ovarian cancer: surgical and systemic treatmentlorusso+-+ovarian.pdfchemotherapy plus or minus...
TRANSCRIPT
Fondazione Policlinico Universitario Agostino Gemelli IRCCS 1
OVARIAN CANCER: SURGICAL AND SYSTEMIC TREATMENT
5th ESO-ESMO Masterclass in Clinical Oncology in Latin America
Lima 03-07/04/2019
Domenica LorussoGynecologic Oncology Unit
Fondazione Policlinico Universitario A Gemelli IRCCS
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Disclosure
Advisory board for
Roche Tesaro MerckAstra ZenecaClovis Oncology
Institutional Research Support from
Pharma Mar, Clovis Oncology and Merck
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Progress in the management of ovarian
cancer: Evolution over 40 years
PARPi, poly adenosine diphosphate ribose polymerase inhibitor.
Key advances in chemotherapy
First use of cisplati
n
First use of
carboplatin
First use of
paclitaxel
First reports of
bevacizumab
Positive evidence
for weekly paclitaxel in
first-line
First use of oral PARPi
1970 1980 1990 2000 2010
30% 40%?50%
?Five-year survival15%
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Ovarian cancer is not a single disease
Romero I et al. Endocrinology 2012; 153: 1593-1602
70 %
2% 5%15%5%
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Advanced ovarian cancer:A ‘chronic’ disease with multiple relapses
PFI: platinum-free interval or duration of disease control without chemotherapy.
du Bois a, Pfisterer J. Zentralbl Gynakol. 2004;126:312-4.
*
CA
-1
25
Time (months)
First-linechemotherapy
Platinum-sensitive relapses
Occlusion
Symptoms
PFI: 12 months
Platinum-resistant relapses
8 months
4 months
Surgery
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Response to treatment in patients with ovarian cancer declines with increasing
disease recurrence
N numbers show total population; confidence lines represent 95% Cls for total population.CI, confidence interval; ORR, overall response rate.
OR
R (
%)
100
90
80
70
60
50
40
30
20
10
01
(n=18)2
(n=50)3
(n=74)4
(n=44)5
(n=32)6–14
(n=55)
Previous lines of chemotherapy received
Total (n=273)Sensitive (n=74)Resistant (n=115)
du Bois a, Pfisterer J. Zentralbl Gynakol. 2004;126:312-4.
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How effective is “watchful waiting”?
Median PFS from placebo arms may provide insights.PFS, progression-free survival.
Aghajanian C et al. J Clin Oncol. 2012;30:2039–45; Coleman RL et al. Gynecologic Oncol. 2015;137:386–91; Ledermann J et al. Lancet Oncol.
2014;15:852–61; Ledermann JA et al. Lancet. 2016;387:1066–74; Marth C, et al. European J Cancer. 2017;70:111–121; Monk BJ et al. Lancet
Oncol. 2014;15:799–808;Pujade-Lauraine E et al. J Clin Oncol. 2014;32:1302–8; Mirza MR et al. N
Engl J Med. 2016;375:2154–64.
6.7
3.4
7.4
5.4
7.6
7.2
12.4
8.4
13.8
10.4
11
8.7
CHEMOTHERAPY 19.1
CHEMOTHERAPY 5.5
CHEMOTHERAPY 9.3
CHEMOTHERAPY 3.9
CHEMOTHERAPY 21
CHEMOTHERAPY 5.5
Aurelia
TRINOVA 1
TRINOVA 2
SOLO-2-gBRCA
0 5 10 15 20 25
OCEANS
GOG 213
ICON 6
NOVA-non-gBRCA
NOVA-gBRCA
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• 1989-1998 MEDLINE - 81 cohorts (Stage III-IV) 6885 pts
Bristow E et al, JCO 20:1248-59, 2002
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Our current goal……72 Months and……. beyond
MICROSCOPIC
RESIDUAL
>1 cm
30 MONTHS
OF ADVANTAGE
40-44 Months<1 cm
30-35 Months
7-10 MONTHS
OF ADVANTAGE
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Results of Previous studies
Presented By Takashi ONDA at 2018 ASCO Annual Meeting
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Trial Design
Presented By Takashi ONDA at 2018 ASCO Annual Meeting
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Overall Survival (N=301)
Presented By Takashi ONDA at 2018 ASCO Annual Meeting
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GOG 172: 42% completed treatment8% never started34% received only one or two cycles
NOT feasible in the majority of patients
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Presented by:
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First line Dose dense in ovarian cancerJGOG-3016
Noriyuki Katsumata et al .Lancet Oncol 2013; 14: 1020–26
PFSOverall survival
Median PFS28.2 months vs 17.5 months
(HR 0.76, 95% CI 0.62–0.91; p=0.0037).
Median overall survival was100.5 vs 62.2 months
(HR 0.79, 95% CI 0.63–0.99; p=0.039).
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0 6 12 18 24 30 36 42 48
Months
0.0
0.2
0.4
0.6
0.8
1.0
Pro
babili
ty o
f pro
gre
ssio
n-f
ree
surv
ival
Median PFS 18.8 vs 16.5
Log-rank test p = 0.18
Unadjusted HR: 0.88 (0.72 – 1.06)
PFS
Presented by: S.PignataPignata et al. Lancet Oncol. 2014 Apr;15(4):396-405
First line Dose dense in ovarian cancerMITO 7
Weekly 405
Every 3-
week
403
0 6 12 18 24 30 36 42 48
Months
0.0
0.2
0.4
0.6
0.8
1.0
Pro
ba
bili
ty o
f su
rviv
al
OS
Median OS n.a. vs 47.9
Log-rank test p = 0.24
Unadjusted HR: 1.20 (0.88 – 1.63)5th
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GOG 262
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22
ICON8 OVERALL SURVIVAL
Data immature – 602 events per comparison required (58% of required events included here)
Arm 1 Arm 2 Arm 3
Standard
Weekly paclitax
el
Weekly carbo-
paclitaxelTotal
PatientsN=522 N=523 N=521
No. of deaths
183 (35%)
167 (32%)
166 (32%)
Log rank (vs Arm 1
only)p=0.21 p=0.3
Median OS
46.5months
48.1 months
54 months
2 year survival(95% CI)
80%(76%, 83%)
82%(79%, 86%)
78%(74%, 81%)
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Two positive trials with bevacizumab
in front line
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Overall Survival
Arm ICP
(n = 625)
Arm IICP + Bev(n = 625)
Arm IIICP + Bev Bev
(n = 623)
Deaths 156 (25.0%) 150 (24.0%) 138 (22.2%)
1-Year Survival 90.6% 90.4% 91.3%
Events were observed in ~ 24% of patients at the time of database lock.
Burger RA et al. Proc ASCO 2010;Abstract LBA1.
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OS benefit is suggested with chemotherapy + Avastin and continued single-agent Avastin in stage IV disease
129 113 95 2872 42 15 5
142 117 104 3073 44 15 10
144
149
154 144 130 117 3783 57 21 10
3
3
3
0
1
0
Time (months)
0 72
1.0
0.8
0.6
0.4
OS
es
tim
ate
12 24 36 48 60
0.2
0.0
CPP
CPB
CPB15
165
165
153
0
0
0
CPP (n=153)
CPB15 (n=165)
CPB15+ (n=165)
CPP CPB CPB15
Deaths, n
(%)
93 (61) 99 (60) 81 (49)
Median
survival
(months)
32.8 32.9 40.6
HR
(95% CI)
0.98
(0.74–1.31)
0.72
(0.53–0.97)
Randall, et al. SGO 2013: Abstract 80Randall, et al. SGO 2013: Abstract 80
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WHICH PATIENTS?
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Trial Chemotherapy Bevacizumab PFS HR
First line
GOG-02181
(n=1873)Paclitaxel
Carboplatin
Concurrent and maintenance
15 mg/kg q3w(3-arm placebo)
0.72
ICON72
(n=1528)Paclitaxel
Carboplatin
Concurrently only 7.5 mg/kg q3w
(2 arm)0.81
Second line
Platinum resistantAurelia3
(n=361)
CaelyxTopotecanPaclitaxel
Concurrent 10 mg/kg q2w
(2 arm)0.48
Platinum sensitiveOCEANS4
(n=484)GemcitabineCarboplatin
Concurrent 15 mg/kg q3w
(2 arm) 0.48
Bevacizumab in ovarian cancer:
four pivotal trials: Dose? Duration? Setting?
1. Burger et al. N Engl J Med 20112. Perren et al. N Engl J Med 2011
3. Pujade-Laurain et al. J Clin Oncol 20124. Aghajanian et al. J Clin Oncol 2012
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HOW LONG?
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2929Study design
aCisplatin permitted in patients with hypersensitivity to carboplatinbA change from one paclitaxel regimen to the alternative during the study was not permitted ECOG PS = Eastern Cooperative Oncology Group performance status; ORR = overall response rate
IV paclitaxel 175 mg/m2 d1 or
80 mg/m2 d1, 8, 15 q3w (4–8 cycles)b
IV carboplatin AUC 5–6 q3w
(4–8 cycles)a
BEV 15 or 7.5 mg/kg IV q3w for up to 36 cycles (2 years)
or until disease progression or unacceptable toxicity
Patients without progression at cycle 36 could
continue therapy after discussion with the Steering Committee
• Epithelial ovarian,
fallopian tube or primary
peritoneal cancer:
– Stage IIB–IV
– Grade 3 stage I/IIA
– Clear-cell carcinoma
(any stage)
– Carcinosarcoma
• Maximally debulked
(prior neoadjuvant
chemotherapy allowed)
• ECOG PS 0–2
– Primary endpoint: Safety (AEs by NCI-CTCAE version 4.03)
– Secondary endpoints: PFS, ORR, duration of response, overall survival
– Exploratory objectives: Optional translational research
Dec 2010‒May 2012:
1021 patients enrolled
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3030
1.00
0.75
0.50
0.25
0
Esti
mate
d p
rob
ab
ilit
y o
f P
FS
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45Time (months)
PFS in ROSiA and ICON7 (ITT populations)
19.3 25.5
1Avastin SmPC; 2Roche data on file 2012 (ICON7 CSR addendum).
ICON7
BEV 7.5 mg/kg
+ CP1,2
ROSiA
BEV 15 (or 7.5) mg/kg
+ CP
Caveats
• Differing tumour assessment schedules
• Prior neoadjuvant chemotherapy permitted in ROSiA
CP = carboplatin + paclitaxel
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Paclitaxel 175 mg/m²
Carboplatin AUC5 q21 days
Bevacizumab 15mg/kg q21 days 15 months
= 22 cycles
Paclitaxel 175 mg/m²
Carboplatin AUC5 q21 days
Bevacizumab 15mg/kg q21 days
30 months
= 44 cycles
ENGOT Ov-15 Trial
AGO-OVAR 17
Study Design
R
N= 900
1:1
Strata
macroscopic residual tumor (yes vs no)
FIGO Stage (IIB-IIIC vs IV)
Study Group
Primary endpoint:
PFS (non inferiority -> superiority)
Main question: treatment duration Bev
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BEYOND PROGRESSION?
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Chemotherapy plus or minus bevacizumab for platinum-sensitive ovarian cancer patients
recurring after a bevacizumab containing first line. The randomized phase 3 trial MITO16B -
MaNGO OV2B - ENGOT OV17
Sandro Pignata, Domenica Lorusso, Florence Joly, Ciro Gallo, Nicoletta Colombo, Cristiana Sessa, Aristotelis Bamias, Carmela Pisano, Frédéric Selle, Eleonora
Zaccarelli, Giovanni Scambia, Patricia Pautier, Maria Ornella Nicoletto, Ugo De Giorgi, Coraline Dubot, Alessandra Bologna, Michele Orditura,
Isabelle Ray-Coquard, Francesco Perrone, Gennaro Daniele
on the behalf of MITO, GINECO, MaNGO, SAKK and HeCOG groups
Sandro Pignata
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Study Design
R
A
N
D
O
M
1:1
Platinum-Based Chemotherapy
Experimental Platinum-Based Chemotherapy
plus Bevacizumab
Platinum-based Chemotherapy:
• Carboplatin + Paclitaxel +/- Beva 15mg/kg q 21
• Carboplatin + Gemcitabine +/- Beva 15mg/kg q 21
• Carboplatin + PLD q 28 +/- Beva 10mg/kg q 14
Standard
Sandro Pignata
Stratification:
• center• relapse during or after 1° line Beva
• performance status
• chemo backbone
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PFS Investigator assessed (primary end-point)
Standard Experimental Log RankP
# events 161 143
Median PFS 8.8 mos 11.8 mos <0.001
HR* (95%CI) 0.51 (0.41-0.65)
*adjusted by:age, PS, centre size, bevacizumab at relapse, chemo backbone,
residual disease at initial surgery
0.0
00
.25
0.5
00
.75
1.0
0
Pro
ba
bili
ty o
f P
FS
202 179 83 30 9 3 0 0 0Experimental203 137 35 10 5 1 0 0 0Control
Number at risk
0 6 12 18 24 30 36 42 48months
Control Experimental
Kaplan-Meier survival estimates
Sandro Pignata
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HGOC patients can be classified into three molecular subgroups: BRCAmut, BRCA-like, Biomarker Negative
Presented By Iain McNeish at 2015 ASCO Annual Meeting
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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
SOLO 1 TRIAL: 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
CI, confidence interval; NR, not reached
60.4% progression free
at 3 years
26.9% progression free
at 3 years
131 103 82 65 56 53 47 41 39 38 31 28 22 6 5 1 0 0 0 0118
No. at risk
Placebo
260 229 221 212 201 194 184 172 149 138 133 111 88 45 36 4 3 0 0 0240Olaparib
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1st LINE OC TREATMENT: FUTURE APPROACHES
ImmumeTx
Anti-angiogenic
iPARP
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Niraparib is being assessed for maintenance therapy in the first-line setting in the PRIMA study
High-grade Stage III or IV ovarian cancer (all comers) and achieved a CR or PR
following front-line platinum-based chemotherapy
R 2:1
Niraparib
300 mg daily
Placebo
daily
Endpoint assessment
Stratification factors
• Neoadjuvant chemotherapy administered: Yes or No
• Best response to 1st platinum therapy: CR or PR
• HRD status: positive or negative/not determined
Enrolment completed June 2018 (N=733)
Results expected end 2019
Primary endpointHierarchical testing for PFS (radiologic, central review)
• PFS in HRD positive population (HR 0.5)
• PFS in ITT population (HR 0.65)
Key secondary
endpoints
Overall survival | Patient-reported outcomes (FOSI, EQ-5D-5L, EORTC-QLQ-
30, EORTC-QLQ-OV28) | Safety & tolerability | Time to CA-125 progression
Niraparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high grade serous
epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.
Please consult the summary of product characteristics.
CR, complete response; EORTC-QLQ-30, European Organisation for Research and Treatment of Cancer; EORTC-QLQ-OV28, EORTC–Ovarian
Cancer Module; EQ-5D-5L, European QoL five-dimension five-level questionnaire; FOSI, FACIT ovarian cancer symptom index; HR, hazard ratio;
HRD, homologous recombination deficiency; ITT, intention to treat; PFS, progression free survival; PK, pharmacokinetic; PR, partial response;
QoL, quality of life; R, randomized. ClinicalTrials.gov. PRIMA. Available at: https://clinicaltrials.gov/ct2/show/NCT02655016. Accessed
October 2018.
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Bevacizumab 15 mg/kg Q3W 15 months + placebo 2 years
Bevacizumab 15 mg/kg Q3W 15 months +
olaparib 300 mg BID 2 years
PD†
Phase III trial of olaparib in combination with bevacizumab as first-line maintenance therapy in patients with advanced ovarian cancer
PAOLA-1: Study Design
• FIGO stage IIIb–IV high-grade serous/endometrioid or non-mucinous BRCA mutation ovarian, fallopian tube or primary peritoneal cancer
• First line•Surgery (primary or interval)•Platinum–taxane based
chemotherapy• ≥3 cycles of bevacizumab†
• CR/PR NED
Patient eligibility
PFS
Primary endpoint
Status: recruitingTarget enrolment:
612
Stratification factors• Tumour BRCA status • First-line outcome
La combinación de olaparib y bevacizumab no está autorizado en España. The combination of olaparib and bevacizumab is not approved in Spain.
2:1
R
Maintenance
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Carboplatin AUC 6 q3wk
Bev 15 mg/kg X 16 cycles
Placebo q3w X 22 cycles
Paclitaxel 175 mg/m2 q3wk
Bev 15 mg/kg q3wk
Carboplatin AUC 6 q3wk
Bev 15 mg/kg X 16 cycles
Atezo 1200 mg q3w X 22 cycles
Paclitaxel 175 mg/m2 q3wk
Bev 15 mg/kg q3wk
Stratification variables
• Stage/debulking status
• ECOG PS
• PDL1 IC0 vs IC1+
• Adjuvant/Neo-adjuvant
No cross-over
• Previously untreated ovarian, fallopian tube, or peritoneal cancer
• Post-operative Stage III w/macroscopic residual disease, Stage IV
• ECOG PS 0-2
R1:1
Imagyn trial
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PRIMA Imagyn050
ENGOT OV39
Athena First ENGOT OV43 Duo-O Total
Sponsor Tesaro Roche Clovis Tessaro Merck Astra Zeneca
Group leader GEICO(GOG) GOG(MITO) GOG(NCRI) GINECO
(GOG??)
BGOG(leading
) – unsure
whether GOG
will join as
supporting
groups
AGO(GOG)
ENGOT Model C C C C C
Randomisatio
n
After CT Upfront Maintenance Upfront Upfront Upfront
Bev in
Standardarm
No Yes No Optional Optional Yes
Exp. Arm Nira - TC-Bev-
Atezo
- Ruca-
Nivolu
- Ruca
- Nivolu
- Nira
- Nira + O42
BRCA+: Ola +
Pembro
BRCA-:
Pembro
Pembro+Ola
- Durva
- Durva+Ola
NACT allowed Yes Yes Yes Yes Yes Yes
RT=0 NO after PDS
YES after IDSNo but Under
discussion
CR/NED after CT No Yes Yes
Endpoint PFS PFS + OS PFS PFS PFS+OS PFS
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Recurrent Ovarian Cancer
• 50-90% of patients with advanced ovarian cancer will have a relapse in less than 5 years depending on:
– the FIGO stage at diagnosis,
– use of neo-adjuvant chemotherapy and
– residual disease after upfront cytoreductive surgery.
43
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Hanker LC, et al. Ann Oncol 2012
Prognosis after relapse: AGO/GINECO meta-database 1620 pts with documented therapy for relapse
Patients receiving 2nd 3rd, 4th line of CT, impact on PFS and OS
N. of patients receiving CT2nd line of CT n = 1022 (63%)3rd line n = 690 (42%)4th line n = 498 (30%)5th line n = 398 (25%)
But, OS correlated to lines of treatment
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Surgery in relapse: the new reality
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Recurrent Ovarian Cancer: Population Characteristics
Pisano et al. Ther Clin Risk Manag. 2009;5:421-426; Gadducci et al. Anticancer Res. 2001;21:3525-3533.
PRIMARY
THERAPY
0 3 6 12 18 24
Refractory
Resistant
Partially Sensitive
Fully Sensitive
months
Therapy-free interval (months)
Response
Rate (%)
Response
Rate
PFS
Overall
Survival
32
9
90166
217
366
Survival
(days)
100
80
60
40
20
1000
800
600
400
200
00-3/Pr 0-3 3-6 6-9 9-12 12-18 ≥18
A GiNECO study:Therapy-freeInterval and Efficacy
Pujade-Lauraine E et al. Proc Am Soc Clin Oncol 21: 2002 (abstr 829)
PLATINUM SENSITIVITY IS A CONTINUUS VARIABLE!!!
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Systematic Treatment, Decisional factors How to treat patient?
Duration of response to initial platinum therapy
BRCA mutation status
Previous agents used
Toxicities experienced in 1st-line setting
Patient’s performance
status
Patient and physician preference
Choice of
systematic
therapy
•Neurotoxicity
•Hypersentivity
•Hematotoxicity
Bevacizumab
parp inh
1st line CT
National label
•Yes
•No
•Unknown
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Platinum is not an option(formerly platinum-resistant)
• Definition by GCIG:
• Short TFIp (minimum < 6 m) based on symptomatic relapse or RECIST criteria.
• Progression on therapy.
• Platinum allergy or residual toxicity.
Expected OS is usually short, around 12 months
• Main objectives of treatment:
– QoL
– Toxicity
– Control of symptoms
• Treatment in control arm can include a non-platinum drug as a single agent or in combination.
• Chemotherapy options: – Single agent: weekly paclitaxel,
PLD, Topotecan, gemcitabine…
– Combination: Trabectedine-PLD*
5th OCCC of the GCIG: Recurrent Disease. Ann Oncol. 2016 Dec 19
*If TFIp > 6 months
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Role of Yondelis+PLD in PPS Ovarian Cancer: OS data
Events/censored:177/37
Cox regression:
HR: 0.64 (0.47-0.86)
p=0.0027
Yondelis+PLD
Median=22.4 months
Median=16.4 months
PLD
Monk BJ et al. J Clin Oncol. 2011:29(suppl):abstr 5046.Sehouli J, Gonzalez A. Ann Oncol 2011. Epub 2011 Jul 6. DOI: 10.1093/annonc/mdr321
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WHEN PLATINUM IS NOT AN OPTION: BEYOND CHEMOTHERAPY
E Pujade-Laurine et al. JCO 2014
AURELIA
Chemotherapy vs chemo-beva
• 361 patients wereenrolled betweenOctober 2009 and April2011.
• Options of chemotherapyweekly paclitaxel, topotecan or PLD.
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Parp Inhibitor: active disease setting
Rucaparib Pooled Analysis (ESMO 2016)
(103 pts)
Olaparib US Label(137 pts)
Potential Line of Therapy
≥3rd line treatment (regardless platinum sensitivity)
≥4th line treatment (regardless platinum sensitivity)
Dosing 600 mg BID 400 mg BID
Potential labelPopulations
Tumour BRCAmut (includes germline and somatic mutations)
Germline BRCAmut
Most commonGrade ≥3 AEs in treatment setting
• Fatigue (11%)• Anaemia (23%)• ALT/AST (11%)
• Fatigue (8%)• Anaemia (18%)• Abdominal pain (8%)
Dose interruptions/ reductions due to side effects
• 8%• 44.3%
• 36%• 42%
ORR (RECIST 1.1) by investigator
54% 34%
Progression free survival (median, months)
10.0 7.0
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Toxicity and patient’s preference shouldguide the selection of platinum-doublet
ICON41
GEICO 01042
AGO-OVAR 2.53 CALYPSO4
Paclitaxel-Carboplatin
Gemcitabine-Carboplatin
PLD-Carboplatin
Toxicity AlopeciaNeuropathyArthralgia
Myelotoxicity EPPMucositis
Thrombopenia
1. Parmar. Lancet 2005; 2. Gonzalez-martín. Ann Oncol 2005; 3. Pfisterer. JCO 2006
1. Parmar. Lancet 2005; 2. Gonzalez-martín. Ann Oncol 2005; 3. Pfisterer. J Clin Oncol 20064. Pujade Laurine. J Clin Oncol 2010
PLD: Pegylated liposomal doxorubicin
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Bevacizumab plus chemotherapy for ovarian cancer
bev, bevacizumab; CG, carboplatin + gemcitabine; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival
1. Aghajanian C, et al. J Clin Oncol. 2012;30:2039–45; 2. Coleman RL, et al. Lancet Oncol 2017; Epub ahead of print: April 21, 2017..
CG + placebo(n=242)
CG + bev(n=242)
Events, n (%) 187 (77) 151 (62)
Median PFS, months (95% CI) 8.4(8.3–9.7)
12.4(11.4–12.7)
Stratified analysis HR (95% CI)Log-rank p-value
0.484 (0.388–0.605)<0.0001
242 177 45 11 3 0CG + placebo
MonthsNo. at risk
242 203 92 33 11 0CG + bev
1.0
Pro
po
rtio
n p
rog
ressio
n fre
e
0 6 12 18 24 30
0.8
0.6
0.4
0.2
0
CG + placebo
CG + bevacizumab
Treatment
Median OS
(months)
Hazard Ratio (95% Cl)P-value
Standard Chemo (n=337)
42.20.829
(0.683, 1.005)
P=0.056Standard Chemo + BEV (n=337)
37.3
Chemotherapy
No. at risk
(number censored)
Chemotherapy +
bevacizumab
337 (0) 303 (15) 234 (17) 152 (30) 69 (77) 18 (109)
Time since randomisation (months)
337 (0) 306 (8) 253 (9) 183 (20) 75 (82) 28 (110)
Chemotherapy
Chemotherapy + bevacizumab
PFS in theOCEANS study1
OS in the GOG-213 study2
100
Ove
rall
su
rviv
al (%
)
0 1
2
2
4
3
6
4
8
6
0
80
60
40
20
0
HR 0.829 (95% CI 0.683-1.005); p=0.056
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1. AstraZeneca. Olaparib Summary of Product Characteristics. 2017; 2. AstraZeneca. Olaparib Prescribing Information. 2014; 3. TESARO. Niraparib Prescribing Information. 2017; 4. Clovis Oncology. Rucaparib Prescribing Information. December 2016
EMA, European Medicines Agency; FDA, US Food & Drug Administration;PARP, poly(ADP-ribose) polymerase
PARP Inhibitors: A Recap
PARP inhibitors approved for use in patients with ovarian cancer
PARP inhibitor
Authority
Indication
Olaparib
EMADec
2014
Monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic) high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy1
Olaparib is not approved in Europe as a monotherapy in the treatment setting
US FDADec
2014
Monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated (as detected by anFDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy2
Aug 2017
Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy2
Niraparib
EMASept 2017
Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy3
US FDAMar 2017
Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy3
Rucaparib
EMA Not approved for use in Europe
US FDADec
2016
Monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic; as detected by an FDA-approved companion diagnostic for rucaparib) associated advanced ovarian cancer who have been treated with two or more chemotherapies4
PARP inhibitors in clinical development
Veliparib; Talazoparib. Veliparib and talazoparib are not approved for use.
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Platinum combination followed by iPARPOlaparib study design and patient selection
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
Placebo
n=99
Olaparib
300 mg bid
n=196
Primary endpoint: Investigator-assessed PFS
• Germilne BRCA1/2
mutation
• Platinum-sensitive
relapsed ovarian
cancer
• At least 2 prior lines of
platinum therapy
• CR or PR to most
recent platinum
therapy
Ra
nd
om
ize
d
2:1
SOLO-2 aim and design
295 patients
Pujade-Laurine et al. SGO 2017
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Platinum combination followed by iPARPOlaparib data on primary endpoint: BRCA mutated patients
Study-19 PFS SOLO-2 PFS
Pujade-Laurine et al. SGO 2017
11.2 vs 4.3 monthsHR 0.18 (95% CI: 0.10-0.31)
Ledermann et al. Lancet Oncol. 2014;15(8):852–861
No. at risk
OlaparibPlacebo
10090
80
70
60
50
40
30
20
10
0P
rogr
essi
on
-fre
e su
rviv
al (
%)
Months since randomization
0 3 6 9 12
15
18
21
24
27
30
19.1
Olaparib
Placebo
5.5
19.1 VS 5.5 monthsHR 0.3 (95% CI: 0.22-0.41)5t
h ESO-E
SMO L
atin
Amer
ican
Mas
terc
lass i
n Clin
ical O
ncolo
gy
gBRCAmut203
Treat until Progression of Disease
Niraparib 300 mg once daily
Placebo
Non-gBRCAmut350
Treat until Progression of Disease
Niraparib 300 mg once daily Placebo
2:1 Randomization 2:1 Randomization
Platinum-Sensitive Recurrent High Grade Serous Ovarian Cancer
Response to Platinum Treatment
Treatment with 4-6 Cycles of Platinum-based Therapy
553
Mirza MR et al. N Engl J Med 2016
Platinum combination followed by iPARPNiraparib: ENGOT ov16-NOVA study design
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Platinum combination followed by iPARPNiraparib: ENGOT ov16-NOVA primary end-point
Treatment
PFSMedian(95% CI)
(Months)
Hazard Ratio(95% CI)p-value
Niraparib
(N=138)21.0
(12.9, NR)0.27
(0.173, 0.410)
p<0.0001Placebo
(N=65)5.5
(3.8, 7.2)
PFS: gBRCAmut
Treatment
PFSMedian(95% CI)
(Months)
Hazard Ratio(95% CI)p-value
Niraparib
(N=234)9.3
(7.2, 11.2)0.45
(0.338, 0.607)
p<0.0001Placebo
(N=116)3.9
(3.7, 5.5)
PFS: non-gBRCAmut
Mirza MR et al. N Engl J Med 2016
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61
ARIEL3: DIAGRAM OF ANALYSIS COHORTS
ITT population (n=564)
130 rucaparib 66 placebo + 106 rucaparib 52 placebo + 139 rucaparib 71 placebo
HRD cohort (n=354)
130 rucaparib 66 placebo + 106 rucaparib 52 placebo
BRCA-mutant cohort (n=196)
130 rucaparib 66 placebo
564 enrolled/randomised
196 BRCA mutant 368 BRCA wild type
158 BRCA wild type/
LOH high‡
161 BRCA wild type/
LOH low
49 BRCA wild type/
LOH indeterminate
130 germline
BRCA mutant*
56 somatic
BRCA mutant†
10 undefined
BRCA mutant
*No more than 150 patients with a known deleterious germline BRCA mutation were to be enrolled to ensure enough patients with carcinomas associated with a somatic BRCA mutation or
wild-type BRCA were enrolled to determine statistical significance between rucaparib and placebo in the HRD cohort and the ITT population. †Deleterious BRCA mutation detected by next-
generation sequencing of tumour tissue but not by central germline blood test. ‡For LOH high, a cutoff of ≥16% genomic LOH was prespecified for ARIEL3.
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62
ARIEL3: INVESTIGATOR-ASSESSED PROGRESSION-FREE SURVIVAL
BRCA mutant HRD ITT
Median(month
s) 95% CI
Rucapa
rib
(n=236)
13.6 10.9–
16.2
Placebo
(n=118)
5.4 5.1–5.6
HR, 0.32;
95% CI, 0.24–
0.42;
P<0.0001
Median(month
s) 95% CI
Rucapa
rib
(n=375)
10.8 8.3–
11.4
Placebo
(n=189)
5.4 5.3–5.5
HR, 0.36;
95% CI, 0.30–
0.45;
P<0.0001
At risk (events)
Rucaparib
130 (0)93 (23)63 (46)35 (58)15 (64) 3 (67) 0 (67)
Placebo 66 (0) 24 (37) 6 (53) 3 (55) 1 (56) 0 (56)
Rucaparib, 48% censored Placebo, 15% censored
At risk (events)
Rucaparib
236 (0)161
(55)
96
(104)
54
(122)
21
(129)5 (134)0 (134)
Placebo118 (0)40 (68)11 (95) 6 (98) 1 (101)0 (101)
Rucaparib, 43% censored Placebo, 14% censored
At risk (events)
Rucaparib
375 (0)228
(111)
128
(186)
65
(217)
26
(226)5 (234)0 (234)
Placebo189 (0)63
(114)
13
(160)7 (164)2 (167)1 (167)0 (167)
Rucaparib, 38% censored Placebo, 12% censored
Median(month
s) 95% CI
Rucapa
rib
(n=130)
16.6 13.4–
22.9
Placebo
(n=66)
5.4 3.4–6.7
HR, 0.23;
95% CI, 0.16–
0.34;
P<0.0001
Visit cutoff date: 15 April 2017.
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Ovarian cancer: conclusions
Treatment according to histotype is the future!
Antiangiogenic agents and parp inhibitors are changing the natual history of ovarian cancer disease.
Immunotherapy results actually deluding!!!!
The best treatment algorytm is that which allows patients to receive all the available and effective treatment options, possibly in the appropriate sequence.
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