maintenance therapy for ovarian cancer – do the benefits outweigh the risks?

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

[email protected]

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

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


PlaceboPlacebo

II

ArmArm

Cytotoxic Cytotoxic (6 cycles)(6 cycles)

BEV 15 mg/kgBEV 15 mg/kg


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)

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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

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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

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00 66 1212 1818 2424 3030

ASCO 2011Aghajanian C et al J Clin Oncol 29: 2011 (suppl; abstr LBA5007)

1.0

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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

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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 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

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.


1. AZD 2281 (KU-0059436) = Olaparib



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)


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)

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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


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

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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

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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

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Percentage of Patients


Study 19: PFS by BRCAm status

Presented by: Jonathan Ledermann et al at ASCO 2013

0


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• 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


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Olaparib BRCAm

Olaparib BRCAwt

0.9

0.8

0.7

0.6

0.5

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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)


Study 19: OS in BRCAm patients

0


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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


Study 19:Time to second subsequent therapy (PFS2)

0


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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


0


0

1.0

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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)


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


1. AZD 2281 (KU-0059436) = Olaparib



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

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ch

an

ge

fro

m b

as

eli

ne

in

siz

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f ta

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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


1. AZD 2281 (KU-0059436) = Olaparib



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

[email protected]@chw.edu

maintenance therapy for ovarian cancer – do the benefits outweigh the risks?

Documents

months cp bev bev arm

months cp bevbev19

pfs benefit

int j gynecol cancer

promising targets

crsclinical crs

yearspathological crs

j clin oncol