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PARPi in Ovarian Cancer:
Turnaround in journey of
epithelial ovarian cancer
Chandan Das
Medical Oncology
PGIMER, Chandigarh
OVERVIEW
PARP & PARPi
Frontline Maintenance
PSR maintenance
PARPi in treatment
3
a mPFS values measured from beginning of chemotherapy (ie, day of randomization) to the first disease progression and, thereafter, from one progression to the subsequent
one or to death.
L, line; mPFS, median progression-free survival; PFS, progression-free survival.
Hanker LC, et al. Ann Oncol. 2012;23(10):2605-12.
mPFS
10.2 mo
(95% CI: 9.6–10.7)
mPFS
6.4 mo
(95% CI:
5.9–7.0)
mPFS
5.6 mo
(95% CI:
4.8–6.2)
mPFS
4.4 mo
(95% CI:
3.7–4.9)
mPFS
4.1 mo
(95% CI:
3.0–5.1)
mPFS
18.2 mo
(95% CI: 17.3–19.1)
5L 6L
4L
3L
2L
1L
Fourth
Recurrence
Fifth
Recurrence
Third
Recurrence
Second
Recurrence
First
Recurrence
Note: Data depict historical
mPFS of watch-and-wait,
and do not represent PFS
observed with
maintenance treatment.
The Unmet Need
~80%
Median PFS decreases after every recurrence:
How to prevent/Delay Relapse ?
 Pazopanib
 2 month PFS benefit
 Hypertension
 Bleeding
 Hypothyroidism
 Hepatotoxic
 Bevacizumab
 4 month PFS benefit
 Hypertension
 Bleed
 Perforation
 Proteinuria
 Ideal Maintenance
 Effective
 Safe
 Specific
gBRCA and sBRCA mutation in Ca Ovary
5
Approximately
40%
of patients with BRCAm OC may have no
relevant family history2,3
Approximately
20%
of OC patients a gBRCAm1,
while an additional
5-9%
may have a sBRCAm2
1. Alsop K, et al. J Clin Oncol 2012; 30:2654-63 2. Pal T, et al. Cancer 2005; 104:2807-16 3. Vergote I, et al. Eur J Cancer 2016; 69:127-34 4. Kwong A, et al. Asia-Pac J Clin Oncol, 2019; 1-12; 4. Susana Beatriz Goncalves, et al.
Journal of Clinical Oncology 2019 37:15_suppl, e17050-e17050
The use of family history, age and histology type alone for patient selection in BRCAm testing would miss a
significant proportion of cases.4 Offering gBRCA test may also miss significant sBRCAm population.
Approximately
29%
of OC patients
Harbour
tBRCAm
Targeting DNA repair Defect
PARP
PARPi
PARPi in frontline maintenance Ca Ovary
SOLO-1Olaparib in first line Ca Ovary Maintenance
SOLO1 5 year PFS
Olaparib
(N=260)
Placebo
(N=131)
118 (45) 100 (76)
56.0 13.8
42.2
HR 0.33 (95% CI 0.25–0.43)
Events, n(%)
Median PFS,months
Difference, months
Median treatmentduration:
Olaparib, 24.6months
Placebo†
, 13.9months
Patientsfreefromdisease
progressionanddeath(%)
Placebo
Olaparib
51%
88%
35%
74%
27%
60%
22%
52%
21%
48%
2-year
treatment cap*100
90
80
70
60
50
40
30
20
10
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Months sincerandomization
No. at risk
Olaparib 260 229 212 194 173 140 129 115 101 91 58 30 2 0
Placebo 131 103 65 53 41 38 30 24 23 22 16 3 0
SOLO 1
Subgroup
Analysis
n(%)
Olaparib
(n=260)
Placebo
(n=130)
AnyAE 256 (98) 120 (92)
Grade ≥3AE 103 (40) 25 (19)
Serious AE 55 (21) 17 (13)
AE leading to dose interruption 136 (52) 22 (17)
AE leading to dose reduction 75 (29) 4 (3)
AE leading to treatment discontinuation 30 (12) 4 (3)
MDS/AML 3 (1) 0 (0)
New primarymalignancy 7 (3) 5 (4)
No additional cases of MDS/AML reported;
incidence remained <1.5%
Follow-up for MDS/AML continued until death due to anycause
Overall Patients in CR at baseline
PFS2
Olaparib
(n=260)
Placebo
(n=131)
Olaparib
(n=189)
Placebo
(n=101)
Events, n(%) 80 (31) 61 (47) 49 (26) 45 (45)
Event free at 5years,
%
64 41 68 44
Median,months NR 42.1 NR 52.9
HR 0.46
(95% CI 0.33–0.65)
HR 0.48
(95% CI 0.32–0.71)
TSST
Events, n(%) 95 (37) 77 (59) 64 (34) 56 (55)
Event free at 5years,
%
62 36 65 39
Median,months NR 40.7 NR 47.7
HR 0.46
(95% CI 0.34–0.63)
HR 0.50
(95% CI 0.35–0.72)
SOLO1: Secondary efficacy outcomes
PAOLA 1 Trial
OLAPARIB
PAOLA 1:PFS
VELIA/GOG-3005Veliparib +Carboplatin/Paclitaxel
 Primary endpoint: PFS in Arm 1 vs Arm 3 with hierarchical testing in BRCA
mutation positive, HRD positive, and whole population
Patients with newly diagnosed
high-grade serous ovarian
cancer, FIGO Stage III or IV,
ECOG PS 0-2, and no CNS
metastases
(N = 1140)
Carboplatin + Paclitaxel +
Veliparib 150 mg BID
(n = 382)
Carboplatin + Paclitaxel +
Placebo
(n = 375)
Carboplatin + Paclitaxel +
Veliparib 150 mg BID
(n = 383)
Coleman. ESMO 2019. Abstr LBA3.
Veliparib 400 mg BID
Placebo
Placebo
Combination CT: Cycles 1-6 Maintenance: Cycles 7-36
Carboplatin AUC 6 Q3W + paclitaxel 80 mg/m2 QW or 175 mg/m2 Q3W.
Stratification by stage, region, type of
cytoreduction, residual disease, CT regimen,
gBRCA status*
*Germline BRCA mutation status added as stratification factor ~ 14 mos after trial initiation due to noted imbalance.
VELIA/GOG-3005: PFS for Patients With BRCA
Mutations
CT + Veliparib  Veliparib CT + Placebo  Placebo
Events, n/N (%) 34/108 (31.5) 51/92 (55.4)
Median PFS, mos (95%
CI) 34.7 (31.8-NR) 22.0 (17.8-29.1)
Slide credit: clinicaloptions.comColeman. ESMO 2019. Abstr LBA3. Reproduced with permission.
0
20
40
60
80
100
PFS(%)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
108
92
102
90
99
89
97
88
95
84
90
80
88
74
82
63
80
57
76
50
73
46
65
38
53
29
45
24
38
19
30
13
21
6
14
4
9
2
5
0
1 1 0
Veliparib
throughout
Control
HR: 0.44 (95% CI: 0.28-0.68; P < .001)
Mos From Randomization
Combination Maintenance
Patients at Risk, n
VELIA/GOG-3005: PFS for Patients With
HRD (Including BRCA Mutations)
CT + Veliparib  Veliparib CT + Placebo  Placebo
Events, n/N (%) 87/214 (40.7) 124/207 (59.9)
Median PFS, mos
(95% CI) 31.9 (25.8-38.0) 20.5 (17.8-22.8)
Coleman. ESMO 2019. Abstr LBA3. Reproduced with permission.
0
20
40
60
80
100
PFS(%)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
214
207
203
199
195
196
191
191
182
183
167
170
161
158
150
134
140
119
130
104
121
97
109
79
82
55
72
47
58
34
44
22
30
11
19
9
14
4
5
2
1
0
1 0
HR: 0.57 (95% CI: 0.43-0.76; P < .001)
Mos From Randomization
Combination Maintenance
Veliparib
throughout
Control
Patients at Risk, n
VELIA/GOG-3005: PFS in ITT Patient
Population (Regardless of HRD or BRCA
Mutation Status)
Slide credit: clinicaloptions.com
CT + Veliparib  Veliparib CT + Placebo  Placebo
Events, n/N (%) 191/382 (50.0) 237/375 (63.2)
Median PFS, mos (95%
CI) 23.5 (19.3-26.3) 17.3 (15.1-19.1)
Coleman. ESMO 2019. Abstr LBA3. Reproduced with permission.
0
20
40
60
80
100
PFS(%)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
382
375
352
356
337
340
329
328
308
297
275
260
253
236
228
202
208
172
192
153
172
143
153
119
111
84
95
70
76
55
55
36
38
21
26
16
19
10
7
3
2
0
1 0
HR: 0.68 (95% CI: 0.56-0.83; P < .001)
Mos From Randomization
Combination Maintenance
Veliparib
throughout
Control
Patients at Risk, n
Maintenance Niraparib After Initial
Therapy for Ovarian Cancer (PRIMA):
Phase III Study Design
 Double-blind, randomized, placebo-controlled phase III trial
 Primary endpoint: PFS by BICR
 Hierarchical testing in patients with HRD (HR benefit: 0.5) followed by the overall patient population
(HR benefit: 0.65)
 Key secondary endpoint: OS; other secondary endpoints: PFS2, TFST, patient-reported
outcomes, safety
Patients with newly diagnosed
advanced ovarian cancer with CR or PR
following first-line platinum-based CT;
high-grade serous or endometroid
pathology; stage III with residual
disease, stage IV, or inoperable
(N = 730)
Niraparib 200-300* mg QD
(n = 484)
Placebo
(n =244)
Stratification by 1L platinum CT,
CR/PR to 1L therapy, HRD status
Tx for 36 mos or
until PD
*Initiated treatment with 300 mg QD for patients ≥ 77
kg and with platelets ≥ 150,000/μL, 200 mg QD for
patients < 77 kg and/or with platelets < 150,000/μL.
González-Martin. ESMO 2019. Abstr LBA1.
PRIMA: PFS in HRD and Overall Patient
Populations (Primary Endpoint)
PFS in HRD Population PFS in Overall Patient Population
HR: 0.43 (95% CI: 0.31-0.59; P < .001)
Median PFS, Mos
21.9
10.4
Niraparib
Placebo
HR: 0.62 (95% CI: 0.50-0.76; P < .001)
Median PFS, Mos
13.8
8.2
Niraparib
Placebo
100
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Mos Since Randomization
PFS(%)
Pts at Risk, n
Niraparib
Placebo
247
126
231
117
215
99
189
79
184
70
168
57
111
34
76
21
66
21
42
11
22
5
19
5
13
4
4
1
0
0
*
** ** * ***
* *** ** ******** ** ******** ** ******* *****
* * **** * ***** * **
100
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Mos Since Randomization
PFS(%)
Pts at Risk, n
Niraparib
Placebo
487
246
454
226
385
177
312
133
295
117
253
90
167
60
111
32
94
29
58
17
29
6
21
6
13
4
4
1
0
0
*** ** **
**
**** **
******
****
*
**
**** *
*
*
***
* *** *
****
** **** ** ** ** ***** ** ******* * ***** * **
Frontline maintenance Options
PARPi in Second line maintenance Ca Ovary
Platinum sensitive relapse
Phase II Study 19 of Olaparib Maintenance in
Platinum-Sensitive Recurrent Ovarian Cancer
 Primary endpoint: PFS (RECIST 1.0)
 Secondary endpoints: OS, safety, tolerability
 Exploratory endpoints: time to first subsequent therapy or death, time to
second subsequent therapy or death
Patients with platinum-sensitive,
recurrent high-grade serous
ovarian cancer; ≥ 2 prior
platinum-based regimens with
CR/PR to most recent platinum-
based therapy; stable CA-125
(N = 265)
Treatment until
disease
progression
Olaparib
400 mg BID PO
(n = 136)
Placebo
BID PO
(n = 129)
Ledermann. NEJM. 2012;366:1382.
Study 19 :PFS
Ledermann. NEJM. 2012;366:1382.
HR: 0.35 (95% CI: 0.25-0.49; P < .001)
Treatment
Number of Patients
With Event (%)
Median PFS,
Mos
Olaparib 60 (44.1) 8.4
Placebo 93(72.1) 4.8
Olaparib
Placebo
Mos
150 3 6 9 12
1.0
0.8
0.6
0.4
0.2
0
ProbabilityofPFS
Patients at Risk, n
Olaparib
Placebo
136
129
104
72
51
23
23
7
6
1
0
0
Study 19:OS
Study 19:Exploratory endpoints in BRCAm
“
”
SOLO2: Final OS Analysis of
Maintenance Olaparib in Platinum-
Sensitive, Relapsed Ovarian Cancer
with BRCA Mutation
SOLO2 Trial design
Baseline characteristics
Characteristic
Olaparib
(n = 196)
Placebo
(n = 99)
Primary tumor location, %
 Ovary
 Fallopian tube/primary
peritoneal
 Other/Missing
83
16
2
87
13
0
Histology, %
 Serous
 Endometrioid
 Mixed/Missing
93
5
2
87
8
5
gBRCA mutation by Myriad testing,
%
 BRCA1
 BRCA2
67
30
62
35
ECOG PS 0/1, % 83/16 78/22
Characteristic
Olaparib
(n = 196)
Placebo
(n = 99)
Prior platinum response, %
 Complete
 Partial
46
54
47
53
# prior platinum regimens, %
 2
 3
 4
 ≥ 5
56
31
9
4
63
20
12
5
Platinum-free interval, %
 > 6-12 months
 > 12 months
40
60
40
60
Prior bevacizumab, % 17 20
> 2 cm target lesions at BL, % 15 18
SOLO2: Investigator-Assessed PFS
Pujade-Lauraine. Lancet Oncol. 2017;1274.
100
80
60
40
20
0
PFS(%)
Mos
Olaparib
Placebo
HR: 0.30 (95% CI: 0.22-0.41; P <
.0001)
Patients at Risk, n
Olaparib
Placebo
196
99
182
70
156
37
134
22
118
18
104
17
89
14
82
12
32
7
29
6
3
0
2
0
0
0
360 3 6 9 12 15 18 21 24 27 30 33
Olaparib for the maintenance treatment of PSR OC1-3
Phase III study3
Recurrent BRCAm ovarian cancer after two prior lines of
platinum therapy (n=295)
Maintenance in patients achieving a CR/PR on
platinum therapy
Olaparib tablets PO 300mg BID
Olaparib significantly prolonged PFS compared with placebo
(HR 0.30; 95% CI 0.22 to 0.41; p<0.0001)
Study 19
Phase II study1,2
Recurrent ovarian cancer after two or more prior lines of
platinum therapy (n=265)
Maintenance in patients achieving a CR/PR on
platinum therapy
Olaparib capsules PO 400mg BID
Olaparib significantly prolonged PFS compared with placebo
(HR 0.35; 95% CI 0.25 to 0.49; p<0.00001)
Trend towards benefit for overall survival (HR of 0.73; 95% CI
0.55 to 0.95; nominal p=0.025; statistical significance not reached)
Improvements in PFS and OS were also seen in the non-BRCAm
subgroup (HR 0.54 [95% CI 0.34 to 0.85], p=0·0075; and HR 0.83
[95% CI 0.55 to 1.24], nominal P=0.37; respectively)
BID=twice daily; BRCAm=BRCA1/2 mutation; CI=confidence interval; CR=complete response; HR=hazard ratio; non-BRCAm=no mutations in BRCA1/2; OC=ovarian cancer; OS=overall survival;
PFS=progression-free survival; PO=orally; PR=partial response; PSR=platinum-sensitive relapsed
1. Ledermann J, et al. N Engl J Med. 2012;366(15):1382–1392; 2. Ledermann J, et al. Lancet Oncol. 2016;17(11):1579–1589; 3. Pujade-Lauraine et al. Lancet Oncol. 2017;18(9):1274–1284
Final OS analysis
OS Adjusted for subsequent PARP inhibitor use
(in 38% placebo, 10% olaparib pts)
Olaparib
(n = 196)
Placebo
(n = 99)
Events, n (%) 116 (59) 65 (66)
Median OS, mos 51.7 38.8
HR (95% CI) 0.75 (0.54-1.00); P = .0537
Olaparib
(n = 196)
Placebo
(n = 99)
Events, n (%) 116 (59) 61 (62)
Median OS, mos 51.7 35.4
HR (95% CI) 0.56 (0.35-0.97)100
90
80
70
60
50
40
30
20
10
0
Overallsurvival(%)
Mos
780 6 12 18 24 30 36 42 48 54 60 66 72
No.at
risk
Olaparib
Placebo
196
99
192
99
187
93
172
79
145
66
130
57
120
50
105
42
98
38
86
33
77
31
39
16
7
0
0
0
42
%
33
%
Olaparib
Placebo
100
90
80
70
60
50
40
30
20
10
0
Overallsurvival(%)
Mos
780 6 12 18 24 30 36 42 48 54 60 66 72
No.at risk
Olaparib
Placebo
Placebo adjusted
196
99
99
192
99
99
187
93
92
172
79
75
145
66
60
130
57
50
120
50
46
105
42
34
98
38
0
86
33
0
77
31
0
39
16
0
7
0
0
0
0
0
Place
Placebo, adjusted
SOLO2: Time to Subsequent Therapy and
Duration of Treatment Exposure
Time to Subsequent Therapy
Olaparib
(n = 196)
Placebo
(n = 99)
Events, n (%) 139 (71) 86 (87)
Median TFST, mos 27.4 7.2
HR (95% CI) 0.37 (0.28-0.48); P < .0001
Duration of Treatment Exposure
100
90
80
70
60
50
40
30
20
10
0
Patientsevent-free(%)
Months since randomization
780 6 12 18 24 30 36 42 48 54 60 66 72
28
%
13
%
Olaparib
Placebo
Olaparib
(n = 195)
Placebo
(n = 99)
≥ 1
years
≥ 2
years
≥ 3
years
≥ 4
years
≥ 5
years
Patientsexposedtotreatment(%)
10
090
80
70
60
50
40
30
20
10
0
62
21
45
13
31
12
27
9
22
9
Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 6002-6002.
Final Safety Analysis
Safety outcome
Olaparib (n = 195) Placebo (n = 99)
Primary Final Primary Final
Mean total treatment duration, mos 17.4 29.1 9.0 13.1
Any TEAE, %
 Grade ≥ 3
 Serious
98
37
18
99
46
26
95
18
8
95
19
8
TEAE leading to:
 Dose interruption, %
 Dose reduction, %
 Discontinuation, %
45
25
11
50
28
17
18
3
2
19
3
3
MDS/AML, %
 During safety follow-up (TEAE)
2 8
4
4 4
0
Pneumonitis, % 2 2 0 0
MDS/AML Risk
SOLO2: Treatment-Emergent Adverse Events
Poveda. ASCO 2020. Abstr 6002. Reproduced with permission.
All grades
Grade ≥ 3
100 80 60 40 20 0 0 20 40 60 80 100
TEAEs (%)
Olaparib (N = 195)
29.1 months
Placebo (N = 99)
13.1 months
Mean total treatment duration
Nausea
Fatigue or asthenia
Anemia
Vomiting
Diarrhea
Abdominal pain
Headache
Constipation
Neutropenia
Decreased appetite
Cough
Dysgeusia
Dizziness
Back pain
Arthralgia
Thrombocytopenia
Hypomagnesemia
Dyspepsia
35
392
102
201
20
313
3
6
14
23
4
11
6
6
6
142
14
41
10
9
76 3
67 6
2146
40
28
34
3
1
3
126
23
24
24 7
1
19 1
19
17 1
16
16
216
115
15
SOLO 2 Conclusions
14m
PFS
improved
20m
TSST
improved
17m
OS
improved
“
”
Health-related Quality of Life and Patient-
Centred Outcomes With Olaparib Maintenance
After Chemotherapy in Patients With Platinum-
Sensitive, Relapsed Ovarian Cancer and a
BRCA1/2 Mutation (SOLO2/ENGOT Ov-21): A
Placebo-Controlled, Phase 3 Randomized Trial
MICHAEL FRIEDLANDER 1, VAL GEBSKI 2, EMMA GIBBS 2, LUCY DAVIES 3, RALPH BLOOMFIELD 4, FELIX HILPERT 5, LARI B WENZEL 6, DANIEL EEK 7, MANUEL
RODRIGUES 8, ANDREW CLAMP 9, RICHARD T PENSON 10, DIANE PROVENCHER 11, JACOB KORACH 12, TOMASZ HUZARSKI 13, LAURA VIDAL 14, VANDA
SALUTARI 15, CLARE SCOTT 16, MARIA ORNELLA NICOLETTO 17, KENJI TAMURA 18, DAVID ESPINOZA 2, FLORENCE JOLY 19, ERIC PUJADE-LAURAINE
Trial Outcome Index Score
SOLO2: Quality-Adjusted PFS
Olaparib
(n = 185)
Placebo
(n = 94)
Difference
(95% CI)
P Value
Mean PFS, mos 17.55 8.94 8.61
(6.47 to 10.87)
< .0001
Mean utility (mixed model) 0.80 0.81 -0.02
(-0.05 to 0.02)
.284
QAPFS, mos 13.96 7.28 6.68
(4.98 to 8.54)
< .0001
SOLO2: Time Without Symptoms of Disease or Toxicity
• TWiST duration
significantly
longer with
olaparib vs
placebo
Duration, Mos Olapari
b
(n =
185)
Placeb
o
(n = 94)
Differen
ce
(95% CI)
P Value
TWiST 13.5 7.21 6.29
(2.95-
8.58)
< .0001
Toxicity 3.69 0.71 2.98
(1.52-
4.68)
.0002
NOVA : Niraparib in PSR Ovary
March 30 - April 2, 2014
Sheraton Sonoma County
Petaluma, California
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%
Mirza MR et al. N Engl J Med 2016; Presidential Symposium, ESMO 2016
ENGOT-OV16 / NOVA:PFS:gBRCA+
BRCAwt
Treatment
PFS
Median
(95% CI)
(Months)
Hazard
Ratio
(95% CI)
p-value
% of Patients
without
Progression
or Death
12 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
PFS
Median
(95% CI)
(Months)
Hazard
Ratio
(95% CI)
p-value
% of Patients
without
Progression
or Death
12 mo 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
Treatment
PFS
Median
(95% CI)
(Months)
Hazard
Ratio
(95% CI)
p-value
% of Patients
without
Progression or
Death
12 mo 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 HRD-negative
Mirza MR et al. N Engl J Med 2016; Presidential Symposium, ESMO 2016
ENGOT-OV16 / NOVA:PFS in Non-Germline BRCA mutant
*CR (defined by RECIST v1.1) or PR (defined by RECIST v1.1 and/or a GCIG CA-125 response [CA-125 within normal range]) maintained until entry to ARIEL3 (≤8 weeks of last dose of
chemotherapy). †ATM, ATR, ATRX, BARD1, BLM, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, RAD50,
RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RPA1.
ARIEL3: Rucaparib in Relapsed Ca Ovary
• HRR status by NGS mutation analysis
 BRCA1 or BRCA2
 Non-BRCA HRR gene†
 None of the above
• Response to recent platinum
 CR
 PR
• Progression-free interval after
penultimate platinum
 6 to <12 months
 ≥12 months
Patient eligibility Stratification
• High-grade serous or endometrioid
epithelial OC, primary peritoneal, or
fallopian tube cancers
• Sensitive to penultimate platinum
• Responding to most recent platinum
(CR or PR)*
 Excludes patients without assessable
disease following second surgery
• CA-125 within normal range
• No restriction on size of residual tumour
• ECOG PS ≤1
• No prior PARP inhibitors
Placebo
BID
n=189
Rucaparib
600 mg BID
n=375
Randomisation2:1
5
0
ARIEL 3: PFS
Selecting the Best PARPi Maintenance
PARPi in treatment
Study 42: Olaparib Monotherapy
SOLO 3 : Olaparib vs non platinum therapy in PSR
Ovary
SOLO 3: Efficacy
SOLO 3: PFS ITT Polulation
Study 10 /2a: Rucaparib Mono therapy
QUADRA: Niraparib for HRD+Ca Ovary
Future of PARPi
Future of PARPi
OReO Study: Olaparib Retreatment in
Platinum-Sensitive Ovarian Cancer
MEDIOLA
Turnaround time for Ca Ovary with PARPi
PFS TSST OS QOL
Acceptable
AE
Holy Grails of Ovarian Cancer
Complete
Cytoreductive
Surgery
Platinum
Sensitivity
PARP
Inhibition
PARP inhibitor in Ca Ovary

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PARP inhibitor in Ca Ovary

  • 1. PARPi in Ovarian Cancer: Turnaround in journey of epithelial ovarian cancer Chandan Das Medical Oncology PGIMER, Chandigarh
  • 2. OVERVIEW PARP & PARPi Frontline Maintenance PSR maintenance PARPi in treatment
  • 3. 3 a mPFS values measured from beginning of chemotherapy (ie, day of randomization) to the first disease progression and, thereafter, from one progression to the subsequent one or to death. L, line; mPFS, median progression-free survival; PFS, progression-free survival. Hanker LC, et al. Ann Oncol. 2012;23(10):2605-12. mPFS 10.2 mo (95% CI: 9.6–10.7) mPFS 6.4 mo (95% CI: 5.9–7.0) mPFS 5.6 mo (95% CI: 4.8–6.2) mPFS 4.4 mo (95% CI: 3.7–4.9) mPFS 4.1 mo (95% CI: 3.0–5.1) mPFS 18.2 mo (95% CI: 17.3–19.1) 5L 6L 4L 3L 2L 1L Fourth Recurrence Fifth Recurrence Third Recurrence Second Recurrence First Recurrence Note: Data depict historical mPFS of watch-and-wait, and do not represent PFS observed with maintenance treatment. The Unmet Need ~80% Median PFS decreases after every recurrence:
  • 4. How to prevent/Delay Relapse ?  Pazopanib  2 month PFS benefit  Hypertension  Bleeding  Hypothyroidism  Hepatotoxic  Bevacizumab  4 month PFS benefit  Hypertension  Bleed  Perforation  Proteinuria  Ideal Maintenance  Effective  Safe  Specific
  • 5. gBRCA and sBRCA mutation in Ca Ovary 5 Approximately 40% of patients with BRCAm OC may have no relevant family history2,3 Approximately 20% of OC patients a gBRCAm1, while an additional 5-9% may have a sBRCAm2 1. Alsop K, et al. J Clin Oncol 2012; 30:2654-63 2. Pal T, et al. Cancer 2005; 104:2807-16 3. Vergote I, et al. Eur J Cancer 2016; 69:127-34 4. Kwong A, et al. Asia-Pac J Clin Oncol, 2019; 1-12; 4. Susana Beatriz Goncalves, et al. Journal of Clinical Oncology 2019 37:15_suppl, e17050-e17050 The use of family history, age and histology type alone for patient selection in BRCAm testing would miss a significant proportion of cases.4 Offering gBRCA test may also miss significant sBRCAm population. Approximately 29% of OC patients Harbour tBRCAm
  • 9. PARPi in frontline maintenance Ca Ovary
  • 10. SOLO-1Olaparib in first line Ca Ovary Maintenance
  • 11. SOLO1 5 year PFS Olaparib (N=260) Placebo (N=131) 118 (45) 100 (76) 56.0 13.8 42.2 HR 0.33 (95% CI 0.25–0.43) Events, n(%) Median PFS,months Difference, months Median treatmentduration: Olaparib, 24.6months Placebo† , 13.9months Patientsfreefromdisease progressionanddeath(%) Placebo Olaparib 51% 88% 35% 74% 27% 60% 22% 52% 21% 48% 2-year treatment cap*100 90 80 70 60 50 40 30 20 10 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Months sincerandomization No. at risk Olaparib 260 229 212 194 173 140 129 115 101 91 58 30 2 0 Placebo 131 103 65 53 41 38 30 24 23 22 16 3 0
  • 13. n(%) Olaparib (n=260) Placebo (n=130) AnyAE 256 (98) 120 (92) Grade ≥3AE 103 (40) 25 (19) Serious AE 55 (21) 17 (13) AE leading to dose interruption 136 (52) 22 (17) AE leading to dose reduction 75 (29) 4 (3) AE leading to treatment discontinuation 30 (12) 4 (3) MDS/AML 3 (1) 0 (0) New primarymalignancy 7 (3) 5 (4) No additional cases of MDS/AML reported; incidence remained <1.5% Follow-up for MDS/AML continued until death due to anycause Overall Patients in CR at baseline PFS2 Olaparib (n=260) Placebo (n=131) Olaparib (n=189) Placebo (n=101) Events, n(%) 80 (31) 61 (47) 49 (26) 45 (45) Event free at 5years, % 64 41 68 44 Median,months NR 42.1 NR 52.9 HR 0.46 (95% CI 0.33–0.65) HR 0.48 (95% CI 0.32–0.71) TSST Events, n(%) 95 (37) 77 (59) 64 (34) 56 (55) Event free at 5years, % 62 36 65 39 Median,months NR 40.7 NR 47.7 HR 0.46 (95% CI 0.34–0.63) HR 0.50 (95% CI 0.35–0.72) SOLO1: Secondary efficacy outcomes
  • 16. VELIA/GOG-3005Veliparib +Carboplatin/Paclitaxel  Primary endpoint: PFS in Arm 1 vs Arm 3 with hierarchical testing in BRCA mutation positive, HRD positive, and whole population Patients with newly diagnosed high-grade serous ovarian cancer, FIGO Stage III or IV, ECOG PS 0-2, and no CNS metastases (N = 1140) Carboplatin + Paclitaxel + Veliparib 150 mg BID (n = 382) Carboplatin + Paclitaxel + Placebo (n = 375) Carboplatin + Paclitaxel + Veliparib 150 mg BID (n = 383) Coleman. ESMO 2019. Abstr LBA3. Veliparib 400 mg BID Placebo Placebo Combination CT: Cycles 1-6 Maintenance: Cycles 7-36 Carboplatin AUC 6 Q3W + paclitaxel 80 mg/m2 QW or 175 mg/m2 Q3W. Stratification by stage, region, type of cytoreduction, residual disease, CT regimen, gBRCA status* *Germline BRCA mutation status added as stratification factor ~ 14 mos after trial initiation due to noted imbalance.
  • 17. VELIA/GOG-3005: PFS for Patients With BRCA Mutations CT + Veliparib  Veliparib CT + Placebo  Placebo Events, n/N (%) 34/108 (31.5) 51/92 (55.4) Median PFS, mos (95% CI) 34.7 (31.8-NR) 22.0 (17.8-29.1) Slide credit: clinicaloptions.comColeman. ESMO 2019. Abstr LBA3. Reproduced with permission. 0 20 40 60 80 100 PFS(%) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 108 92 102 90 99 89 97 88 95 84 90 80 88 74 82 63 80 57 76 50 73 46 65 38 53 29 45 24 38 19 30 13 21 6 14 4 9 2 5 0 1 1 0 Veliparib throughout Control HR: 0.44 (95% CI: 0.28-0.68; P < .001) Mos From Randomization Combination Maintenance Patients at Risk, n
  • 18. VELIA/GOG-3005: PFS for Patients With HRD (Including BRCA Mutations) CT + Veliparib  Veliparib CT + Placebo  Placebo Events, n/N (%) 87/214 (40.7) 124/207 (59.9) Median PFS, mos (95% CI) 31.9 (25.8-38.0) 20.5 (17.8-22.8) Coleman. ESMO 2019. Abstr LBA3. Reproduced with permission. 0 20 40 60 80 100 PFS(%) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 214 207 203 199 195 196 191 191 182 183 167 170 161 158 150 134 140 119 130 104 121 97 109 79 82 55 72 47 58 34 44 22 30 11 19 9 14 4 5 2 1 0 1 0 HR: 0.57 (95% CI: 0.43-0.76; P < .001) Mos From Randomization Combination Maintenance Veliparib throughout Control Patients at Risk, n
  • 19. VELIA/GOG-3005: PFS in ITT Patient Population (Regardless of HRD or BRCA Mutation Status) Slide credit: clinicaloptions.com CT + Veliparib  Veliparib CT + Placebo  Placebo Events, n/N (%) 191/382 (50.0) 237/375 (63.2) Median PFS, mos (95% CI) 23.5 (19.3-26.3) 17.3 (15.1-19.1) Coleman. ESMO 2019. Abstr LBA3. Reproduced with permission. 0 20 40 60 80 100 PFS(%) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 382 375 352 356 337 340 329 328 308 297 275 260 253 236 228 202 208 172 192 153 172 143 153 119 111 84 95 70 76 55 55 36 38 21 26 16 19 10 7 3 2 0 1 0 HR: 0.68 (95% CI: 0.56-0.83; P < .001) Mos From Randomization Combination Maintenance Veliparib throughout Control Patients at Risk, n
  • 20. Maintenance Niraparib After Initial Therapy for Ovarian Cancer (PRIMA): Phase III Study Design  Double-blind, randomized, placebo-controlled phase III trial  Primary endpoint: PFS by BICR  Hierarchical testing in patients with HRD (HR benefit: 0.5) followed by the overall patient population (HR benefit: 0.65)  Key secondary endpoint: OS; other secondary endpoints: PFS2, TFST, patient-reported outcomes, safety Patients with newly diagnosed advanced ovarian cancer with CR or PR following first-line platinum-based CT; high-grade serous or endometroid pathology; stage III with residual disease, stage IV, or inoperable (N = 730) Niraparib 200-300* mg QD (n = 484) Placebo (n =244) Stratification by 1L platinum CT, CR/PR to 1L therapy, HRD status Tx for 36 mos or until PD *Initiated treatment with 300 mg QD for patients ≥ 77 kg and with platelets ≥ 150,000/μL, 200 mg QD for patients < 77 kg and/or with platelets < 150,000/μL. González-Martin. ESMO 2019. Abstr LBA1.
  • 21. PRIMA: PFS in HRD and Overall Patient Populations (Primary Endpoint) PFS in HRD Population PFS in Overall Patient Population HR: 0.43 (95% CI: 0.31-0.59; P < .001) Median PFS, Mos 21.9 10.4 Niraparib Placebo HR: 0.62 (95% CI: 0.50-0.76; P < .001) Median PFS, Mos 13.8 8.2 Niraparib Placebo 100 80 60 40 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Mos Since Randomization PFS(%) Pts at Risk, n Niraparib Placebo 247 126 231 117 215 99 189 79 184 70 168 57 111 34 76 21 66 21 42 11 22 5 19 5 13 4 4 1 0 0 * ** ** * *** * *** ** ******** ** ******** ** ******* ***** * * **** * ***** * ** 100 80 60 40 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Mos Since Randomization PFS(%) Pts at Risk, n Niraparib Placebo 487 246 454 226 385 177 312 133 295 117 253 90 167 60 111 32 94 29 58 17 29 6 21 6 13 4 4 1 0 0 *** ** ** ** **** ** ****** **** * ** **** * * * *** * *** * **** ** **** ** ** ** ***** ** ******* * ***** * **
  • 23. PARPi in Second line maintenance Ca Ovary
  • 25. Phase II Study 19 of Olaparib Maintenance in Platinum-Sensitive Recurrent Ovarian Cancer  Primary endpoint: PFS (RECIST 1.0)  Secondary endpoints: OS, safety, tolerability  Exploratory endpoints: time to first subsequent therapy or death, time to second subsequent therapy or death Patients with platinum-sensitive, recurrent high-grade serous ovarian cancer; ≥ 2 prior platinum-based regimens with CR/PR to most recent platinum- based therapy; stable CA-125 (N = 265) Treatment until disease progression Olaparib 400 mg BID PO (n = 136) Placebo BID PO (n = 129) Ledermann. NEJM. 2012;366:1382.
  • 26. Study 19 :PFS Ledermann. NEJM. 2012;366:1382. HR: 0.35 (95% CI: 0.25-0.49; P < .001) Treatment Number of Patients With Event (%) Median PFS, Mos Olaparib 60 (44.1) 8.4 Placebo 93(72.1) 4.8 Olaparib Placebo Mos 150 3 6 9 12 1.0 0.8 0.6 0.4 0.2 0 ProbabilityofPFS Patients at Risk, n Olaparib Placebo 136 129 104 72 51 23 23 7 6 1 0 0
  • 29. “ ” SOLO2: Final OS Analysis of Maintenance Olaparib in Platinum- Sensitive, Relapsed Ovarian Cancer with BRCA Mutation
  • 31. Baseline characteristics Characteristic Olaparib (n = 196) Placebo (n = 99) Primary tumor location, %  Ovary  Fallopian tube/primary peritoneal  Other/Missing 83 16 2 87 13 0 Histology, %  Serous  Endometrioid  Mixed/Missing 93 5 2 87 8 5 gBRCA mutation by Myriad testing, %  BRCA1  BRCA2 67 30 62 35 ECOG PS 0/1, % 83/16 78/22 Characteristic Olaparib (n = 196) Placebo (n = 99) Prior platinum response, %  Complete  Partial 46 54 47 53 # prior platinum regimens, %  2  3  4  ≥ 5 56 31 9 4 63 20 12 5 Platinum-free interval, %  > 6-12 months  > 12 months 40 60 40 60 Prior bevacizumab, % 17 20 > 2 cm target lesions at BL, % 15 18
  • 32. SOLO2: Investigator-Assessed PFS Pujade-Lauraine. Lancet Oncol. 2017;1274. 100 80 60 40 20 0 PFS(%) Mos Olaparib Placebo HR: 0.30 (95% CI: 0.22-0.41; P < .0001) Patients at Risk, n Olaparib Placebo 196 99 182 70 156 37 134 22 118 18 104 17 89 14 82 12 32 7 29 6 3 0 2 0 0 0 360 3 6 9 12 15 18 21 24 27 30 33
  • 33. Olaparib for the maintenance treatment of PSR OC1-3 Phase III study3 Recurrent BRCAm ovarian cancer after two prior lines of platinum therapy (n=295) Maintenance in patients achieving a CR/PR on platinum therapy Olaparib tablets PO 300mg BID Olaparib significantly prolonged PFS compared with placebo (HR 0.30; 95% CI 0.22 to 0.41; p<0.0001) Study 19 Phase II study1,2 Recurrent ovarian cancer after two or more prior lines of platinum therapy (n=265) Maintenance in patients achieving a CR/PR on platinum therapy Olaparib capsules PO 400mg BID Olaparib significantly prolonged PFS compared with placebo (HR 0.35; 95% CI 0.25 to 0.49; p<0.00001) Trend towards benefit for overall survival (HR of 0.73; 95% CI 0.55 to 0.95; nominal p=0.025; statistical significance not reached) Improvements in PFS and OS were also seen in the non-BRCAm subgroup (HR 0.54 [95% CI 0.34 to 0.85], p=0·0075; and HR 0.83 [95% CI 0.55 to 1.24], nominal P=0.37; respectively) BID=twice daily; BRCAm=BRCA1/2 mutation; CI=confidence interval; CR=complete response; HR=hazard ratio; non-BRCAm=no mutations in BRCA1/2; OC=ovarian cancer; OS=overall survival; PFS=progression-free survival; PO=orally; PR=partial response; PSR=platinum-sensitive relapsed 1. Ledermann J, et al. N Engl J Med. 2012;366(15):1382–1392; 2. Ledermann J, et al. Lancet Oncol. 2016;17(11):1579–1589; 3. Pujade-Lauraine et al. Lancet Oncol. 2017;18(9):1274–1284
  • 34. Final OS analysis OS Adjusted for subsequent PARP inhibitor use (in 38% placebo, 10% olaparib pts) Olaparib (n = 196) Placebo (n = 99) Events, n (%) 116 (59) 65 (66) Median OS, mos 51.7 38.8 HR (95% CI) 0.75 (0.54-1.00); P = .0537 Olaparib (n = 196) Placebo (n = 99) Events, n (%) 116 (59) 61 (62) Median OS, mos 51.7 35.4 HR (95% CI) 0.56 (0.35-0.97)100 90 80 70 60 50 40 30 20 10 0 Overallsurvival(%) Mos 780 6 12 18 24 30 36 42 48 54 60 66 72 No.at risk Olaparib Placebo 196 99 192 99 187 93 172 79 145 66 130 57 120 50 105 42 98 38 86 33 77 31 39 16 7 0 0 0 42 % 33 % Olaparib Placebo 100 90 80 70 60 50 40 30 20 10 0 Overallsurvival(%) Mos 780 6 12 18 24 30 36 42 48 54 60 66 72 No.at risk Olaparib Placebo Placebo adjusted 196 99 99 192 99 99 187 93 92 172 79 75 145 66 60 130 57 50 120 50 46 105 42 34 98 38 0 86 33 0 77 31 0 39 16 0 7 0 0 0 0 0 Place Placebo, adjusted
  • 35. SOLO2: Time to Subsequent Therapy and Duration of Treatment Exposure Time to Subsequent Therapy Olaparib (n = 196) Placebo (n = 99) Events, n (%) 139 (71) 86 (87) Median TFST, mos 27.4 7.2 HR (95% CI) 0.37 (0.28-0.48); P < .0001 Duration of Treatment Exposure 100 90 80 70 60 50 40 30 20 10 0 Patientsevent-free(%) Months since randomization 780 6 12 18 24 30 36 42 48 54 60 66 72 28 % 13 % Olaparib Placebo Olaparib (n = 195) Placebo (n = 99) ≥ 1 years ≥ 2 years ≥ 3 years ≥ 4 years ≥ 5 years Patientsexposedtotreatment(%) 10 090 80 70 60 50 40 30 20 10 0 62 21 45 13 31 12 27 9 22 9 Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 6002-6002.
  • 36. Final Safety Analysis Safety outcome Olaparib (n = 195) Placebo (n = 99) Primary Final Primary Final Mean total treatment duration, mos 17.4 29.1 9.0 13.1 Any TEAE, %  Grade ≥ 3  Serious 98 37 18 99 46 26 95 18 8 95 19 8 TEAE leading to:  Dose interruption, %  Dose reduction, %  Discontinuation, % 45 25 11 50 28 17 18 3 2 19 3 3 MDS/AML, %  During safety follow-up (TEAE) 2 8 4 4 4 0 Pneumonitis, % 2 2 0 0
  • 38. SOLO2: Treatment-Emergent Adverse Events Poveda. ASCO 2020. Abstr 6002. Reproduced with permission. All grades Grade ≥ 3 100 80 60 40 20 0 0 20 40 60 80 100 TEAEs (%) Olaparib (N = 195) 29.1 months Placebo (N = 99) 13.1 months Mean total treatment duration Nausea Fatigue or asthenia Anemia Vomiting Diarrhea Abdominal pain Headache Constipation Neutropenia Decreased appetite Cough Dysgeusia Dizziness Back pain Arthralgia Thrombocytopenia Hypomagnesemia Dyspepsia 35 392 102 201 20 313 3 6 14 23 4 11 6 6 6 142 14 41 10 9 76 3 67 6 2146 40 28 34 3 1 3 126 23 24 24 7 1 19 1 19 17 1 16 16 216 115 15
  • 40. “ ” Health-related Quality of Life and Patient- Centred Outcomes With Olaparib Maintenance After Chemotherapy in Patients With Platinum- Sensitive, Relapsed Ovarian Cancer and a BRCA1/2 Mutation (SOLO2/ENGOT Ov-21): A Placebo-Controlled, Phase 3 Randomized Trial MICHAEL FRIEDLANDER 1, VAL GEBSKI 2, EMMA GIBBS 2, LUCY DAVIES 3, RALPH BLOOMFIELD 4, FELIX HILPERT 5, LARI B WENZEL 6, DANIEL EEK 7, MANUEL RODRIGUES 8, ANDREW CLAMP 9, RICHARD T PENSON 10, DIANE PROVENCHER 11, JACOB KORACH 12, TOMASZ HUZARSKI 13, LAURA VIDAL 14, VANDA SALUTARI 15, CLARE SCOTT 16, MARIA ORNELLA NICOLETTO 17, KENJI TAMURA 18, DAVID ESPINOZA 2, FLORENCE JOLY 19, ERIC PUJADE-LAURAINE
  • 42. SOLO2: Quality-Adjusted PFS Olaparib (n = 185) Placebo (n = 94) Difference (95% CI) P Value Mean PFS, mos 17.55 8.94 8.61 (6.47 to 10.87) < .0001 Mean utility (mixed model) 0.80 0.81 -0.02 (-0.05 to 0.02) .284 QAPFS, mos 13.96 7.28 6.68 (4.98 to 8.54) < .0001
  • 43. SOLO2: Time Without Symptoms of Disease or Toxicity • TWiST duration significantly longer with olaparib vs placebo Duration, Mos Olapari b (n = 185) Placeb o (n = 94) Differen ce (95% CI) P Value TWiST 13.5 7.21 6.29 (2.95- 8.58) < .0001 Toxicity 3.69 0.71 2.98 (1.52- 4.68) .0002
  • 44. NOVA : Niraparib in PSR Ovary
  • 45. March 30 - April 2, 2014 Sheraton Sonoma County Petaluma, California 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% Mirza MR et al. N Engl J Med 2016; Presidential Symposium, ESMO 2016 ENGOT-OV16 / NOVA:PFS:gBRCA+
  • 46. BRCAwt Treatment PFS Median (95% CI) (Months) Hazard Ratio (95% CI) p-value % of Patients without Progression or Death 12 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 PFS Median (95% CI) (Months) Hazard Ratio (95% CI) p-value % of Patients without Progression or Death 12 mo 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 Treatment PFS Median (95% CI) (Months) Hazard Ratio (95% CI) p-value % of Patients without Progression or Death 12 mo 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 HRD-negative Mirza MR et al. N Engl J Med 2016; Presidential Symposium, ESMO 2016 ENGOT-OV16 / NOVA:PFS in Non-Germline BRCA mutant
  • 47. *CR (defined by RECIST v1.1) or PR (defined by RECIST v1.1 and/or a GCIG CA-125 response [CA-125 within normal range]) maintained until entry to ARIEL3 (≤8 weeks of last dose of chemotherapy). †ATM, ATR, ATRX, BARD1, BLM, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RPA1. ARIEL3: Rucaparib in Relapsed Ca Ovary • HRR status by NGS mutation analysis  BRCA1 or BRCA2  Non-BRCA HRR gene†  None of the above • Response to recent platinum  CR  PR • Progression-free interval after penultimate platinum  6 to <12 months  ≥12 months Patient eligibility Stratification • High-grade serous or endometrioid epithelial OC, primary peritoneal, or fallopian tube cancers • Sensitive to penultimate platinum • Responding to most recent platinum (CR or PR)*  Excludes patients without assessable disease following second surgery • CA-125 within normal range • No restriction on size of residual tumour • ECOG PS ≤1 • No prior PARP inhibitors Placebo BID n=189 Rucaparib 600 mg BID n=375 Randomisation2:1 5 0
  • 49. Selecting the Best PARPi Maintenance
  • 51. Study 42: Olaparib Monotherapy
  • 52. SOLO 3 : Olaparib vs non platinum therapy in PSR Ovary
  • 54. SOLO 3: PFS ITT Polulation
  • 55. Study 10 /2a: Rucaparib Mono therapy
  • 56. QUADRA: Niraparib for HRD+Ca Ovary
  • 59. OReO Study: Olaparib Retreatment in Platinum-Sensitive Ovarian Cancer
  • 61. Turnaround time for Ca Ovary with PARPi PFS TSST OS QOL Acceptable AE
  • 62. Holy Grails of Ovarian Cancer Complete Cytoreductive Surgery Platinum Sensitivity PARP Inhibition