FOCUS SULLA TERAPIA CON OLAPARIB
Marilena Di NapoliOncologia Medica Uro-Ginecologica
IRCCS - Fondazione “G. Pascale”
Napoli
Ovarian cancer: not unique disease
Selected genomic alterations and their
frequencies in high-grade serous ovarian
Konstantinopulos PA, et al Cancer Discovery 2015
TCGA Consortium. Nature 2011;Turner, et al. Nat Rev Cancer 2004; Patch, et al, Nature 2015
Prevalence of BRCA mutations in ovarian
cancer
Approximately 50% of HGSOCs exhibit genetic or epigenetic alterations
of HR pathway genes.
Germline BRCA1 and BRCA2 mutations are the most common
alterations, and are present in:
14–15% of all EOCs
22.6% of HGSOCs
Somatic BRCA1 and BRCA2 mutations have been identified in 6-7% of
HGSOCs
Up to 44% have no family history
Konstantinopulos PA, et al Cancer Discovery 2015
PARP Inhibitors
Olaparib indications: US vs Europe
US approval:
PAST: Olaparib monotherapy in patient with germline mutated BRCA OC who have
received > 3 or more chemotherapy treatments together with a companion diagnsostic
test (BRCA analysis CDx). 1
PRESENT: maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tubeor primary peritoneal cancer, who are in a complete or partial response to platinum-basedchemotherapy.
European approval:
Olaparib monotherapy for the maintenance treatment of adult patient with
platinum-sensitive relapsed BRCA-mutated (Germline/somatic) OC, high grade
sereous, fallopian tube, or primary peritoneal cancer who are in response
(compleate or partial) to platinum-based chemotherapy. 2
From February 2018 Lynparza is indicated as monotherapy for the maintenancetreatment of adult patients with platinum-sensitive relapsed high-grade epithelialovarian, fallopian tube, or primary peritoneal cancer who are in response (complete orpartial) to platinum-based chemotherapy
1. Kaufman B, et al. J Clin Oncol 2015
. 2. Ledermann J et al. New Engl J Med 2012
Study 19: Phase II trial design, endpoints and
BRCA testing
N=265
• ‘Platinum-sensitive’
recurrent high-grade
serous ovarian cancer
• ≥2 prior regimens of
platinum-based
chemotherapy
• Complete or partial
response to most
recent platinum-based
regimen
Olaparib maintenance
monotherapy
(400 mg bid, capsules)
n=136
n=129Placebo (bid, capsules)
Double-blind
randomization
1:1
Treatment until progression
BRCA testing:
• Previous local germline BRCA testing (case report forms)
• Retrospective germline BRCA testing or tumour BRCA testing
BRCAm: n=136
BRCAwt:* n=118
Primary endpoint:
Progression-free survival (PFS)
by RECIST 1.0
Secondary endpoints included:
Overall survival (OS),
safety and tolerability
Exploratory endpoints:
Time to first subsequent therapy
or death (TFST), time to second
subsequent therapy or death (TSST)
*BRCAwt patients did not have a detected BRCAm or had a BRCAm of unknown significance
bid, twice daily; BRCAwt, BRCA1/2 wild type; RECIST, Response Evaluation Criteria in Solid Tumors
Statistically significant
improvement in
progression-free
survival with
olaparib1,2
BRCAm subgroup:
Median PFS (olaparib vs placebo): 11.2 months vs 4.3
months HR=0.18, P<0.0001
Overall population:
Median PFS (olaparib vs placebo): 8.4 months vs 4.8
months HR=0.35, P<0.0001
Study 19: Progression free survival results
CI, confidence interval; DCO, data cut-off; FSI, first subject in
OS data maturity: 77%
Alpha (two-sided) = 0.95%
Additional follow-up since
previous analysis = 3 years
28 Aug 2008 31 Oct 2011 26 Nov 2012
FSI
OS data maturity: 38%
Alpha (two-sided) = 0.1%
HR=0.94
95% CI 0.63–1.39, P=0.751
OS data maturity: 58%
Alpha (two-sided) = 3%
HR=0.88
95% CI 0.64–1.21, P=0.442
30 Sep 2015
DCO DCO DCO
. Ledermann J et al. New Engl J Med 2012;366:1382–1392; 2. Ledermann J et al. Lancet
Oncol 2014;15:852–861 Jonathan A Ledermann at ASCO 2016
Study 19 OS analyses
Final analysis of the long-term benefit of
olaparib in pts with PSR SOC in Study 19
CI, confidence interval; DCO, data cut-off; FSI, first subject in. Ledermann J et al. New Engl J Med 2012;366:1382–1392; 2. Ledermann J et al. Lancet
Oncol 2014;15:852–861 Jonathan A Ledermann at ASCO 2017
79% data maturity
DCO, median OS follow-up was 78.0 months
Key slides ESGO 2017
© 2018– FSE/ANM
Biomarker characterization in patients receiving olaparib for ≥6 years
Patients receiving
olaparib for ≥6 years
n=15
sBRCAm
n=3
BRCAm
n=9
RAD51B
mutation
BRCAwt
n=5
gBRCAwt;
tBRCA unknown
n=1
BRCA2m
n=5
BRCA1m
n=3
BRCA1m and
BRCA2m
n=1
HRR
uncertain
n=5
HRRwt
n=2
HRRm
n=1
HRD +ve
n=1*
HRD -ve
n=1*
HRD +ve
n=1
= Foundation Medicine T5 panel result
= Myriad HRD score result
*2/5 BRCAwt patients had no available Myriad HRD score resultgBRCAwt, germline BRCA wild type; HRRm, HRR mutation; HRRwt, HRR wild type; tBRCA, tumour BRCA.
Olaparib OVAIO
Mod. da Friedlander M, et al. ESGO Annual Meeting 2017
Long-term exposure to treatment
Charlie Gourley, et al 2017 ASCO Meeting
SOLO-1, -2, -3
Randomized phase III studies of Olaparib in OC
*Primary endpoint for HRQoL was trial outcome index (TOI) of the FACT-O (Functional Assessment of Cancer Therapy – Ovarian)
Sensitivity analysis: PFS by blinded independent central review (BICR)
• Key secondary endpoints:
Time to first subsequent therapy or death (TFST), time to second progression (PFS2),
time to second subsequent therapy or death (TSST), overall survival (OS)
Safety, health-related quality of life (HRQoL*)
SOLO2/ENGOT-Ov21: study design
Placebo
n=99
Olaparib
tablets
300 mg bid
n=196Primary endpoint
Investigator-assessed
PFS
Patients
• BRCA1/2 mutation
• Platinum-sensitive relapsed
ovarian cancer
• At least 2 prior lines of
platinum therapy
• CR or PR to most recent
platinum therapy
Random
ized
2:1
Presented by Pujade-Lauraine at SGO 2017 annual meeting
No. at risk
OlaparibPlacebo
19699
18270
15637
13422
11818
10417
8914
8212
327
296
30
20
00
100
90
80
70
60
50
40
30
20
10
0
Pro
gres
sio
n-f
ree
surv
ival
(%
)
Months since randomization
0 3 6 9 12 15 18 21 24 27 30 33 36
19.1
Olaparib
Placebo
5.5
Olaparib
(n=196)
Placebo
(n=99)
Events (%) 107 (54.6) 80 (80.8)
Median PFS, months 19.1 5.5
HR 0.30
95% CI 0.22 to 0.41
P<0.0001
Median follow-up was 22.1 months in the olaparib group and 22.2 months for placebo
Presented by Pujade-Lauraine at SGO 2017 annual meeting
PFS by investigator assessment
Subgroup analysis of PFS
Olaparib better Placebo better
Presented by Pujade-Lauraine at SGO 2017 annual meeting
Months since randomization
Pro
gres
sio
n-f
ree
su
rviv
al (%
)
100
90
80
70
60
50
40
30
20
10
00 3 6 9 12 15 18 21 24 27 33
30.25.5
30
No. at risk
OlaparibPlacebo
19699
17662
14826
12818
11216
10314
8814
8211
306
285
30
10
Olaparib
(n=196)
Placebo
(n=99)
Events (%) 81 (41.3) 70 (70.7)
Median PFS, months 30.2 5.5
HR 0.25
95% CI 0.18 to 0.35
P<0.0001
PFS sensitivity analysis using BICR
Olaparib
Placebo
Presented by Pujade-Lauraine at SGO 2017 annual meeting
Total adverse events
Characteristic, n (%)Olaparib
(n=195)
Placebo
(n=99)
Any AE 192 (98.5) 94 (94.9)
Any AE grade ≥3 72 (36.9) 18 (18.2)
Any SAE 35 (17.9) 8 (8.1)
Any AE leading to dose reduction 49 (25.1) 3 (3.0)
Any AE leading to discontinuation of study treatment 21 (10.8) 2 (2.0)
Any AE with an outcome of death 1 (0.5) 0
AE, adverse event; SAE, serious adverse event Presented by Pujade-Lauraine at SGO 2017 annual meeting
Most common hematologic adverse events
Event, n (%) Olaparib (n=195) Placebo (n=99)
All grades Grade ≥3 All grades Grade ≥3
Anemia* 85 (43.6) 38 (19.5) 8 (8.1) 2 (2.0)
Neutropenia* 38 (19.5) 10 (5.1) 6 (6.1) 4 (4.0)
Thrombocytopenia* 27 (13.8) 2 (1.0) 3 (3.0) 1 (1.0)
MDS/AML: 4 cases in olaparib group (2.1%), including one case of CMML
4 cases in placebo group (4.0%)
*Grouped termsPresented by Pujade-Lauraine at SGO 2017 annual meeting
Most common non-hematologic adverse events
All grades (frequency ≥20%)
Olaparib Placebo
100 75 50 25 0 0 25 50 75 100Adverse events (%)
Dysgeusia 7.126.7
Headache 13.125.1
Decreased appetite 11.122.1
Nausea 33.375.9
Fatigue/asthenia 39.465.6
Vomiting 19.237.4
Constipation 23.220.5
Diarrhea 20.232.8
Abdominal pain 31.324.1
Grade ≥3 (frequency ≥2.5%)
Other AEs of interestElevated ALT: 10 patients in olaparib group (5.1%) vs 4 patients in placebo group (4.0%)Elevated AST: 4 patients in olaparib group (2.1%) vs 4 patients in placebo group (4.0%)
2.6
1.02.6
2.04.1
3.0
1.0
2.6 3.0
0.5
Presented by Pujade-Lauraine at SGO 2017 annual meeting
Health-related quality of life: TOI of the FACT-O
TOI over first 12 months Olaparib (n=185) Placebo (n=94)
Change from baseline, adjusted mean −2.90 −2.87
TOI, trial outcome index; FACT-O, Functional Assessment of Cancer Therapy – Ovarian
Estimated difference in adjusted means = −0.03 (95% CI −2.19 to 2.13, P=0.98)
Presented by Pujade-Lauraine at SGO 2017 annual meeting
WHAT ABOUT RECHALLENGE?
Olaparib in first line:SOLO-1 Phase III trial- BRCAm population only
First-line maintenance
Response to platinum-
based chemotherapy
Olaparib
300mg os bid
Placebo
344 patients
PFS/PFS2/OS + QoL
Randomization
2:1
Olaparib in first line: PAOLA 1 study design
MITO 31
A phase II trial of Olaparib in patients with recurrent ovarian cancer wild type for
germline and somatic BRCA mutations: a MITO translational study
QoL !!!!!
In conclusione….
QoL !!!!!
In conclusione….
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