Papel de olaparib en el abordaje del cáncer de ovario

Antonio González MartínClínica Universidad de Navarra, Madrid

GEICO (Grupo Español de Investigación en Cáncer de Ovario)ENGOT (European Network of Gynecological Oncological Trials groups)

Disclousure

• I have received from Astra Zeneca

– Travel grants

– Payment for advisory role

– Fee for lectures

• I have participated as investigator in several trials sponsored by AZ including but not limited to SOLO-1 and PAOLA-1

Agenda

• From preclinical data to the approvals in recurrent ovarian cancer

• Olaparib in front line ovarian cancer

• A view to the future

Targeting the DNA repair defect in BRCA mutant cellsas a therapeutic strategy

Hannah farmer… Alan Ashworth. Nature 2005

Clinical Development

Fase IExpansion

cohortNon-BRCA mutated

RR 50% (8/16) in

OC and BRCA mut

Dose up to 400 bidFong P et al. New Eng J Med 2009

RR 43% (23/50)

OC and BRCA mut

Fong P et al. J Clin Oncol 2010

RR 24% (11/46)

OC and BRCA wt

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

Olaparib in pre-treated BRCA mutated OC

• 193 OC patients with gBRCA1 (77%) orgBRCA2 (23%) mut

• Mean prior regimens for advanceddisease: 4

• PS 28%; PR 56%; PRf 10%

• ORR: 31% (95%CI 24.6-38.1)

• Median PFS: 7 months

• Median OS: 16.6 months

• Analysis of 137 pts with > 3 lines ofTx showed ORR 34% with a median duration of 7.9 months

Kaufman et al. J Clin Oncol 2015

Platinum combination followed by iPARPOlaparib study-19 design and results

Primary end point : PFS

Olaparib 400 mg po

bid

Randomized 1:1

Placebopo bid

• 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

Study-19 aim and design

265 patients

Ledermann J, et al. N Engl J Med 2012;366:1382–92

Study-19 PFS

0

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 18P

rob

ab

ilit

y o

f

pro

gre

ss

ion

-fre

e s

urv

ival

Time from randomization (months)

Hazard ratio 0.35,

(95% CI, 0.25–0.49);

P<0.00001

Randomized treatment

Placebo

Olaparib 400 mg bid monotherapy

8.4 mos

4.8 mos

Platinum combination followed by iPARPOlaparib study-19 design and results

Primary end point : PFS

Olaparib 400 mg po

bid

Randomized 1:1

Placebopo bid

• 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

Study-19 aim and design

265 patients

Ledermann J, et al. N Engl J Med 2012;366:1382–92

Study-19 PFS BRCAmut

11.2 vs 4.3 monthsHR 0.18 (95% CI: 0.10-0.31)

Ledermann et al. Lancet Oncol. 2014;15(8):852–861

Long-term outcome with olaparib in Study-19

15% 11%

Lederman et al. Lancet Oncol 2016; 17: 1579–89

SOLO-2 is a randomised Phase 3 study of maintenanceolaparib in patients with BRCAm PSR OC

Olaparib (n=196)

300mg** po bid

Placebo(n=99)

Randomise within

8 weeks of last

chemotherapy dose

Randomise 2:1

N=295

• Stratification by response to

previous platinum-based

chemotherapy, time to disease

progression in penultimate

platinum-based chemotherapy

Pujade-Lauraine et al. Lancet Oncol. 2017;18:1274-1284

• Platinum-sensitive high-grade serous or endometrioid ovarian cancer

• 2 previous platinum regimens

• Last chemotherapy was platinum-based to which they had a maintained PR or CR prior to enrolment

• Documented BRCAm, or patient willing to consent to testing (only those with deleterious or suspected deleterious germline mutations will be randomised)

19.1 vs 5.5 monthsHR 0.3 (95% CI: 0.22-0.41)

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Agenda

• From preclinical data to the approvals in recurrent ovarian cancer

• Olaparib in front line ovarian cancer

• A view to the future

SOLO-1: Study design

*Upfront or interval attempt at optimal cytoreductive surgery for stage III disease and either biopsy and/or upfront or interval

cytoreductive surgery for stage IV disease. BICR, blinded independent central review; ECOG, Eastern Cooperative Oncology

Group; FACT-O, Functional Assessment of Cancer Therapy – Ovarian Cancer; FIGO, International Federation of Gynecology

and Obstetrics; HRQoL, health-related quality of life; PFS2, time to second progression or death;

RECIST, Response Evaluation Criteria in Solid Tumours; TOI, Trial Outcome Index

• Newly diagnosed, FIGO

stage III–IV, high-grade serous

or endometrioid ovarian,

primary peritoneal or fallopian

tube cancer

• Germline or somatic BRCAm

• ECOG performance status 0–1

• Cytoreductive surgery*

• In clinical complete response or

partial response after platinum-

based chemotherapy

Olaparib 300 mg bd

(N=260)

Placebo

(N=131)

2:1 randomization

• Study treatment

continued until

disease progression

• Patients with no

evidence of disease at

2 years stopped

treatment

• Patients with a partial

response at 2 years

could continue

treatment

Primary endpoint

• Investigator-assessed PFS

(modified RECIST 1.1)

Secondary endpoints

• PFS using BICR

• PFS2

• Overall survival

• Time from randomization to

first subsequent therapy or

death

• Time from randomization to

second subsequent therapy

or death

• HRQoL (FACT-O TOI score)

Stratified by response

to platinum-based

chemotherapy

2 years’ treatment if no evidence of disease

PFS by investigator assessment

0 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

0

10

20

30

40

50

60

70

80

90

100

3

Inve

stig

ato

r-as

sess

ed

pro

gre

ssio

n-f

ree

surv

ival

(%

)

Months since randomization

Olaparib

Placebo

Olaparib

(N=260)

Placebo

(N=131)

Events (%) [50.6% maturity] 102 (39.2) 96 (73.3)

Median PFS, months NR 13.8

HR 0.30

95% CI 0.23, 0.41; P<0.0001

NR, not reached

260 229 221 212 201 194 184 172 149 138 133 111 88 45 36 4 3 0 0 0240Olaparib 260 229 221 212 201 194 184 172 149 138 133 111 88 45 36 4 3 0 0 0240Olaparib

131 103 82 65 56 53 47 41 39 38 31 28 22 6 5 1 0 0 0 0118

No. at risk

Placebo

Percentage of patients remaining progression free over time

0 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

0

10

20

30

40

50

60

70

80

90

100

3

Inve

stig

ato

r-as

sess

ed

pro

gre

ssio

n-f

ree

surv

ival

(%

)

Months since randomization

260

131

229

103

221

82

212

65

201

56

194

53

184

47

172

41

149

39

138

38

133

31

111

28

88

22

45

6

36

5

4

1

3

0

0

0

0

0

0

0

No. at risk

Olaparib

Placebo

Olaparib

Placebo

240

118212

0

10

20

30

40

50

60

70

80

90

100

Fre

e o

f p

rog

ress

ion

or

dea

th (

%)

Olaparib Placebo

12 months 24 months 36 months 48 months

87.7

51.4

73.6

34.6

60.4

26.9

52.6

11.4

172 111 465 41 28 1No. at risk

Based on Kaplan-Meier estimates, after 3 years, 60.4% of patients in the olaparib arm were progression free,

compared with 26.9% of patients in the placebo arm

Summary of efficacy endpoints

0 10 20 30 40 50 60

Olaparib (N=260) Placebo (N=131)

40.7

Median not reached

15.1

41.9

51.8

51.8

41.9

Median not reached

Median not reached

13.8

41.9

Months since randomization

HR 0.45

95% CI 0.32, 0.63; P<0.0001

Median time to

second subsequent

therapy or death

Median time to first

subsequent therapy

or death

Median PFS2

HR 0.30

95% CI 0.22, 0.40; P<0.0001

HR 0.50

95% CI 0.35, 0.72; P=0.0002

HR 0.30

95% CI 0.23, 0.41; P<0.0001Median PFS

Milestones in PFS for OC in Front-Line

GOG-47CisplatinHR 0.75

1986 1996

GOG-111Paclitaxel

HR 0.7

2006

GOG-172Intraperitoneal

HR 0.8

2011

GOG-218Bevacizumab

HR 0.71

SOLO-1OlaparibHR 0.3

2018

Agenda

• From preclinical data to the approvals in recurrent ovarian cancer

• Olaparib in front line ovarian cancer

• A view to the future

HRD=homologous recombination deficiency; CR=complete response; PR=partial response; PFS=progression-free survival;

ENGOT ov26 / PRIMA Study

Endpoint assessment

Niraparib 300 mg

Placebo

Platinum responsive ovarian cancer

Stage III or IV ovarian

CR or PR with front line platinum-based chemotherapy

HRDpos or HRDneg/not determined (nd) tumor

2:1 Randomization

PFS in HRDpos patients; hierarchical analysis for all patients regardless of HRD status

Primary Endpoint

Overall survival (OS), patient reported outcomes (PRO’s), time to first

subsequent treatment, progression- survival-2 , time to CA-125 progression,

safety and tolerability of study therapy

Key Secondary Endpoints

pre-enrollment screening:

•centralized HRD testing for

all patients

•local sBRCA and/or gBRCA

test results are allowed

Stratification factors:

•Use of NACT: yes or no

•Best tumor response: CR or PR

•HRD status: pos or neg/nd

• Patients with sBRAC or tBRCAmut

will be stratified as HRDpos

• Patients with unknown or wild type

BRCA will be stratified based on

HRD test results

CONFIDENTIAL

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

• Olaparib tablets administered at 600 mg daily for up to 2 years.

PAOLA 1 / ENGOT OV-25

Stratification factors:

First-line treatment outcome (complete resection after initial surgery and NED atscreening, complete resection at interval debulking surgery and NED at screening,incomplete resection at initial or interval debulking surgery and in CR at screening, PRat screening) & gBRCA status (yes, no, unknown)

Front line for Stage III/IV with PARPi / IO / Bev

TRIAL Setting Patient selection Arms

AGO / DUO-O ENGOT Ov46

Front line tBRCAnon-mut*PDS or IDS Any residualLGSOC excluded

CP-Bev-placebo-placeboCP-Bev-Durvalumab-placeboCP-Bev-Durvalumab-Olaparib

BGOG /ENGOT Ov43 Front line tBRCA non-mut*, Any histotypePDS or IDS Any residualBev optional

CP-Placebo-PlaceboCP- Pembro-PlaceboCP- Pembro-Olaparib

GINECO/ FIRSTENGOT Ov44

Front line PDS (high risk) or IDSBev optionalMucinous excluded

CP-Placebo-PlaceboCP-Placebo-NiraparibCP-TSR042-Niraparib

ATHENA GOG3020 / ENGOT Ov45

Maintenance after front line

Stage III-IV and high gradePDS or IDSResponse to platinum

Rucaparib-NivolumabRucaparib-PlaceboNivolumab-PlaceboPlacebo-Placebo

* Separate clinical trial for tBRCA-mutated

Conclusiones

El inhibidor de PARP olaparib has sido el primero en mostrar el extraordinario beneficio del mantenimiento en pacientes BRCA mutadas tras respuesta a platino:

• En recaída platino-sensible (Study-19)

• En primera primera línea (SOLO-1)

Ambos hitos han cambiado la visión, el manejo y el pronóstico de las pacientes con cáncer de ovario

Muchas gracias

Antonio González MartínClínica Universidad de Navarra, Madrid

GEICO (Grupo Español de Investigación en Cáncer de Ovario)ENGOT (European Network of Gynecological Oncological Trials groups)