Presentación de PowerPoint...PAOLA 1 / ENGOT OV-25 Stratification factors: First-line treatment...
Transcript of Presentación de PowerPoint...PAOLA 1 / ENGOT OV-25 Stratification factors: First-line treatment...
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)
©20
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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)