presentación de powerpoint · tfst (time from randomisation to first subsequent therapy or death)...

BASES RACIONALES DEL USO DE TRATAMIENTOS SISTÉMICOS EN CÁNCER DE OVARIO CON BRCA MUTADOSDr. Gonzalo H Giornelli20 de abril, 2018. Códoba, Argentina.

EN QUÉ ES DEFICIENTE EL CÁNCER DE OVARIO BRCA MUT?

DEFICIENCIA EN RECOMBINACIÓN HOMÓLOGA

Cáncer de ovario: neoplasia heterogénea

Ovarian cancer: ”caos genético”

1 2 3 4 5

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DEFICIENCIA EN LA RECOMBINACIÓN HOMÓLOGA EN CÁNCER DE OVARIO

50% OF HGSOC HAVE SOME MUTATION RESULTING IN HOMOLOGOUS

RECOMBINATION DEFFICIENT (HRd) PHENOTYPE.

MECANISMOS DE REPARACIÓN DEL ADN EN CÉLULAS NORMALES

G T

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C3’

5’ 3’

5’

P PP

MRN

CHK 1 CHK 2

Cdc 25

P

CHECK POINT ACTIVATION CELL-CYCLE ARREST

T

AC

GT

AC

G

P P

P

p53

p21 BAX

P

APOPTOSIS

H2AXH2AX

FAFA

FA

RAD51RAD51RAD51

RAD51 RAD51 RAD51

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T

A

TC

T

AC

G T

A

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AC

GG C

AGG

T

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Complex senses damage

Recruitmaint/activation ATM

HOMOLOGOUS RECOMBINATION

©Dr Juan Pablo Sade

NHEJ en HRd luego de daño por CARBOPLATINO al DNA

DSB

BRCA defficient cell

NHEJ-loss of genetic materialgenetic instability

BRCA1

HRd creates LSST Apoptosis

KU

DNA PK

HRD EN CO BRCAmut.Consecuencias: LSST, NHEJ, TAI


BRCA defficient cell

OC:” genetic chaos”

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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.

BRCA 1 & 2 ASSOCIATED OVARIAN CANCER

HEREDITARY OVARIAN CANCER






• Sensibilidad a PARPi.

Germline BRCA ½ mutations are prognostic

Prediction/ comprehension on disease behaviour.

Respuesta a platino y otros agentes

Effect of platinum-based cemotherapy in BMOC

ORR a QT basada en platino BRCAmut vs BRCAwt

Respuesta a Trabectidina/ PLD

Respuesta a PLD (doxorrubicina liposomal)

0 10 20 30 40 50 60 70 80

ORR

PFS

ORR

PFS

BRCA wt

BRCA m

Safra et alN=40

Adams et alN=23

PFS 7,1 m





• Impacto en el tratamiento. Respuesta a platino y otros agentes


PARP INHIBITORSOLAPARIB-NIRAPARIB-RUCAPARIB

Clasificación de PARPi

SSB

PARP

PARP y BER


SSB

PARPPARPi

PARPi.Mecanismo de acción

DSB


PARP Inhibitors and Homologous Recombination repair of DNA damage

Survival

Normal cell

Repair by Homologous Recombination

During the replication process unrepaired SSBs are converted into DSBs

Replicating cells

DNA SSBs occur all the time in cells and PARP detects and repairs them

PARP

No effective repair

(No HR pathway)

Cell death

Cancer cell with HRD

Tumour specific

killing by PARP

inhibitor

OC:” genetic chaos”

1 2 3 4 5

6 7 8 9 10 11

12 13 14 15 16 17 18

19 20 21 22 X

1 2 3 4 5

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18

19 20 21 22 X

1 2 3 4 5

12 13 14 15 16 17 18

Farmer et al Nature 2005

INHIBIDORES DEL PARPPoly(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

DNA Repair Defect

Homologous Recombination Deficiency

Olaparib (AZD2281)Phase I/II trials

1. Fong et al. N Engl J Med 20092. Fong et al. J Clin Oncol 20103. Audeh et al. Lancet 2010

Olaparib en CO BRCA mutado y no-BRCA mutado

BRCA, platinum resistant or refractory

BRCA, platinum sensitive

Non-BRCA, platinum resistant or refractory

Non-BRCA, platinum sensitive

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n (

%)

Ovarian BRCA

Ovarian non-BRCA

Gelmon KA, et al. Lancet Oncol 2011;12:852–61

Olaparib activity in BRCAmut

and BRCAwt

Activity greater in ‘platinum-sensitive’ compared with ‘platinum-resistant’ relapse

Mutaciones germinales y somáticas de BRCA en HGSOC

gBRCA, germline BRCA; HR, homologous recombination; sBRCA, somatic BRCA.

BRCA1 Germline

8%

BRCA2 Germline

6%

BRCA1 Somatic

3%BRCA2

Somatic3%

BRCA1 Methylation

11%

EMSY Amplification

6%PTEN Loss

5%Other HRD7%

CCNE1 Amplification

15%

MMR Germline

2%

Other 34%

HR-deficientNot HR-deficient

gBRCA-mutated14%

HR-deficient 30%

sBRCA-mutated6%

Levine, D. Personal communication;

PARP I Y SENSIBILIDAD A PLATINO

N

Plat sens 13

Plat resist 24

Plat refr 13

TOTAL 50

STUDY 9

STUDY 9

PARP I EN LA FASE DE MANTENIMIENTO

Qué es la “fase de mantenimiento”?

“ESTUDIO 19” Fase II Randomisado de mantenimiento con olaparib en CO seroso de alto grado, recaída platino-sensible.

• 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

Olaparib

400 mg po bid

Randomised 1:1

Placebo

po bid

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

Treatment

until

disease

progression

Primary end point: PFSSept 2008–Feb 2010bid, twice daily; CA-125, Cancer Antigen 125; CR, complete response; po, orally; PR, partial response.

Ledermann J et al. N Engl J Med 2012;366:1382–1392

PFS - ‘Study 19’ olaparib mantenimiento

136 104 51 23 6 0 0

129 72 23 7 1 0 0

At risk (n)

Olaparib

Placebo

0

Time from randomisation (months)

0.6

0.8

0.9

0

0.1

0.2

0.3

0.4

0.5

0.7

1.0

3 6 9 12 15 18

Placebo

Olaparib 400 mg bid

Randomised treatment

Pro

po

rtio

n o

f p

atie

nts

pro

gre

ssio

n fre

e

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;366:1382–1392

Olaparib (n=74)Placebo

(n=62)

Events/total

patients (%)60/136 (44.1) 93/129 (72.1)

Median PFS,

months 8.4 4.8

HR=0.35 95% CI: 0.25, 0.49; P<0.001

PFS - ‘Study 19’ olaparib maintenanceen pacientes con BRCAm:

Olaparib BRCAm

Placebo BRCAm

74 59 34 15 5 0

62 35 13 2 0 0

0


0

1.0

Pro

po

rtio

n o

f p

atie

nts

pro

gre

ssio

n-f

ree

3 6 9 12 15

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

Number at risk

Olaparib BRCAm

Placebo BRCAm

NC, not calculable.

Ledermann J et al. Lancet Oncol 2014;15:852–861

BRCAm subgroup (n=136)


(n=62)

Events/total

patients (%)26/74 (35%) 46/62 (74%)

Median PFS,

months (95% CI)

11.2

(8.3, NC)

4.3

(3.0, 5.4)

HR=0.1895% CI: 0.10, 0.31; P<0.0001

Study 19 subgroupo BRCAm segundoanálisis interino de sobrevida

14 patients (23%) from the placebo arm

received post-discontinuation

PARP inhibitor treatment

Nuevos end-pointsTFST (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)*

All patients who received

treatment were included in

exploratory endpoint analyses

PFS TSSTPFS2 OS

Intermediate clinical endpoints

Olaparib maintenance monotherapy

First subsequent

treatment response

Chemo Chemo

Progression

Progression

Progression

*TSST is a surrogate for PFS2

TFST


Number of patients at risk:

Olaparib 74 61 43 30 26 25 21 20 20 19 17 16 8 1 0

Placebo 62 33 16 9 7 4 4 4 2 2 2 2 2 0 0

0

10

20

30

40

50

60

70

80

90

100

No

t o

n f

irst

su

bse

qu

ent

ther

apy

(%)


0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

Olaparib

Placebo



(n=62)

TFST events, n

(%)53 (72) 59 (95)

Median TFST,

months 15.6 6.2

HR=0.3295% CI 0.22–0.48

P<0.00001

‘Study 19’ olaparib mantenimiento: pacientes BRCAm

TFST

Maturity: 82%

Updated exploratory analysis

Ledermann J et al. J Clin Oncol 34, 2016 (suppl; abstr 5501).

Slides presented at ASCO 2016

Number of patients at risk:

Olaparib 74 69 56 40 32 29 25 23 21 20 19 18 9 1 0

Placebo 62 57 42 25 18 9 6 5 5 3 3 3 3 0 0

0

10

20

30

40

50

60

70

80

90

100

No

t o

n s

eco

nd

su

bse

qu

ent

ther

apy

(%)


0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

Olaparib

Placebo



(n=62)

TSST events, n

(%)52 (70) 56 (90)

Median TSST,

months 22.0 15.3

HR=0.4195% CI 0.28–0.62

P=0.00001

‘Study 19’ olaparib mantenimiento: pacientes BRCAm

TSST

Updated exploratory analysisMaturity: 79%

Updated exploratory analysis

Ledermann J et al. J Clin Oncol 34, 2016 (suppl; abstr 5501). Slides presented at ASCO 2016


STUDY 19 ANÁLISIS DE SOBREVIDA GLOBAL

OS data maturity: 77%Alpha (two-sided) = 0.95%Additional follow-up since previous analysis = 3 years

OS data maturity: 38%Alpha (two-sided) = 0.1%

HR=0.9495% CI 0.63–1.39, P=0.75

OS data maturity: 58%Alpha (two-sided) = 3%

HR=0.8895% CI 0.64–1.21, P=0.44

30 Sep 2015

DCO

CI, confidence interval; DCO, data cut-off; FSI, first subject in

28 Aug 2008 31 Oct 2011 26 Nov 2012

FSI DCO DCO

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;366:1382–1392


Sobrevida global actualizada de Study 19- olaparibmantenimiento

Maturity 77 %

Maturity 70%

Ledermann et al ASCO 2016; Lancet Oncol 2016

Whole study population

BRCAm subgroup

0

5

10

15

20

25

30

35

40

45

50

≥1 ≥2 ≥3 ≥4 ≥5 ≥6

PA

TIEN

TS O

N O

LAP

AR

IB (

%)

TIME ON OLAPARIB (YEARS)

Overall study population

BRCAm subgroup

BRCAwt subgroup

40%

18%

15% 13%

5%

24%

EXPOSICIÓN PROLONGADA EN BRCA mut y wt en Estudio 19OLAPARIB 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)

Ledermann et al ASCO 2016


BRCAm subgroup

BRCAwt subgroup



0

5

10

15

20

25

30

35

40

45

50

≥1 ≥2 ≥3 ≥4 ≥5 ≥6

PA

TIEN

TS O

N O

LAP

AR

IB (

%)


46%

28%

22%

16% 15%

5%




BRCAm subgroup

BRCAwt subgroup



0

5

10

15

20

25

30

35

40

45

50

≥1 ≥2 ≥3 ≥4 ≥5 ≥6

PA

TIEN

TS O

N O

LAP

AR

IB (

%)


33%

19%

14% 14%12%

5%



30

Months

Chemo Maintenance

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Primary endpoint

Secondary endpoints

Key exploratoryendpoints

TFST

TSST

PFS

OS

0 5 10 15 20 25 35

Months (median)

4.3

30.2

4.6

6.2

15.3

Placebo

HR: 0.18 (95% CI 0.10–0.31), p<0.00001

HR: 0.62 (95% CI 0.41–0.94), p=0.02480; NS

HR: 0.41 (95% CI 0.28–0.62), nominal p=0.00001

HR: 0.32 (95% CI 0.22–0.48), nominal p<0.00001

6.9 months

4.7 months

9.4 months

6.7 months Difference between arms

11.2

34.9

15.6

22

Olaparib 400 mg bid

Resúmen de END POINTS del ESTUDIO 19. Olaparib comomantenimiento

AstraZeneca. Data on file LYN/002/JUN16

Olaparib Study 19Progression-free survival in BRCAwt (excludes gBRCA & sBRCA)

Ledermann et al Lancet Oncol 2014BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance)

OLAPARIB MANTENIMIENTO EN BRCA MUT SOLO 2

Eviencia FASE III

SOLO 2

SOLO 2 PFS

mPFS 19,1 meses

PARPi como tratamiento de mantenimiento

SOLO 2

STUDY 19

OLAPARIB APROBAFO POR ANMATComo mantenimiento en pacientes BRCA mut somáticas ogermnales , luego de respuesta completa o parcial a quimioterapiabasada en platino, en recaída platino-sensible.

NOVA trial

N Engl J Med 2016;375:2154-64

Non-gBRCAmut gBRCAmut

2:1 Randomization 2:1 Randomization

Niraparib300 mg QD

PlaceboNiraparib

300 mg QDPlacebo

n=234 n=116 n=138 n=65

Primary Endpoint• PFS; >90% power to detect 4.8-month improvement (HR 0.50)• Non-gBRCAmut cohort endpoint assessed hierarchically to control type 1 error: HRD+ population first,

followed by entire population

NOVA: Niraparib maintenance en HGSOC recaído platino –sensible

• Phase III, multicenter, randomized, double-blind, placebo-controlled study

• Relapsed high-grade serous histology or known gBRCAmut

• ≥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

NOVA: Niraparib maintenance en HGSOC recaído platino –sensible

Treatment

PFS

Median

(95% CI)

(Months)

Hazard Ratio

(95% CI)p-value

% of Patients without

Progression or Death

12 mo

18 mo

Niraparib

(N=138)

21.0(12.9, NE)

0.27

(0.173, 0.410)

p<0.0001

62%

50%

Placebo

(N=65)

5.5(3.8, 7.2)

16%

16%

Progression-free Survival: gBRCAmut

Mirza et al ESMO 2016

Treatment

PFSMedia

n(95%

CI)(Mont

hs)

Hazard Ratio

(95% CI)p-value


Progression or Death

12 mo

18 mo

Niraparib

(N=234)

9.3

(7.2, 11.2)

0.45

(0.338, 0.607)

p<0.0001

41%

30%

Placebo

(N=116)

3.9(3.7,

5.5)

14%

12%

Progression-free Survival: Non-gBRCAmut

NOVA: Niraparib maintenance en HGSOC recaídoplatino –sensible


Courtesy of Tesaro/Myriad Genetics

Testeo de HRD

o Loss of Heterozygosity, o Large-scale State Transitions, o Telomeric Imbalance

BRCAwt

Treatment

PFSMedia

n(95%

CI)(Mont

hs)

Hazard Ratio(95%

CI)p-

value


Progression or Death12 mo

18 mo

Niraparib

(N=71)

9.3

(5.8, 15.4)

0.38

(0.231, 0.628)

p=0.0001

45%

27%

Placebo

(N=44)

3.7

(3.3, 5.6)

11%

6%

Treatment

PFSMedia

n(95%

CI)(Month

s)

Hazard Ratio(95%

CI)p-

value



18 mo

Niraparib

(N=35)

20.9(9.7, NR)

0.27

(0.081, 0.903)

p=0.0248

62%

52%

Placebo(N=12)

11.0(2.0, NR)

19%

19%

sBRCAmut

NR=Not reached

Treatment

PFSMedian

(95% CI)

(Months)

Hazard Ratio(95%

CI)p-

value



18 mo

Niraparib

(N=92)

6.9

(5.6, 9.6)

0.58

(0.361, 0.922)

p=0.0226

27%

19%

Placebo

(N=42)

3.8

(3.7, 5.6)

7% 7%

HRD-positive

NOVA: análisis exploratorio: PFS en Subgrupos

no-gBRCAmutHRD-negative


TRIALS CON RUCAPARIB

Rucaparib: eficacia y tolerabilidad

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

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

Study 10(NCT01482715)

n=62

n=42

ARIEL2(NCT01891344)

n=315

n=64

Safety Population (n=377)

Efficacy Population (n=106)

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).

Study 10 and ARIEL2 parts 1 & 2

Kristeliet et al ESMO 2016

RUCAPARIB. ARIEL 2

Rucaparib: PFS en ARIEL 2 (evaluación de eficacia)

Median (months) 95% CI Range10.0 7.3–12.5 0.0–22.1+

+ Censored; Censoring rate: 47%

Progression-free at 6 months:79%

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.

Rucaparib: ORR según investigador, en poblaciónevaluada para eficacia.

Parameter

Study 10n=42

ARIEL2n=64

Efficacy populationn=106

n (%)[95% CI]

Investigator-assessed RECIST ORR(confirmed CR+PR)

25 (59.5)[43.3–74.4]

32 (50.0)[37.2–62.8]

57 (53.8)[43.8–63.5]

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-assessedRECIST/GCIG CA-125 ORR

75 (70.8)[61.1–79.2]

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; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors.

Rucaparib: Mejor respuesta para lesiones target en población evaluada para eficacia

-120

-100

-80

-60

-40

-20

0

20

40

60

80

Ch

ange

fro

m B

ase

line

in S

um

of

the

Dia

met

er o

f Ta

rget

Les

ion

s†(%

)

N=103*+ = Ongoing

BRCA1

BRCA2

BRCA mutation origin uncertain

Somatic BRCA mutation

Germline BRCA mutation

*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).

ARIEL 3- Rucaparib Maintenance Trial

TOXICIDADES DE PARPI

TOXICIDADES DE PARPI

• Key side effects

• Dose modification

• Early discontinuation due to Adverse Events

• Quality of Life measurements on maintenance therapy

Adapted from Ledermann et al Lancet Oncol 2015; ASCO 2016

Study 19: Treatment Outcome Index (TOI)cambios del basal a 6 meses

• HRQoL, as measured by TOI, was similar for olaparib and placebo and remained consistent over time

1

Time point (months)

LS

M a

nd

95%

CI

2

Olaparib

Placebo

8

–8

3 64 5

6

4

2

0

–6

–4

–2

1

Time point (months)

LSM

and

95%

CI

2

8

–8

3 64 5

6

4

2

0

–6

–4

–2

103 94 71 65 49 39Placebo

102 99 99 86 79 65Olaparib

49 45 34 31 21 19Placebo

54 52 57 48 45 42Olaparib

Patients with BRCAm (MMRM analysis)Overall population

LSM, least squares mean; MMRM, mixed model repeated measures.

Olaparib

Placebo

Ledermann J et al. ESMO, Madrid, Spain, 2014, poster

885PD

NOVA trial- Niraparib- TOXICIDADES

Mirza et al NEJM ; 2106

Event — no. (%)Niraparib(N=367)

Placebo(N=179)

Thrombocytopeniaa 124 (33.8) 1 (0.6)

Anemiab 93 (25.3) 0

Neutropeniac 72 (19.6) 3 (1.7)

Fatigued 30 (8.2) 1 (0.6)

Hypertension 30 (8.2) 4 (2.2)

NOVA Trial Niraparib:EA’S Grado 3-4 en ≤ 5% pacientes

*There were no Grade 5 events.

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.


Event — no. (%)

Dose

Reductions

(N=367)

Events That Occurred After

Cycle 3(N=296)

Dose

Discontinuation

s (N=367)

Thrombocytopeniaa 148 (40.3) 7 (2.4) 12 (3.3)

Anemiab 68 (18.5) 50 (16.9) 5 (1.4)

Neutropeniac 32 (8.7) 8 (2.7) 7 (1.9)

Fatigued 20 (5.4) 9 (3.0) 12 (3.3)

Hypertension 5 (1.4) - 1

NOVA Trial Niraparib: Ajuste de dosis debido a EA’S

Mandatory dose reductions for hematology laboratory abnormalities were required for thrombocytopenia,

anemia, and neutropenia

Any Grade Grade 3/4 Any Grade


Olaparib study 19 y Niraparib NOVA : reducción de dosis y discontinuación por EA’s

Niraparib Placebo

SAE 110 ( 30%)

27 ( 15%)

AE leading to dose interruptions

253 (69%)

9 (5%)

AE leading to dose reduction

244 (65%)

26 (15%)

AE leading to treatment discontinuation

54 ( 15%) 4 (2%)

Olaparib Placebo

SAE 25 (18%) 11 (9%)

AE Leading to dose interruptions

49 (36%) 21 (16%)

AE leading to dose reductions

59 (43%) 29 (23%)

AE leading to treatment discontinuation

8 (6%) 2 (2%)

Ledermann et al Lancet Oncol 2016 Mirza et al NEJM 2016

CREATININA

OTROS EFECTOS ADVERSOS ESPECIALES…

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.

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 inhcheck point inmunológico, muestran resultados promisorios, que pueden ampliar las indicaciones de estos agentes.

Muchas gracias…

presentación de powerpoint · tfst (time from randomisation to first subsequent therapy or death)...

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