Maintenance Therapy for Ovarian Cancer –
Do the Benefits Outweigh the Risks?
Bradley J. Monk, MD, FACS, FACOG
Professor and Director
Division of Gynecologic Oncology
Department of Obstetrics and Gynecology
Creighton University School of Medicine at
St. Joseph’s Hospital and Medical Center,
a Dignity Health Member
University of Arizona Cancer Center-Phoenix Arizona USA
bradley.monk@chw.edu
Newly Diagnosed Advanced Ovarian Cancer
Maintenance: The Stakes are High!
Progression
Diagnosis
Symptoms
Evaluation
? SLL
Chemotherapy #1
Maintenance
Secondary
Surgery
Chemo #2 Chemo #3+
What we know…
Supportive
Staging
Care
•Rate of response is high (CR + PR) >75%
•Second assessment operations find disease > 40% of
CR’s
•Clinical CR’s have >50% recurrence risk at 2 years
•Pathological CR’s have >40% risk at 2 years
•Option applies to CR’s and documented PR’s
Maintenance Strategies in
Epithelial Ovarian Cancer
• Anti-angiogenesis
• Chemotherapy
• Clinical trial – PARP inhibitor
4th Ovarian Cancer Consensus Conference
25 – 27 June 2010
UBC Life Sciences Institute, Vancouver, British Columbia
B-2 What Are the Promising Targets for Future
Therapeutic Approaches?
• The most promising targets in clinical trials are angiogenesis
and homologous recombination deficiency.
Int J Gynecol Cancer 2011: 21; 756-762
Maintenance Strategies in
Epithelial Ovarian Cancer
• Anti-angiogenesis
• Chemotherapy
• Clinical trial – PARP inhibitor
GOG#218
ICON-7
GOG-0218: Schema
Arm
Carboplatin (C) AUC 6
Front-line:
Epithelial OV, PP
or FT cancer
• Stage III optimal
(macroscopic)
• Stage III
suboptimal
• Stage IV
n=1800 (planned)
Paclitaxel (P) 175 mg/m2
R
A
N
D
O
M
I
Z
E
I
Placebo
Carboplatin (C) AUC 6
1:1:1
Paclitaxel (P) 175 mg/m2
BEV 15 mg/kg
II
Placebo
Carboplatin (C) AUC 6
Stratification variables:
• GOG performance status
(PS)
• Stage/debulking status
Paclitaxel (P) 175 mg/m2
III
BEV 15 mg/kg
Cytotoxic
(6 cycles)
Maintenance
(16 cycles)
15 months
GOG-0218
CA-125 To Determine Progression
Protocol-defined
PFS analysis
CA-125-censored
PFS analysis
CP (Arm I)
10.3 months
12.0 months
CP + BEV  BEV (Arm III)
14.1 months
18.0 months
3.8 months
6.0 months
0.717
0.645
CP (Arm I)
0
20
CP + BEV  BEV (Arm III)
0
29
Median PFS
Absolute diff. median PFS
Hazard ratio
Censored for CA125, %
GOG-0218
Ad Hoc Survival Analysis in Stage IV
Proportion Surviving
1.0
CPP (n=153)
CPB (n=165)
CPB+B (n=165))
0.8
0.6
0.4
Median OS
(months)
0.2
CPP
CPB
CPB+B
32.8
32.9
40.6
HR 0.72, 95% confidence interval 0.53-0.97
0.0
0
12
24
36
48
60
72
Overall Survival (months)
NEJM Data cut-off date August 26, 2011
(ASCO 2010 cut-off date February 5, 2010)
Randall LM et al SGO 2013
11
ICON7: a phase III Gynaecologic Cancer
InterGroup (GCIG) trial of adding bevacizumab
to standard chemotherapy in women with newly
diagnosed epithelial ovarian, primary peritoneal
or fallopian tube cancer
Tim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan
Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey,
Philip Beale, Andreas Cervantes, Amit Oza
on behalf of GCIG ICON7 collaborators
(MRC/NCRI, AGO-OVAR, GINECO, NSGO, ANZGOG,
GEICO, NCIC-CTG)
ESMO
2010 N Engl J Med. 2011 Dec 29;365(26):2484-96.
ICON7: Study Design
Carboplatin AUC 6*
Front-line EOC,
PP or FT cancer
Paclitaxel 175 mg/m2
• Stage I-IIA (Gr 3
or CC)
• Stage IIB/C
• Stage III
• Stage IV
Carboplatin AUC 6*
n=1528
Primary endpoints:
PFS
Secondary
endpoints: OS, RR,
safety, QOL,
cost-effectiveness,
translational
No IRC present
Paclitaxel 175 mg/m2
Stratification variables:
• Stage/surgery
• Time since surgery
• GCIG group
**
Bevacizumab
7.5 mg/kg
AVASTIN
12 months
*Might vary based on GCIG group
**Omit cycle 1 bevacizumab if <4 weeks from surgery
Perren, et al. ESMO 2010
ICON 7 PFS Benefit: Academic Analysis
CP
CPB7.5+
392 (51)
367 (48)
17.3
19.0
Proportion alive without progression
1.00
Events, n (%)
Median, months
0.75
Log-rank test
p=0.0041
HR (95% CI)
0.81 (0.70–0.94)
0.50
0.25
CP
CPB7.5+
17.3
19.0
0
0
3
6
9
12
15
18
21
24
27
30
216
263
143
144
91
50
25
73
36
19
Perren, et al. ESMO 2010
Time (months)
Number at risk
CP
764
CPB7.5+
764
723
748
693
715
556
647
464
585
307
399
ICON 7
Summary of Updated Results
Parameter
PFS
Protocol-Defined
Analysis
HR = 0.87, P = .039
CP
17.4 months
CP + BEVBEV
19.8 months
OS
Bulk Disease
Analysis
HR = 0.84, P = .099
HR = 0.64, P = .002
CP
28.8 months
CP + BEVBEV
36.6 months
Kristensen G, et al. J Clin Oncol.2011;29: (suppl; abstr LBA5006)
AGO-OVAR 16
• Phase III randomized, placebo-controlled, double-blind, multicenter
• N=940 patients randomized (1:1) from June 2009 to August 2010
• Pazopanib administered at 800 mg daily for up to 24 months*
First-line
surgery and
chemotherapy
(allowed: dosedense, IP,
neoadjuvant)
If not PD
+ tumor
< 2 cm
R
A
N
D
O
M
I
Z
E
Pazopanib
24 months
Placebo
24 months
Observation
(to PD)
Survival
follow-up
(post-PD)
Median 7 months from
ICF
diagnosis to randomization
*Original design was for 12 months and later amended to 24 months
Du Bois A et al J Clin Oncol 31, 2013 (suppl; abstr LBA5503)
AGO-OVAR 16
Primary Endpoint: Progression-free Survival (RECIST)
Median time from
1
Diagnosis: 7 months
Pazopanib: 472 pts. / 237 events
median 17.9 (15.9 - 21.8) mos
Placebo: 468 pts. / 273 events
median 12.3 (11.8 - 17.7) mos
Δ= 5.6 months
0.5
HR = 0.766 (95% CI: 0.643-0.911)
Stratified log-rank test: P = 0.0021
0
0
Patients
at risk
472
468
6
332
318
12
18
234
208
171
164
24
91
88
30
19
20
36(months)
1
Du Bois A et al J Clin Oncol 31, 2013 (suppl; abstr LBA5503)
AGO-OVAR 16
Adverse Events Grade 3-4 per Patient
occurring in at least 1% in the Pazopanib Arm
Grade 3/4 adverse events
Placebo
(N=461)
Pazopanib
(N=477)
Δ
Hypertension
26 (6%)
147 (31%)
121 (25%)
Hypertension (including Grade 2)
80 (17%)
248 (52%)
168 (35%)
Liver-related toxicity
3 (<1%)
45 (9%)
42 (9%)
Neutropenia
7 (2%)
47 (10%)
40 (8%)
Diarrhea
5 (1%)
39 (8%)
34 (7%)
Asthenia / Fatigue
1 (<1%)
13 (3%)
12 (3%)
Thrombocytopenia
3 (<1%)
12 (3%)
9 (2%)
Palmar-plantar erythrodysesthesia
1 (<1%)
9 (2%)
8 (2%)
Headache
3 (<1%)
8 (2%)
5 (1%)
Abdominal pain
5 (1%)
8 (2%)
3 (<1%)
Proteinuria
2 (<1%)
6 (1%)
4 (<1%)
Arthralgia
3 (<1%)
5 (1%)
2 (<1%)
Du Bois A et al J Clin Oncol 31, 2013 (suppl; abstr LBA5503)
OCEANS
Carboplatin AUC 4
Platinumsensitive,
recurrent
OC, PP, FTC
No prior
bevacizumab
n=480
Gemcitabine 1000 mg/m2
d1/8
Placebo to progression
Carboplatin AUC 4
Gemcitabine 1000 mg/m2
d1/8
Bevacizumab 15 mg/kg to progression
Primary endpoint:
PFS
Secondary
endpoints:
ORR, OS, DR, safety
Exploratory
endpoints:
IRC, CA 125
response, ascites
IRC present
Stratification variables:
• Time to recurrence
• Cytoreductive surgery
Aghajanian C et al J Clin Oncol 29: 2011 (suppl; abstr LBA5007)
ClinicalTrials.gov Identifier: NCT00434642
OCEANS: Primary analysis of PFS
Proportion progression free
1.0
0.8
CG + PL
(n=242)
CG + BV
(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
0.6
0.484
(0.388–0.605)
<0.0001
0.4
0.2
0
0
No. at risk
CG + PL
CG + BV
6
12
18
24
30
11
33
3
11
0
0
Months
242
242
177
203
45
92
Aghajanian C et al J Clin Oncol 29: 2011 (suppl; abstr LBA5007)
ASCO 2011
OCEANS: OS Analyses
First Interim Analysisa
0.8
0.6
0.4
GC + PL
(n=242)
0.2
Second Interim Analysisb
1.0
Proportion surviving
Proportion surviving
1.0
GC + BV
(n=242)
0.0
0.8
0.6
0.4
0.2
0.0
0
6
12
18
24
30
36
42
0
6
Months
No. events (%)
Median OS, mo
HR (95% CI)
Log-rank P value
aData
GC + PL
GC + BV
(n=242)
(n=242)
78 (32.2)
63 (26.0)
29.9
35.5
0.751 (0.537–1.052)
.0944
12
18
24
30
36
42
48
54
Months
No. events (%)
Median OS, mo
HR (95% CI)
Log-rank P value
GC + PL
GC + BV
(n=242)
(n=242)
112 (46.3)
123 (50.8)
35.2
33.3
1.027 (0.792–1.331)
.8422
cutoff date: Sept 17, 2010. Median follow-up of 24 months in both arms, with 141 deaths (29% of patients).
cutoff date: Aug 29, 2011. Median follow-up 33.7 months in PL arm and 35.4 months in BV arm, with 235 deaths
(49% of patients).
bData
Maintenance Strategies in
Epithelial Ovarian Cancer
• Anti-angiogenesis
• Chemotherapy
• Clinical trial – PARP inhibitor
Maintenance Chemotherapy: GOG 178
Paclitaxel (3 hrs)
175 mg/m2 q28days x 3
EOC, FT, PP
Stage III/IV
Prior chemo 5–6 cycles
Register 3–8 wks
CCR
Neuropathy ≤ grade II
N = 450 anticipated
Accrual closed 9/6/01
N = 277; 222 with FU
54 progression events
FU = follow-up.
Markman et al, J Clin Oncol 2003.
R
A
N
D
O
M
I
Z
E
Paclitaxel (3 hrs)
175 mg/m2 q28days x 12
End points
• PFS
• OS
Maintenance Chemotherapy: GOG 178
Unadjusted Log Rank
p (1-sided) = .0035
Adjusted Log Rank
p (1-sided) = .0023
Markman et al, J Clin Oncol 2003.
GOG-0212
Phase III Maintenance Therapy Trial
Macromolecular complex
of paclitaxel poliglumex
Patients with stage III/IV
epithelial ovarian or primary
peritoneal cancer, GOG PS ≤
2, and complete response
after surgery plus taxane and
carboplatin
Paclitaxel
Every 28 days for up to 12 courses
Paclitaxel poliglumex
Every 28 days for up to 12 courses
No treatment
( N = 1100)
Primary endpoint: survival
Secondary endpoints: PFS, toxicity, QoL
OPEN TO PATIENT ENTRY MARCH, 2005
CLOSED TO ENROLLMENT JANUARY, 2014
www.clinicaltrials.gov/ct2/show/NCT00108745.
Maintenance Strategies in
Epithelial Ovarian Cancer
• Anti-angiogenesis
• Chemotherapy
• Clinical trial – PARP inhibitor
PARP and Base Excision Repair
DNA damage
PARP
NAD+
poly (ADP-ribose)
PARP recruitment
PARP activation and
assembly of repair factors
PARP
PARG
PARP
XRCC1
LigIII
pol β
PAR degradation via PARG
PNK 1
XRCC1
Vergote, ND; Khanna et al, 2001; Sanchez-Perez, 2006; Kennedy et al, 2006.
LigIII
PNK 1
End processing,
gap filling, and ligation
DNA Repair Inhibitors in Cancer Cells:
2 Modes of Action
• Potentiation
– Inhibition of DNA repair following DNA-damaging agents
– Original hypothesis
• Synthetic lethality
– Selected cancer cells lose DNA repair pathways, whereas
normal cells remain unaffected
– Targeting these defective cells may cause selective cell
kill with an increased therapeutic ratio
– May allow for a novel targeted approach to cancer
treatment
Bentle MS et al J Mol Histol. 2006 Sep;37(5-7):203-18
PARPi in Phase III Development in
Ovarian Cancer
1. AZD 2281 (KU-0059436) = Olaparib
2. MK-4827 = Niraparib
3. CO-338 (AG014699, PF-01367338) =
Rucaparib
 Others with randomized trials in devleopment
 ABT-888 = Veliparib
 BMN 673
No direct clinical comparisons!
Dual Activities of PARP Inhibitors
 Cell cytotoxicity greatest with niraparib
 Dual mechanisms include catalytic inhibition of PARP
and PARP trapping on DNA
Murai J, et al.Cancer Res. 2012 Nov 1;72(21):5588-99.
DT40: avian line with only PARP1:
facilitates assessment of role of
PARP trapping
PARPi in Phase III Development in
Ovarian Cancer
1. AZD 2281 (KU-0059436) = Olaparib
2. MK-4827 = Niraparib
3. CO-338 (AG014699, PF-01367338) =
Rucaparib
Olaparib Development
• Oral small molecule PARPi (low nM)
• Escalation Phase (N = 46)
– All tumors
– BRCA mutation not required (11 BRCA ovarian ca’s)
– 10 Dose levels; administration 2 of 3 weeks up to bid
continuously
• PK and PD determined
• DLT: Myelosuppression, N/V, CNS (mood changes)
• MTD: 400 mg bid
• Expansion Phase (N=52)
– All confirmed BRCA mutation carriers (39 Ovarian ca’s)
– DLT: fatigue, thrombocytopenia, somnolence
– Administration 200 mg bid continuously
1Fong,
2Yap,
ASCO 2006, 2007
ASCO 2007
Phase I: AZD 2281 (Olaparib)
Clinical Activity: RECIST + GCIG (cont.)
Fong et al, 2008.
Phase II: AZD 2281 (Olaparib)
Phase II: BRCA Mutation Ovarian Cohort
Audeh et al, 2009.
Who Will Benefit From
PARPi Treatment?
Sporadic tumors with
intact BRCA function
Courtesy of Robert Coleman, MD.
Adapted from Coleman, 2009.
Even Wider Catch: BRCAness “Profile”
Konstantinopoulos PA, et al. J Clin Oncol. 2010;28:3555.
BRCAness and Response to Chemotherapy
Disease Free Survival
34 v 15 mo
P = 0.01
Konstantinopoulos PA, et al. J Clin Oncol. 2010;28:3555.
Overall Survival
72 v 41 mo
P = 0.006
ESMO 2010
Phase II study of the oral PARP inhibitor olaparib
(AZD2281) versus liposomal doxorubicin in ovarian
cancer patients with BRCA1 and/or BRCA2 mutations
Stan Kaye,1 Bella Kaufman,2 Jan Lubinski,3
Ursula Matulonis,4 Charlie Gourley,5 Beth Karlan,6
Dianna Taylor,7 Mark Wickens,7 James Carmichael7
1. Royal Marsden Hospital, Sutton, Surrey, UK
2. Chaim Sheba Medical Center, Tel Hashomer, Israel
3. Pomeranian Medical University, Szczecin, Poland
4. Dana-Farber Cancer Institute, Boston, MA, USA
5. University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK
6. Cedars-Sinai Medical Center, Los Angeles, CA, USA
7. AstraZeneca, Alderley Park, Macclesfield, UK
Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol. 2012 Feb 1;30(4):372-9.
Clinicaltrials.gov number, NCT00628251
Study Design
Primary objective: Compare efficacy (PFS) of 2 dose levels of olaparib
(200 mg and 400 mg bid) with pegylated liposomal doxorubicin (PLD)
Olaparib
200 mg bid in
28-day cycles
BRCA1/2 germline
carriers with Ovarian Ca
Progressive or recurrent
disease < 12 months
after previous platinumbased chemotherapy
Randomized
1:1:1
Olaparib
400 mg bid in
28-day cycles
mg/m2
PLD 50
IV
every 4 weeks
Stats: HR 0.55 (median PFS of 4 to 7.3 mos)
N planned: 90 (30/arm)
PD or withdrawal
from treatment for
other reason
As above or max
lifetime cumulative
dose reached
Patients in PLD group were allowed to cross over
to
olaparib 400 mg bid on confirmed PD
Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol. 2012 Feb 1;30(4):372-9.
Proportion of Patients Progression Free
Progression-Free Survival
1.0
Median PFS (80% CI)
0.9
Olaparib 200 mg:
Olaparib 400 mg:
6.5 (5.6-8.0) months
8.8 (6.3-9.2) months
0.8
PLD 50 mg/m2:
7.1 (5.5-7.8) months
0.7
Olaparib 200 mg
Olaparib 400 mg
0.6
PLD
0.5
Stats: HR 0.55 (median PFS of 4 to 7.3 mos)
N planned: 90 (30/arm)
0.4
0.3
HR* vs PLD (80% CI)
Olaparib 200 mg: 0.91 (0.60-1.39); P = 0.78
0.2
Olaparib 400 mg: 0.86 (0.56-1.30); P = 0.63
0.1
Olaparib 200 mg + 400 mg: 0.88 (0.62-1.28); P = 0.66
0
0
2
4
6
8
Time From Randomization (months)
10
12
Number of patients at risk:
Olaparib 200 mg
Olaparib 400 mg
PLD
*HR < 1 favors
olaparib.
32
32
33
24
28
25
21
21
18
13
17
15
8
12
8
3
1
3
0
0
0
Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol. 2012 Feb 1;30(4):372-9.
Maintenance Olaparib:
Study design (Study 19)
Patients
•Platinum-sensitive high-grade
serous ovarian cancer
•≥2 previous platinum
regimens
•Maintained PR or CR
following last platinum regimen
Olaparib
400mg bid,
orally
(n=136)
Randomized 1:1
Placebo
(n=129)
Primary endpoint
PFS by RECIST
Secondary
endpoints
TTP by CA-125
(GCIG criteria) or
RECIST, OS,
safety
82 sites in 16 countries
Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003); N Engl J Med. 2012 Apr 12;366(15):1382-92.
Study 19: Progression-free survival
Proportion of patients
progression free
Olaparib
Placebo
1.0
No. of events: Total patients (%) 60:136 (44.1) 93:129 (72.1)
0.9
Median PFS (months)
4.8
8.4
0.8
Hazard ratio 0.35 (95% CI, 0.25–0.49)
P<0.00001
0.7
0.6
0.5
0.4
0.3
0.2
Randomized treatment
Placebo
Olaparib 400 mg bid
0.1
0
0
3
6
9
12
15
18
Time from randomization (months)
At risk (n)
Olaparib 136
Placebo 129
104
51
23
6
0
0
72
23
7
1
0
0
Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003); N Engl J Med. 2012 Apr 12;366(15):1382-92.
Study 19:
Common Adverse Events*
Placebo
(n=128)
Olaparib 400 mg bid
(n=136)
Percentage of Patients
Adverse event
Grade 1/2
Grade 3/4
Grade 1/2
Grade 3/4
Any event
61
35
70
20
Nausea
66
2
35
0
Fatigue
42
7
34
3
Vomiting
29
2
13
1
Diarrhea
21
2
20
2
Headache
18
0
11
1
Decreased appetite
18
0
13
0
Abdominal pain
16
2
23
3
Anemia
12
5
4
1
Dyspepsia
16
0
9
0
*Adverse events graded according to maximum CTCAE version 3.0 grade, experienced by >15% of patients in either
treatment group.
Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003); N Engl J Med. 2012 Apr 12;366(15):1382-92.
Study 19: PFS by BRCAm status
BRCAm (n=136)
Olaparib
Placebo
Events: total pts (%) 26:74 (35.1) 46:62 (74.2)
Median PFS, months
11.2
4.3
HR=0.18
95% CI (0.11, 0.31);
P<0.00001
1.0
Proportion of patients
progression-free
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Olaparib BRCAm
0.2
Placebo BRCAm
0.1
0
0
3
6
9
12
15
Time from randomization (months)
Number at risk
Olaparib BRCAm
74
59
33
14
4
0
Placebo BRCAm
62
35
13
2
0
0
• 82% reduction in risk of disease progression or death with olaparib
Presented by: Jonathan Ledermann et al at ASCO 2013
Study 19: PFS by BRCAm status
BRCAm (n=136)
BRCAwt (n=118)
Olaparib
Placebo
Olaparib
Placebo
Events: total pts (%) 26:74 (35.1) 46:62 (74.2) 32:57 (56.1) 44:61 (72.1)
Median PFS, months
11.2
4.3
5.6
5.5
HR=0.18
HR=0.53
95% CI (0.11, 0.31);
95% CI (0.33, 0.84);
P<0.00001
P=0.007
1.0
Proportion of patients
progression-free
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Olaparib BRCAm
Placebo BRCAm
0.2
Olaparib BRCAwt
0.1
Placebo BRCAwt
0
0
3
6
9
12
15
Time from randomization (months)
Number at risk
Olaparib BRCAm
74
59
33
14
4
0
Placebo BRCAm
62
35
13
2
0
0
Olaparib BRCAwt
57
44
17
9
2
0
Placebo BRCAwt
61
35
10
4
1
0
BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance)
Presented by: Jonathan Ledermann et al at ASCO 2013
Study 19: OS in BRCAm patients
BRCAm (n=136)
Proportion of patients alive
1.0
Olaparib
Placebo
0.9
Deaths: total pts (%)
37:74 (50.0)
34:62 (54.8)
0.8
Median OS, months
34.9
31.9
HR=0.74
95% CI (0.46, 1.19)
P=0.208
0.7
0.6
0.5
0.4
0.3
Randomized treatment
Olaparib BCRAm
Placebo BRCAm
0.2
0.1
0
0
3
6
9
15
18
21
24
27
30
33
36
39
42
12
12
7
4
45
48
Time from randomization (months)
Number at risk
Olaparib BRCAm
Placebo BRCAm
12
74
62
71
62
69
58
67
52
65
50
62
46
57
39
54
36
50
33
48
29
39
29
36
27
26
21
• OS in BRCAwt patients: HR=0.98; 95% CI, 0.62–1.55; P=0.946
– Median OS: olaparib, 24.5 months; placebo, 26.2 months
• 14/62 (22.6%) placebo patients switched to a PARP inhibitor
Presented by: Jonathan Ledermann et al at ASCO 2013
Study 19:
Time to second subsequent therapy (PFS2)
Proportion of patients receiving
study treatment or first
subsequent therapy
BRCAm (n=136)
1.0
Events: total pts (%)
Median PFS, months
0.9
0.8
0.7
Olaparib
Placebo
42:74 (56.8) 49:62 (79.0)
23.8
15.3
HR=0.46
95% CI (0.30, 0.70);
P<0.0003
0.6
0.5
0.4
0.3
Olaparib BRCAm
0.2
Placebo BRCAm
0.1
0
0
5
10
15
20
25
30
35
40
45
Time from randomization (months)
Number at risk
Olaparib BRCAm
74
70
65
50
38
33
30
23
9
0
Placebo BRCAm
62
60
46
31
21
18
11
9
2
0
Presented by: Jonathan Ledermann et al at ASCO 2013
Study 19:
Proportion of patients receiving
study treatment or first
subsequent therapy
Time to second subsequent therapy (PFS2)
1.0
Events: total pts (%)
Median PFS, months
0.9
0.8
0.7
BRCAm (n=136)
BRCAwt (n=118)
Olaparib
Placebo
42:74 (56.8) 49:62 (79.0)
23.8
15.3
HR=0.46
95% CI (0.30, 0.70);
P<0.0003
Olaparib
Placebo
42:57 (73.7) 55:61 (90.2)
17.1
14.7
HR=0.64
95% CI (0.42, 0.96);
P=0.032
0.6
0.5
0.4
0.3
Olaparib BRCAm
0.2
Placebo BRCAm
Olaparib BRCAwt
0.1
Placebo BRCAwt
0
0
5
10
15
20
25
30
35
40
45
50
Time from randomization (months)
Number at risk
Olaparib BRCAm
74
70
65
50
38
33
30
23
9
0
0
Placebo BRCAm
62
60
46
31
21
18
11
9
2
0
0
Olaparib BRCAwt
57
56
48
34
20
16
14
11
3
0
0
Placebo BRCAwt
61
58
48
28
18
8
6
4
2
1
0
BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance)
Presented by: Jonathan Ledermann et al at ASCO 2013
• ORR post-olaparib = 36% (24/67) by RECIST
 Platinum = 40% (19/48) by RECIST
• ORR post-olaparib = 45% (35/78) by RECIST + GCIG
• No evidence of secondary BRCA1/2 mutations detected in
tumor samples of 6 PARPi-resistant patients
Front-Line Olaparib Maintenance Therapy
A Phase III, Randomised, Double Blind, Placebo
Controlled, Multicentre Study of Olaparib
Maintenance Monotherapy in Patients with
BRCA Mutated Advanced (FIGO Stage III-IV)
Ovarian Cancer following First Line Platinum
Based Chemotherapy
(GOG 3004)
ClinicalTrials.gov (identifier: NCT01844986
Olaparib Maintenance Therapy in Platinum
Sensitive Ovarian Cancer
A Phase III, Randomized, Double Blind, Placebo
Controlled, Multicenter Study of Olaparib
Maintenance Monotherapy in Patients with
BRCA Mutated Relapsed Ovarian Cancer
Following Complete or Partial Response
Following Platinum Based Chemotherapy:
SOLO-2
ClinicalTrials.gov (identifier: NCT01874353
PARPi in Phase III Development in
Ovarian Cancer
1. AZD 2281 (KU-0059436) = Olaparib
2. MK-4827 = Niraparib
3. CO-338 (AG014699, PF-01367338) =
Rucaparib
Niraparib: Phase 1/2 Ovarian Cancer Anti-tumor Activity
Percentage change from baseline
in size of target lesions
60
40
20
*
**
**
**
*
*
0
*
*
-20
†
-40
†
*
*
-60
*
-80
***
*
*
Platinum Resistant
Platinum Sensitive @ Recommended Dose
Platinum Sensitive
-100
* BRCA1/2 mutation carriers † Reduction in overall sum of measurable disease but new lesion seen (overall: PD)
-Refractory patient (BRCA mutated) not included



At recommended dose (290/300 mg), 3/4 (75%) platinum sensitive patients
achieved RECIST response
RECIST response rate in platinum-sensitive patients was 46% (6/13)
Response rate (by RECIST and/or GCIG Ca125 criteria) in evaluable platinumresistant patients was 22% (6/27)
Michie Co et al. J Clin Oncol 31, 2013 (suppl; abstr 2513)
NOVA Study Design
ClinicalTrials.gov Identifier:NCT01847274
PARPi in Phase III Development in
Ovarian Cancer
1. AZD 2281 (KU-0059436) = Olaparib
2. MK-4827 = Niraparib
3. CO-338 (AG014699, PF-01367338) =
Rucaparib
A Study of Rucaparib as Switch Maintenance
Following Platinum-Based Chemotherapy in
Patients With Platinum-Sensitive, High-Grade
Serous or Endometrioid Epithelial Ovarian,
Primary Peritoneal or Fallopian Tube Cancer
(ARIEL-3)
ClinicalTrials.gov Identifier:NCT01968213
Summary: PARPi in Phase III
Development as Maintenance Therapy
in Ovarian Cancer
1. AZD 2281 (KU-0059436) = Olaparib
– SOLO-1 = Front-line HGS maintenance in
BRCAmut
– SOLO-2 = Platinum sensitive HGS maintenance in
BRCAmut
2. MK-4827 = Niraparib
– NOVA = Platinum sensitive HGS maintenance in
BRCAmut and BRCAwt
3. CO-338 (AG014699, PF-01367338) = Rucaparib
– ARIEL-3 = Platinum sensitive HGS and
endometrioid maintenance in BRCAmut and
BRCAwt
HGS = High grade serous
Thank You
Bradley.monk@chw.edu