evaluación de eficacia) Progression-free at 6 months: 79% Median (months) 95% CI Range Censored; Censoring rate: 47% Progression-free at 12 months: 41% At risk (events) 106 (0) 93 (9) 85 (14) 69 (19) 43 (37) 31 (40) 21 (43) 14 (49) 8 (54) 3 (55) 3 (55) 2 (56) 0 (56) Of 106 patients, 50 did not have an event of disease progression or death at the data cutoff dates Of these 50 patients, 32 were still on treatment, and 18 discontinued treatment for reasons other than disease progression or death at the data cutoff dates Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). CI, confidence interval.

82 Rucaparib: ORR según investigador, en población evaluada para eficacia. Parameter Investigator-assessed RECIST ORR (confirmed CR+PR) Study 10 n=42 25 (59.5) [ ] ARIEL2 n=64 n (%) [95% CI] 32 (50.0) [ ] Efficacy population n= (53.8) [ ] CR 4 (9.5) 5 (7.8) 9 (8.5) PR 21 (50.0) 27 (42.2) 48 (45.3) SD 12 (28.6) 24 (37.5) 36 (34.0) PD 2 (4.8) 7 (10.9) 9 (8.5) NE 3 (7.1) 1 (1.6) 4 (3.8) Investigator-assessed RECIST/GCIG CA-125 ORR 75 (70.8) [ ] Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016). CR, complete response; GCIG, Gynecologic Cancer InterGroup; NE, not evaluable; ORR, objective response rate; RECIST, Response Evaluation Criteria In Solid Tumors. PR, partial response;

83 Change from Baseline in Sum of the Diameter of Target Lesions (%) Rucaparib: Mejor respuesta para lesiones target en población evaluada para eficacia N=103* + = Ongoing BRCA1 BRCA2 Germline BRCA mutation Somatic BRCA mutation BRCA mutation origin uncertain *Three patients did not have a post baseline scan; For unconfirmed responses; includes the best percent change from baseline up to and including the first overall response of progressive disease. Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016).

84 ARIEL 3- Rucaparib Maintenance Trial

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86 TOXICIDADES DE PARPI

87 TOXICIDADES DE PARPI Key side effects Dose modification Early discontinuation due to Adverse Events Quality of Life measurements on maintenance therapy

88 Adapted from Ledermann et al Lancet Oncol 2015; ASCO 2016

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94 LSM and 95% CI LSM and 95% CI Study 19: Treatment Outcome Index (TOI) cambios del basal a 6 meses Overall population Patients with BRCAm (MMRM analysis) 8 6 Olaparib Placebo 8 6 Olaparib Placebo Time point (months) Time point (months) Olaparib Olaparib Placebo Placebo HRQoL, as measured by TOI, was similar for olaparib and placebo and remained consistent over time LSM, least squares mean; MMRM, mixed model repeated measures. Ledermann J et al. ESMO, Madrid, Spain, 2014, poster 885PD

95 NOVA trial- Niraparib- TOXICIDADES Mirza et al NEJM ; 2106

96 NOVA Trial Niraparib:EA S Grado 3-4 en 5% pacientes Event no. (%) Niraparib (N=367) Placebo (N=179) Thrombocytopenia a 124 (33.8) 1 (0.6) Anemia b 93 (25.3) 0 Neutropenia c 72 (19.6) 3 (1.7) Fatigue d 30 (8.2) 1 (0.6) Hypertension 30 (8.2) 4 (2.2) MDS/AML occurred in 5 of 367 (1.4%) in patients who received niraparib and 2 of 179 (1.1%) in patients who received placebo. *There were no Grade 5 events. Mirza et al ESMO 2016

97 NOVA Trial Niraparib: Ajuste de dosis debido a EA S Event no. (%) Any Grade Grade 3/4 Any Grade Dose Reductions (N=367) Events That Occurred After Cycle 3 (N=296) Dose Discontinuation s (N=367) Thrombocytopenia a 148 (40.3) 7 (2.4) 12 (3.3) Anemia b 68 (18.5) 50 (16.9) 5 (1.4) Neutropenia c 32 (8.7) 8 (2.7) 7 (1.9) Fatigue d 20 (5.4) 9 (3.0) 12 (3.3) Hypertension 5 (1.4) - 1 Mandatory dose reductions for hematology laboratory abnormalities were required for thrombocytopenia, anemia, and neutropenia Mirza et al ESMO 2016

98 Olaparib study 19 y Niraparib NOVA : reducción de dosis y discontinuación por EA s Olaparib Placebo SAE 25 (18%) 11 (9%) AE Leading to dose interruptions AE leading to dose reductions AE leading to treatment discontinuation 49 (36%) 21 (16%) 59 (43%) 29 (23%) 8 (6%) 2 (2%) Niraparib SAE 110 ( 30%) AE leading to dose interruptions AE leading to dose reduction AE leading to treatment discontinuation 253 (69%) 244 (65%) Placebo 27 ( 15%) 9 (5%) 26 (15%) 54 ( 15%) 4 (2%) Ledermann et al Lancet Oncol 2016 Mirza et al NEJM 2016

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100 CREATININA

101 OTROS EFECTOS ADVERSOS ESPECIALES

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103 CONCLUSIONES 1 El cáncer de ovario BRCA mut Tiene mejor sobrevida. Es más quimiosensible. Mantenimiento con olaparib,niraparib y ruvaparib, han demostrado prolongar significativamente el control de la enfermedad (SLP), también son activos en pts SIN BRCA mut. Olaparib y rucaparib son activos como mono droga en BRCA mut.

104 CONCLUSIONES 2 Ofrecer el test de BRCA debe ser práctica de rutina en manejo de OC. Testeo de sbrca mut y HRD van cobrando importancia a medida que las técnicas se refinan.importancia frente a test funcional de sensibilidad a platino. La combinaciones con antiangiogénicos e inh check point inmunológico, muestran resultados promisorios, que pueden ampliar las indicaciones de estos agentes.

105 Muchas gracias