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Maintenance Therapy for Ovarian Cancer – Do the Benefits Outweigh the Risks?
Bradley J. Monk, MD, FACS, FACOGProfessor and Director
Division of Gynecologic OncologyDepartment of Obstetrics and GynecologyCreighton University School of Medicine atSt. Joseph’s Hospital and Medical Center,
a Dignity Health MemberUniversity of Arizona Cancer Center-Phoenix Arizona USA
bradley.monk@chw.edu
Newly Diagnosed Advanced Ovarian Cancer
Maintenance: The Stakes are High!
SymptomsSymptomsSymptomsSymptoms
DiagnosisDiagnosis
Chemotherapy #1Chemotherapy #1Chemotherapy #1Chemotherapy #1
StagingStaging
EvaluationEvaluation? SLL? SLL
ProgressionProgression
Chemo #2Chemo #2Chemo #2Chemo #2 Chemo #3+Chemo #3+Chemo #3+Chemo #3+
SupportiveCare
SecondarySecondarySurgerySurgery
MaintenanceMaintenanceMaintenanceMaintenance
What we know…•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 inEpithelial Ovarian Cancer
• Anti-angiogenesis• Chemotherapy• Clinical trial – PARP inhibitor
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
4th Ovarian Cancer Consensus Conference25 – 27 June 2010UBC Life Sciences Institute, Vancouver, British Columbia
Maintenance Strategies inEpithelial Ovarian Cancer
• Anti-angiogenesis• Chemotherapy• Clinical trial – PARP inhibitor
GOG#218GOG#218
ICON-7ICON-7
GOG-0218: Schema
Front-line: Front-line: Epithelial OV, PP Epithelial OV, PP or FT canceror FT cancer
• Stage III optimal Stage III optimal (macroscopic)(macroscopic)
• Stage III Stage III suboptimalsuboptimal• Stage IVStage IV
n=1800 (planned)n=1800 (planned)
Carboplatin (C) AUC 6Carboplatin (C) AUC 6
Paclitaxel (P) 175 mg/mPaclitaxel (P) 175 mg/m22
PlaceboPlaceboBEV 15 mg/kgBEV 15 mg/kg
IIII
Stratification variables:Stratification variables:• GOG performance status GOG performance status
(PS)(PS)• Stage/debulking statusStage/debulking status
1:1:11:1:1
15 months15 months
Paclitaxel (P) 175 mg/mPaclitaxel (P) 175 mg/m22
Carboplatin (C) AUC 6Carboplatin (C) AUC 6
PlaceboPlacebo
II
ArmArm
Cytotoxic Cytotoxic (6 cycles)(6 cycles)
BEV 15 mg/kgBEV 15 mg/kg
Carboplatin (C) AUC 6Carboplatin (C) AUC 6
Paclitaxel (P) 175 mg/mPaclitaxel (P) 175 mg/m22IIIIII
MaintenanceMaintenance(16 cycles)(16 cycles)
GOG-0218CA-125 To Determine Progression
Protocol-definedPFS analysis
CA-125-censoredPFS analysis
Median PFS
CP (Arm I) 10.3 months 12.0 months
CP + BEV BEV (Arm III) 14.1 months 18.0 months
Absolute diff. median PFS 3.8 months 6.0 months
Hazard ratio 0.717 0.645
Censored for CA125, %
CP (Arm I) 0 20
CP + BEV BEV (Arm III) 0 29
GOG-0218Ad Hoc Survival Analysis in Stage IV
Overall Survival (months)
Pro
po
rtio
n S
urv
ivin
g
CPP (n=153)CPB (n=165)CPB+B (n=165))
0 72
1.0
0.8
0.6
0.4
12 24 36 48 60
0.2
0.0
CPP CPB CPB+B
Median OS (months)
32.8 32.9 40.6
HR 0.72, 95% confidence interval 0.53-0.97
NEJM Data cut-off date August 26, 2011(ASCO 2010 cut-off date February 5, 2010)Randall LM et al SGO 2013
1111
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 cancerTim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan Tim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan
Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey, Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey, Philip Beale, Andreas Cervantes, Amit Oza Philip Beale, Andreas Cervantes, Amit Oza
on behalf of GCIG ICON7 collaborators on behalf of GCIG ICON7 collaborators (MRC/NCRI, AGO-OVAR, GINECO, NSGO, ANZGOG, (MRC/NCRI, AGO-OVAR, GINECO, NSGO, ANZGOG,
GEICO, NCIC-CTG)GEICO, NCIC-CTG)ESMOESMO
2010 N Engl J Med. 2011 Dec 29;365(26):2484-96.2010 N Engl J Med. 2011 Dec 29;365(26):2484-96.
ICON7: Study Design
Stratification variables: Stratification variables: • Stage/surgeryStage/surgery• Time since surgeryTime since surgery• GCIG groupGCIG group *Might vary based on GCIG group*Might vary based on GCIG group
****Omit cycle 1 bevacizumab if <4 weeks from surgeryOmit cycle 1 bevacizumab if <4 weeks from surgery
Paclitaxel 175 mg/mPaclitaxel 175 mg/m22
Carboplatin AUC Carboplatin AUC 6*6*
AVASTINAVASTIN
Carboplatin AUC 6*Carboplatin AUC 6*
Paclitaxel 175 mg/mPaclitaxel 175 mg/m22
Arm A
Arm A
ArmArm BB
12 months12 months
Front-line EOC, Front-line EOC, PP or FT cancerPP or FT cancer
• Stage I-IIA (Gr 3 Stage I-IIA (Gr 3 or CC) or CC)
• Stage IIB/CStage IIB/C• Stage IIIStage III• Stage IVStage IV
n=1528 n=1528
Bevacizumab 7.5 mg/kgBevacizumab 7.5 mg/kg****
Primary endpoints: Primary endpoints: PFSPFS
Secondary Secondary endpoints: OS, RR, endpoints: OS, RR, safety, QOL, safety, QOL, cost-effectiveness,cost-effectiveness,translationaltranslational
No IRC presentNo IRC present
Perren, et al. ESMO 2010
Number at riskCP 764 723 693 556 464 307 216 143 91 50 25CPB7.5+ 764 748 715 647 585 399 263 144 73 36 19
Number at riskCP 764 723 693 556 464 307 216 143 91 50 25CPB7.5+ 764 748 715 647 585 399 263 144 73 36 19
1.00
0.75
0.50
0.25
0
1.00
0.75
0.50
0.25
0
Pro
po
rtio
n a
live
wit
ho
ut
pro
gre
ssi
on
Pro
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n a
live
wit
ho
ut
pro
gre
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on
Time (months)Time (months)
0 3 6 9 12 15 18 21 24 27 300 3 6 9 12 15 18 21 24 27 30
CP CPB7.5+
Events, n (%) 392 (51) 367 (48)
Median, months 17.3 19.0
Log-rank test p=0.0041
HR (95% CI) 0.81 (0.70–0.94)
17.3 19.0
CPCPB7.5+
ICON 7 PFS Benefit: Academic Analysis
Perren, et al. ESMO 2010
ICON 7Summary of Updated Results
ParameterProtocol-Defined
AnalysisBulk Disease
Analysis
PFS HR = 0.87, P = .039
CP 17.4 months
CP + BEVBEV 19.8 months
OS HR = 0.84, P = .099 HR = 0.64, P = .002
CP 28.8 months
CP + BEVBEV 36.6 months
Kristensen G, et al. J Clin Oncol.2011;29: (suppl; abstr LBA5006)
• 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*
ICF
Survival follow-up(post-PD)
First-line surgery and
chemotherapy (allowed: dose-
dense, IP, neoadjuvant)
Placebo 24 months
Pazopanib 24 months
RANDOMIZE
Observation (to PD)
If not PD+ tumor < 2 cm
Median 7 months from diagnosis to randomization
*Original design was for 12 months and later amended to 24 months
AGO-OVAR 16
Du Bois A et al J Clin Oncol 31, 2013 (suppl; abstr LBA5503)
Primary Endpoint: Progression-free Survival (RECIST)
(months)
Δ= 5.6 months
Median time from Diagnosis: 7 months
472 332 234 171 91 19468 318 208 164 88 20 1
Patientsat risk
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 eventsPlacebo(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)
AGO-OVAR 16
OCEANS
Stratification variables: Stratification variables: • Time to recurrenceTime to recurrence• Cytoreductive surgeryCytoreductive surgery
Gemcitabine 1000 mg/mGemcitabine 1000 mg/m22 d1/8d1/8
Carboplatin AUC 4Carboplatin AUC 4
Carboplatin AUC 4Carboplatin AUC 4
Gemcitabine 1000 mg/mGemcitabine 1000 mg/m22 d1/8d1/8
Arm A
Arm A
Arm BArm B
Placebo to progressionPlacebo to progression
Bevacizumab 15 mg/kg to progressionBevacizumab 15 mg/kg to progression
Platinum-Platinum-sensitive, sensitive, recurrentrecurrent
OC, PP, FTCOC, PP, FTC
No prior No prior bevacizumabbevacizumab
n=480n=480
Primary endpoint: Primary endpoint: PFSPFS
Secondary Secondary endpoints:endpoints:ORR, OS, DR, safetyORR, OS, DR, safety
Exploratory Exploratory endpoints:endpoints:IRC, CA 125 IRC, CA 125 response, ascitesresponse, ascites
IRC presentIRC present
ClinicalTrials.gov Identifier: NCT00434642 Aghajanian C et al J Clin Oncol 29: 2011 (suppl; abstr LBA5007)
242242 177177 4545 1111 33 00CG + PLCG + PL
OCEANS: Primary analysis of PFSCG + 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
0.484 (0.388–0.605)
<0.0001
MonthsMonthsNo. at riskNo. at risk
242242 203203 9292 3333 1111 00CG + BVCG + BV
1.0
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
Pro
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n p
rog
res
sio
n f
ree
Pro
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n p
rog
res
sio
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ree
00 66 1212 1818 2424 3030
ASCO 2011Aghajanian C et al J Clin Oncol 29: 2011 (suppl; abstr LBA5007)
1.0
Prop
ortio
n su
rviv
ing
OCEANS: OS Analyses
aData cutoff date: Sept 17, 2010. Median follow-up of 24 months in both arms, with 141 deaths (29% of patients). bData 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).
GC + PL(n=242)
GC + BV(n=242)
No. events (%) 78 (32.2) 63 (26.0)Median OS, mo 29.9 35.5HR (95% CI) 0.751 (0.537–1.052)Log-rank P value .0944
GC + PL (n=242)
GC + BV(n=242)
No. events (%) 112 (46.3) 123 (50.8)Median OS, mo 35.2 33.3HR (95% CI) 1.027 (0.792–1.331)Log-rank P value .8422
0 6 12 18 24 30 36 42
Months
1.0
0.8
0.6
0.4
0.2
0.0
Prop
ortio
n su
rviv
ing
GC + PL(n=242)
GC + BV(n=242)
First Interim AnalysisaSecond Interim Analysisb
0 6 12 18 24 30 36 42 48 54
Months
0.8
0.6
0.4
0.2
0.0
Maintenance Strategies inEpithelial Ovarian Cancer
• Anti-angiogenesis• Chemotherapy• Clinical trial – PARP inhibitor
Maintenance Chemotherapy: GOG 178
EOC, FT, PPStage III/IVPrior chemo 5–6 cyclesRegister 3–8 wksCCRNeuropathy ≤ grade II
Paclitaxel (3 hrs) 175 mg/m2 q28days x 12
Paclitaxel (3 hrs) 175 mg/m2 q28days x 3
RRAANNDDOOMMIIZZEE
N = 450 anticipatedAccrual closed 9/6/01N = 277; 222 with FU54 progression events
End points• PFS• OS
FU = follow-up.
Markman et al, J Clin Oncol 2003.
Unadjusted Log Rankp (1-sided) = .0035
Adjusted Log Rankp (1-sided) = .0023
Markman et al, J Clin Oncol 2003.
Maintenance Chemotherapy: GOG 178
GOG-0212Phase III Maintenance Therapy Trial
Primary endpoint: survivalSecondary endpoints: PFS, toxicity, QoL
OPEN TO PATIENT ENTRY MARCH, 2005
CLOSED TO ENROLLMENT JANUARY, 2014 www.clinicaltrials.gov/ct2/show/NCT00108745.
Macromolecular complexMacromolecular complex of paclitaxel poliglumexof 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
( N = 1100)
Paclitaxel Every 28 days for up to 12 courses
No treatment
Paclitaxel poliglumex Every 28 days for up to 12 courses
Maintenance Strategies inEpithelial Ovarian Cancer
• Anti-angiogenesis• Chemotherapy• Clinical trial – PARP inhibitor
PARP recruitmentPARP
DNA damage
PARP activation and assembly of repair factors
NAD+
poly (ADP-ribose)PARP
PAR degradation via PARG
PARGPARP
End processing,gap filling, and ligation
PNK 1pol β
XRCC1 LigIII
pol β
XRCC1 LigIII
PNK 1
Vergote, ND; Khanna et al, 2001; Sanchez-Perez, 2006; Kennedy et al, 2006.
PARP and Base Excision Repair
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 = VeliparibBMN 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
DT40: avian line with only PARP1: facilitates assessment of role of PARP trapping
Murai J, et al.Cancer Res. 2012 Nov 1;72(21):5588-99.
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, ASCO 2006, 20072Yap, 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 Overall Survival
Konstantinopoulos PA, et al. J Clin Oncol. 2010;28:3555.
34 v 15 mo P = 0.01
72 v 41 mo P = 0.006
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,Stan Kaye,11 Bella Kaufman, Bella Kaufman,2 2 Jan Lubinski,Jan Lubinski,3 3
Ursula Matulonis,Ursula Matulonis,44 Charlie Gourley, Charlie Gourley,55 Beth Karlan, Beth Karlan,6 6
Dianna Taylor,Dianna Taylor,77 Mark Wickens, Mark Wickens,77 James Carmichael James Carmichael77
1. Royal Marsden Hospital, Sutton, Surrey, UK1. Royal Marsden Hospital, Sutton, Surrey, UK
2. Chaim Sheba Medical Center, Tel Hashomer, Israel 2. Chaim Sheba Medical Center, Tel Hashomer, Israel
3. Pomeranian Medical University, Szczecin, Poland3. Pomeranian Medical University, Szczecin, Poland
4. Dana-Farber Cancer Institute, Boston, MA, USA4. Dana-Farber Cancer Institute, Boston, MA, USA
5. University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK5. University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK
6. Cedars-Sinai Medical Center, Los Angeles, CA, USA6. Cedars-Sinai Medical Center, Los Angeles, CA, USA
7. AstraZeneca, Alderley Park, Macclesfield, UK7. AstraZeneca, Alderley Park, Macclesfield, UK
Clinicaltrials.gov number, NCT00628251
ESMO 2010ESMO 2010
Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol. 2012 Feb 1;30(4):372-9.
Randomized
1:1:1
Olaparib 200 mg bid in 28-day cycles
PLD 50 mg/m2 IV every 4 weeks
PD or withdrawal from treatment for
other reason
As above or max lifetime cumulative
dose reached
Primary objective: Compare efficacy (PFS) of 2 dose levels of olaparib (200 mg and 400 mg bid) with pegylated liposomal doxorubicin (PLD)
Study Design
Olaparib 400 mg bid in 28-day cycles
BRCA1/2 germline carriers with Ovarian CaProgressive or recurrent disease < 12 months after previous platinum-based chemotherapy
Patients in PLD group were allowed to cross over to olaparib 400 mg bid on confirmed PD
Stats: HR 0.55 (median PFS of 4 to 7.3 mos)N planned: 90 (30/arm)
Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol. 2012 Feb 1;30(4):372-9.
Progression-Free Survival
Olaparib 200 mg: 6.5 (5.6-8.0) months
Median PFS (80% CI)
Olaparib 400 mg: 8.8 (6.3-9.2) months
PLD 50 mg/m2: 7.1 (5.5-7.8) months
HR* vs PLD (80% CI)
Olaparib 200 mg: 0.91 (0.60-1.39); P = 0.78
Olaparib 400 mg: 0.86 (0.56-1.30); P = 0.63
Olaparib 200 mg + 400 mg: 0.88 (0.62-1.28); P = 0.66
Time From Randomization (months)
Pro
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0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 12108642
*HR < 1 favors olaparib.
32 03813212432 011217212833 038151825
Number of patients at risk:
Olaparib 200 mg
Olaparib 400 mg
PLD
Stats: HR 0.55 (median PFS of 4 to 7.3 mos)N planned: 90 (30/arm)
Olaparib 400 mg
Olaparib 200 mg
PLD
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)
Placebo(n=129)
Olaparib400mg bid,
orally(n=136)
Patients
•Platinum-sensitive high-grade serous ovarian cancer
•≥2 previous platinum regimens
•Maintained PR or CR following last platinum regimen
Primary endpoint
PFS by RECIST
Secondary endpoints
TTP by CA-125 (GCIG criteria) or RECIST, OS, safety
Randomized 1:1
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
0
Time from randomization (months)
136 104 51 23 6 0 0
129 72 23 7 1 0 0
At risk (n)
Olaparib
Placebo
0.6
0.8
0.9
0
0.1
0.2
0.3
0.4
0.5
0.7
1.0
3 6 9 12 15 18
No. of events: Total patients (%)
Median PFS (months)
Olaparib60:136 (44.1)
8.4
Placebo93:129 (72.1)
4.8
Hazard ratio 0.35 (95% CI, 0.25–0.49)P<0.00001
Olaparib 400 mg bidPlacebo
Randomized treatmentPro
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p
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ress
ion
fre
e
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)
*Adverse events graded according to maximum CTCAE version 3.0 grade, experienced by >15% of patients in either treatment group.
Adverse event
Any event
Nausea
Fatigue
Vomiting
Diarrhea
Headache
Decreased appetite
Abdominal pain
Anemia
Dyspepsia
Grade 1/2
61
66
42
29
21
18
18
16
12
16
Olaparib 400 mg bid(n=136)
Grade 3/4
35
2
7
2
2
0
0
2
5
0
Grade 1/2
70
35
34
13
20
11
13
23
4
9
Grade 3/4
20
0
3
1
2
1
0
3
1
0
Percentage of Patients
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
Presented by: Jonathan Ledermann et al at ASCO 2013
0
Time from randomization (months)
0
1.0
Pro
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f p
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nts
p
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ree
3 6 9 12 15
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
• 82% reduction in risk of disease progression or death with olaparib
Olaparib BRCAm
Placebo BRCAm
Number at risk
Olaparib BRCAm
Placebo BRCAm
74 59 33 14 4 0
62 35 13 2 0 0
BRCAm (n=136)
Olaparib PlaceboEvents: total pts (%) 26:74 (35.1) 46:62 (74.2)Median PFS, months 11.2 4.3
HR=0.1895% CI (0.11, 0.31);
P<0.00001
Study 19: PFS by BRCAm status
0
Time from randomization (months)
0
1.0
Pro
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n o
f p
atie
nts
p
rog
res
sio
n-f
ree
3 6 9 12 15
Olaparib BRCAm
Olaparib BRCAwt
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
BRCAm (n=136) BRCAwt (n=118)
Olaparib Placebo Olaparib PlaceboEvents: 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=0.1895% CI (0.11, 0.31);
P<0.00001
HR=0.5395% CI (0.33, 0.84);
P=0.007
Placebo BRCAm
Placebo BRCAwt
Number at risk
Olaparib BRCAm
Olaparib BRCAwt
Placebo BRCAm
Placebo BRCAwt
74 59 33 14 4 0
57 44 17 9 2 0
62 35 13 2 0 0
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
0
Time from randomization (months)
048
1.0
Pro
po
rtio
n o
f p
atie
nts
ali
ve
3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Number at risk
62 62 58 52 50 46 39 36 33 29 29 27 21 12 4Placebo BRCAm74 71 69 67 65 62 57 54 50 48 39 36 26 12 7Olaparib BRCAm
Randomized treatment
Placebo BRCAm
Olaparib BCRAm
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
BRCAm (n=136)
Olaparib Placebo
Deaths: total pts (%) 37:74 (50.0) 34:62 (54.8)
Median OS, months 34.9 31.9
HR=0.7495% CI (0.46, 1.19)
P=0.208
• 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)
0
Time from randomization (months)
0
1.0
Pro
po
rtio
n o
f p
atie
nts
re
ceiv
ing
stu
dy
trea
tme
nt
or
firs
t su
bse
qu
ent
the
rap
y
10 20 30 40
Olaparib BRCAm
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Placebo BRCAm
Number at risk
Olaparib BRCAm
Placebo BRCAm
74
62
5 15 25 35 45
70
60
65
46
50
31
38
21
33
18
30
11
23
9
9
2
0
0
BRCAm (n=136)
Olaparib Placebo
Events: total pts (%) 42:74 (56.8) 49:62 (79.0)Median PFS, months 23.8 15.3
HR=0.4695% CI (0.30, 0.70);
P<0.0003
Presented by: Jonathan Ledermann et al at ASCO 2013
0
Time from randomization (months)
0
1.0
Pro
po
rtio
n o
f p
atie
nts
re
ceiv
ing
stu
dy
trea
tme
nt
or
firs
t su
bse
qu
ent
the
rap
y
10 20 30 40 50
Olaparib BRCAm
Olaparib BRCAwt
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Placebo BRCAm
Placebo BRCAwt
Number at risk
Olaparib BRCAm
Olaparib BRCAwt
Placebo BRCAm
Placebo BRCAwt
74
57
62
61
5 15 25 35 45
70
56
60
58
65
48
46
48
50
34
31
28
38
20
21
18
33
16
18
8
30
14
11
6
23
11
9
4
9
3
2
2
0
0
0
1
0
0
0
0
BRCAm (n=136) BRCAwt (n=118)
Olaparib Placebo Olaparib Placebo
Events: total pts (%) 42:74 (56.8) 49:62 (79.0) 42:57 (73.7) 55:61 (90.2)Median PFS, months 23.8 15.3 17.1 14.7
HR=0.4695% CI (0.30, 0.70);
P<0.0003
HR=0.6495% CI (0.42, 0.96);
P=0.032
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:Time to second subsequent therapy (PFS2)
• 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
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 platinum-
resistant patients was 22% (6/27)
* BRCA1/2 mutation carriers † Reduction in overall sum of measurable disease but new lesion seen (overall: PD)-Refractory patient (BRCA mutated) not included
Pe
rce
nta
ge
ch
an
ge
fro
m b
as
eli
ne
in
siz
e o
f ta
rge
t le
sio
ns
Platinum Resistant Platinum SensitivePlatinum Sensitive @ Recommended Dose
*
*
****
*
**
*
*
**
* * * *
*
*
††
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 Cancer1. 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.eduBradley.monk@chw.edu
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