PARP inhibition in ovarian cancer · 2 2 RELEVANT DISCLOSURES •Advisory Boards ( no personal...

PARP INHIBITORS IN OVARIAN CANCER

Jonathan A Ledermann

UCL Cancer Institute

University College London, UK

Valencia. March 2015

22

RELEVANT DISCLOSURES

• Advisory Boards ( no personal remuneration) for:– AstraZeneca– Clovis– Tesaro

• Chief Investigator: ‘AstraZeneca Study 19’

PARP INHIBITORS IN OVARIAN CANCER

• Defining a role for PARP inhibitors in serous ovarian cancer– BRCA and non BRCA-mutated ovarian cancer

• What are the indications for PARP inhibitors in 2015?

• Which PARP inhibitors and indications are on the horizon?

• Combination therapy – emerging strategies

PATIENT SELECTION

• Clear rationale for PARP inhibition of BRCA mutated tumours• Emerging evidence that the HRD phenotype is present in up to 50 %

high grade serous tumours• How should this be tested?

– In combination with chemotherapy?– Maintenance ?

Targeting BRCA and non-BRCA mutations

120

100

80

60

40

20

0

–20

–40

–60

–80

–100

Bes

t ch

ange

fro

m b

asel

ine

in s

ize

of

targ

et le

sio

n (

%)

Ovarian BRCA

Ovarian non-BRCA

Gelmon KA, et al. Lancet Oncol 2011;12:852–61

End of therapy for relapse Restart chemotherapy for clinical

progression

Placebo

PARP inhibitor (olaparib)

TREATMENT PATHWAY FOR RECURRENT OVARIAN CANCER

Randomised maintenance trial

PFS and restart chemotherapy

PFS, progression-free survival.

RANDOMISED TRIAL OF MAINTENANCE OLAPARIB IN PLATINUM-SENSITIVE HIGH-GRADE SEROUS RELAPSED OVARIAN CANCER – ‘STUDY 19’

• Aim: to assess the efficacy and safety of olaparib as a maintenance treatment

• Design: randomised, double-blind, placebo-controlled phase II maintenance study265 patients in 82 investigational sites in 16 countries

Olaparib

400 mg po bid

Randomised 1:1

Placebo

po bid

Patients:

• Platinum-sensitive high-grade serous ovarian

cancer

• 2 previous platinum regimens

• Last chemotherapy was platinum-based, to which

they had

a maintained PR or CR prior to enrolment

• Stable CA-125

Treatment

until

disease

progression

Primary end point: PFSSept 2008–Feb 2010

bid, twice daily; CA-125, Cancer Antigen 125;

CR, complete response; po, orally; PR, partial response.Ledermann J et al. N Engl J Med 2012;366:1382–1392

PATIENT CHARACTERISTICSOlaparib

400 mg bid(n=136)

Placebo(n=129)

Median age, years (range) 58 (21–89) 59 (33–84)

ECOG status, n0 / 1 / 2 / unknown 110 / 23 / 1 / 2 95 / 30 / 2 / 2

BRCA mutation status, n (%)*BRCA1

BRCA2

BRCA1 & BRCA2

Known negative

Unknown

25 (18)

6 (4)

0

18 (13)

87 (64)

20 (16)

7 (5)

1 (1)

20 (16)

81 (63)

Prior chemotherapy regimensMedian (range) 3 (0–11)* 3 (2–8)

Time from completion of final platinum chemotherapy to randomisation, days

Median (range)39 (15–517) 41 (14–70)

Ledermann J et al. N Engl J Med 2012;366;1382–1392

PROGRESSION-FREE SURVIVAL IN ‘STUDY 19’

136 104 51 23 6 0 0

129 72 23 7 1 0 0

At risk (n)

Olaparib

Placebo

0

Time from randomisation (months)

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

Placebo

Olaparib 400 mg bid

Randomised treatment

Pro

po

rtio

n o

f p

atie

nts

pro

gre

ssio

n f

ree

CI, confidence interval; HR, hazard ratio.

Olaparib PlaceboEvents/total patients (%)

60/136 (44.1)

93/129 (72.1)

Median PFS, months 8.4 4.8

HR=0.35 (95% CI: 0.25, 0.49)

P<0.001

Ledermann J et al. N Engl J Med 2012;366:1382–1392

INTERIM OS AND SUBGROUP ANALYSIS*• Interim OS analysis (38% maturity): HR=0.94; 95% CI 0.63–1.39; P=0.75• BRCA1/2 mutation (BRCAm) status was not required for study entry, but was known

for 97/265 patients (36.6%)

*Subgroup analysis pre-specified in study protocol.

OS, overall survival.

Hypothesis: olaparib maintenance therapy may lead to a greater PFS and OS benefit vs placebo

in patients with a known BRCAm

Favours olaparib

Size of circle is proportional to number of events

Blue band represents 95% CI for overall population

Olaparib 400 mg bid

52/136 (38%)

8/31 (26%)

11/18 (61%)

33/87 (38%)

Placebo

49/129 (38%)

12/28 (43%)

5/20 (25%)

32/81 (40%)

HR (olaparib:placebo) and 95% CIs

Overall

BRCAm positive

BRCAm negative

BRCAm status unknown

0.125 0.25 0.5 1.0 2.0 4.0 8.0 16.0

Ledermann J et al. N Engl J Med 2012;366:1382–1392; AstraZeneca data on file

– 118 (44.5%) patients were defined as BRCA1/2 wildtype for this analysis

– 136 (51.3%) patients had a known deleterious BRCAm (BRCAm dataset)

– 11 (4.2%) patients had neither a tumor nor a germline result available

STUDY 19: PFS IN PATIENTS WITH BRCAmOVARIAN CANCER

Olaparib BRCAm

Placebo BRCAm

74 59 34 15 5 0

62 35 13 2 0 0

0


0

1.0

Pro

po

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f p

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nts

pro

gre

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n-f

ree

3 6 9 12 15

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

Number at risk

Olaparib BRCAm

Placebo BRCAm

BRCAm (n=136)

Olaparib Placebo

Events/total patients (%)

26/74 (35%)

46/62 (74%)

Median PFS, months (95% CI)

11.2(8.3, NC)

4.3(3.0, 5.4)

HR=0.1895% CI: 0.10, 0.31;

P<0.0001

NC, not calculable.

Ledermann J et al. Lancet Oncol 2014;15:852–861

STUDY 19: PFS BY BRCA MUTATION STATUS

Olaparib BRCAwt

Placebo BRCAwt

57 45 18 9 2 0

61 35 10 4 1 0

BRCAm (n=136) BRCAwt (n=118)

Olaparib Placebo Olaparib Placebo

Events/total patients (%) 26/74 (35%) 46/62 (74%) 32/57 (56.%) 44/61 (72%)

Median PFS, months (95% CI)

11.2(8.3, NC)

4.3(3.0, 5.4)

7.4(5.5, 10.3)

5.5(3.7, 5.6)

HR=0.1895% CI: 0.10, 0.31; P<0.0001

HR=0.5495% CI: 0.34, 0.85; P=0.0075

74 59 34 15 5 0

62 35 13 2 0 0

Number at risk

0


3 6 9 12 15

Olaparib BRCAm

Placebo BRCAm

Olaparib BRCAwt

Placebo BRCAwt0

1.0

Pro

port

ion

of p

atie

nts

prog

ress

ion

-fre

e 0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1


Olaparib BRCAm

Placebo BRCAm

STUDY 19: UPDATED OS IN PATIENTS WITH BRCAmut OVARIAN CANCER

483 6 9 12 15 18 21 24 27 30 33 36 39 42 45


Pro

port

ion

of p

atie

nts

aliv

e

62 62 58 52 50 46 39 36 33 29 29 27 21 10 4

74 71 69 67 65 62 56 53 50 48 39 36 26 12 7 0 0

0 0

Olaparib BRCAm

Placebo BRCAm

BRCAm (n=136)

Olaparib Placebo

Deaths/total patients (%)

37/74 (50%) 34/62 (55%)

Median OS, months (95% CI)

34.9(29.2, NC)

31.9(23.1, 40.7)

HR=0.7395% CI: 0.45, 1.17

P=0.19

0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Number at risk

Olaparib BRCAm

Placebo BRCAm

OS analysis, performed at 52% maturity


STUDY 19: PFS AND OS EVENTS BY BRCA1 AND BRCA2 MUTATION STATUS

BRCA mutation* Treatment arm n Events, n (%)†

PFS

BRCA1Olaparib 400 mg bid

Placebo

48

45

18 (37.5)

32 (71.1)


Placebo

26

18

8 (30.8)

15 (83.3)

OS


Placebo

48

45

26 (54.2)

27 (60.0)


Placebo

26

18

11 (42.3)

8 (44.4)

*The patient in the placebo arm with both a BRCA1 and BRCA2 mutation is included in both the BRCA1 and BRCA2 subgroups†Number and percentage of PFS and OS events recorded at the respective data cut-offs (PFS: 30 June 2010; OS: 26 November 2012)

Ledermann J et al. Lancet Oncol 2014;15:852–861 (Supplementary Appendix, p 2)

TIME TO SECOND SUBSEQUENT THERAPY: A NEW EXPLORATORY ENDPOINT• TFST ( TIME FROM RANDOMISATION TO FIRST SUBSEQENT THERAPY)• TSST (TIME FROM RANDOMISATION TO SECOND SUBSEQUENT THERAPY OR DEATH)• PFS2 (TIME FROM RANDOMISATION TO SECOND OBJECTIVE DISEASE PROGRESSION OR DEATH)*

All patients who received treatment were included in exploratory endpoint

analyses

PFS TSSTPFS2 OS

Intermediate clinical endpoints

Olaparib maintenance monotherapy

First subsequent

treatment response

Chemo Chemo

Progression

Progression

Progression

*PFS2 is a surrogate for TSST Ledermann J et al. Lancet Oncol 2014;15:852–861

TFST

STUDY 19: TIME TO FIRST SUBSEQUENT THERAPY (TFST) IN PATIENTS WITH BRCAmut OVARIAN CANCER

• TFST was significantly improved in the olaparib group vs placebo in the overall population, irrespective of BRCAmutation status (BRCAm group data shown here)

TFST, time from randomisation to first subsequent therapy or death.

0


0

100N

ot

on

fir

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ub

seq

uen

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erap

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)

10 20 30 40

90

80

70

60

50

40

30

20

10

5 15 25 35 45

Number at risk

62 41 21 12 7 6 5 5 1 0 0Placebo

74 65 49 35 29 26 25 21 7 0 0Olaparib

Olaparib Placebo


46/74 (62%) 54/62 (87%)

Median TFST, months (95% CI)

15.6(12.3, 28.2)

6.2(5.3, 9.2)

HR=0.33(95% CI: 0.22, 0.50);

P<0.0001

Olaparib

Placebo


STUDY 19: TIME TO SECOND SUBSEQUENT THERAPY (TSST) IN PATIENTS WITH BRCAmut OVARIAN CANCER

PFS2, time from randomisation to second objective disease progression or death; TSST, time from randomisation to second subsequent therapy or death.

0


0

100

10 20 30 40

90

80

70

60

50

40

30

20

10

5 15 25 35 45

Number at risk

62 60 45 30 20 17 10 8 1 0 0Placebo BRCAm

74 70 65 50 37 33 30 23 9 0 0Olaparib BRCAm

Olaparib

Placebo

BRCAm (n=136)

Olaparib Placebo


42/74 (57%) 49/62 (79%)

Median TSST, months (95%CI)

23.8 (17.7, NC)

15.2 (13.9, 18.7)

HR=0.4495% CI: 0.29, 0.67;

P<0.00013

Pro

po

rtio

n o

f p

atie

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rec

eivi

ng

stu

dy

trea

tmen

t o

r fi

rst

sub

seq

uen

t th

erap

y

TSST is a surrogate for PFS2


OVERVIEW OF EFFICACY ANALYSES IN PATIENTS WITH A BRCA1/2 MUTATION

0

Month

355 10 15 20 25 30

Primary endpoint

Placebo

Olaparib 400 mg bid

ChemoMaintenance treatment

OS

3.0-month difference31.9

34.9

HR: 0.73 (95% CI 0.45, 1.71), P=0.192

TSST(Exploratory)


23.8

HR: 0.44 (95% CI 0.29, 0.67), nominal P=0.00013

TFST(Exploratory)


15.6

HR: 0.33 (95% CI 0.22, 0.50), nominal P<0.0001

PFS6.9-month difference4.3

11.2

HR: 0.18 (95% CI 0.10, 0.31), P<0.0001

ChemoChemo

TFST, time from randomisation to first subsequent therapy or death; TSST, time from randomisation to second subsequent therapy or death

Ledermann J et al. Lancet Oncol 2014;15:852–861 (Supplementary Appendix, p 5)

STUDY 19 (BRCAm): SAFETY PROFILE CONSISTENT WITH OVERALL POPULATION

Grade ≥ 3

Olaparib

(N=74)

Placebo

(N=62)

1 (1%) 0

5 (7%) 1 (2%)

2 (3%) 0

2 (3%) 1 (2%)

0 2 (3%)

4 (5%) 1 (2%)

0 0

0 0

0 0

BRCAm (N=96)

Preferred term (%)

All grades

Olaparib

(N=74)

Placebo

(N=62)

Nausea 54 (73%) 20 (32%)

Fatigue 40 (54%) 23 (37%)

Vomiting 27 (36%) 5 (8%)

Diarrhoea 22 (30%) 12 (19%)

Abdominal pain 17 (23%) 18 (29%)

Anaemia 19 (26%) 3 (5%)

Constipation 14 (19%) 7 (11%)

Decreased appetite 14 (19%) 6 (10%)

Abdominal pain upper 14 (19%) 4 (6%)


**

*

*

STUDY 19: TOLERABILITY PROFILE ALLOWS FOR MAINTENANCE TREATMENT

Adverse events (%)

Overall BRCAm

Olaparib (N=136)

Placebo(N=128)

Olaparib (N=74)

Placebo(N=62)

Any AE 132 (97%) 119 (93%) 72 (97%) 58 (94%)

Any AE Grade ≥ 3 55 (40%) 28 (22%) 28 (38%) 11 (18%)

Any serious AE 25 (18%) 11 (9%) 11 (21%)* 3 (7%)*

Any AE leading to discontinuation

7 (5%) 2 (2%) 5 (9%)* 0*

Any AE leading to death 2 (1%) 0 1 (2%)* 0*

*Data cut off: 26 November 2012. Olaparib, N=53; Placebo, N=43.

Ledermann J et al. Lancet Oncol 2014;15:852–861; AstraZeneca data on file

45%

25%

17%

9%7%

5%

0%

10%

20%

30%

40%

50%

60%

70%

80%

≥ 1 year ≥ 2 years ≥ 3 years

Olaparib (N=53)

Placebo (N=43)

STUDY 19 (BRCAm): 25% TREATED FOR ≥2 YEARS

BRCAm (N=96)

Median duration

(months)

11.1

4.4

Data cut off: 26 November 2012

AstraZeneca data on file

SINGLE AGENT ACTIVITY OLAPARIB IN PLATINUM-RESISTANT OVARIAN CANCER WITH A BRCA MUTATION

Kaufman et al J Clin Oncol 2014

Sonnenblick A, et al. Nat Rev Clin Oncol. 2014 Oct 7. [Epub ahead of print].

PARP Inhibitor Company Target PARP Route ofAdministration

Findings of key trials, if available, and/or phase of development

Olaparib(AZD2281)

AstraZeneca PARP1/2/3 OralPhase II trials demonstrated efficacy in BRCA-mutation carriers;

Currently being evaluated in the adjuvant setting in patients with TNBC

Veliparib (ABT-888)

Abbvie PARP1/2 OralPhase I trials - acceptable safety profile and promising antitumor activity, especially in BRCA-deficient patients with ovarian cancer.

Phase II studies are ongoing; phase III planned

Rucaparib(AG-014, 699; CO-338)

Clovis Oncology PARP1/2Oral or

intravenousOngoing phase II/III study in BRCA-mutation carriers with mBC or

advanced-stage ovarian cancer

BMN-673BioMarin

PharmaceuticalPARP1/2 Oral

Impressive antitumour activity in patients with BRCA mutations; Currently, phase II–III studies in patients with germline BRCA

mutations are ongoing

CEP-9722Teva

Pharmaceutical Industries

PARP1/2 OralClear evidence of PARP inhibition has been demonstrated in preclinical

studies, and early studies in patients

Niraparib(MK4827)

Tesaro PARP1/2 OralPhase I–II studies have revealed antitumor activity, especially in

patients with germline BRCA mutations; Phase III study in platinum-sensitive ovarian cancer ongoing

mBC, metastatic breast cancer; PARP, poly(ADP-ribose) polymerase; TNBC, triple-negative breast cancer

THE RANGE OF PARP INHIBITORS IN CLINICAL USE AND DEVELOPMENT

SOLO-1 & SOLO 2 PROGRAMMEBRCAMUT POPULATION ONLY• First-line maintenance• Maintenance in ‘platinum-sensitive’ setting

Response to platinum-based chemotherapy

Olaparib

Placebo

SOLO-1 344 patients2 years

PFS/PFS2/OS + QoL

SOLO-2 264 patientsto progression

PFS/PFS2/OS + Qol

Randomisation2:1

Olaparib tablets- 300 mg bd

NOVA AND ARIEL3 PROGRAMMES

Both studies include a BRCAm and High Grade Serous wild type subsets

Platinum-sensitive ovarian cancer

responding to platinum-based therapy

PARPi

Placebo

Niraparib360 patients2 cohorts - BRCAm & BRACwt

Rucaparib540 patients2 cohorts – BRCAm & BRCAwt

Identification of companion diagnostic marker to select patients with HRD, most likely to benefit

Randomisation2:1

COMBINING OLAPARIB WITH CEDIRANIB• Preclinical data suggest a synergy between PARP inhibitors and anti-

angiogenic drugs

• Phase 2 open-label randomized study

• Platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer

• Olaparib ± cediranib continued to progression

Platinum-sensitive recurrent

ovarian cancer Cediranib 30mg daily +

Olaparibcapsules

200mg BID

Olaparibcapsules 400mg

BID

Disease progression by

RECIST v1.1 criteria

Randomise 1:1

Liu et al Lancet Oncol 2014

Figure 2

Olaparib Ced/Olap

PFS events 28 19

Median PFS 9.0 mo 17.7 mo

p=0.005

HR 0.42 (95% CI: 0.23-0.76)

PROGRESSION-FREE SURVIVAL


Figure 3


PFSBRCA Non-carrier/Unknown

Olaparib Cediranib/Olaparib

events 15 9

median 5.7 mo 16.5 mo

p=0.008

HR 0.32 (95% CI: 0.14-0.74)

PFSBRCA Mutation Carrier

Olaparib Cediranib/Olaparib

events 13 10

median 16.5 mo 19.4 mo

p=0.16

HR 0.55 (95% CI: 0.24-1.27)

CEDIRANIB/OLAPARIB IN BRCA MUTATION CARRIERS

FUTURE PLANS

• Combination of chemotherapy and veliparib in first-line treatment (NRG/GOG)

• Maintenance after first-line therapy in HGSOC with niraparib ( ENGOT OV26)

• Combining olaparib with bevacizumab as maintenance therapy in first-line setting ( PAOLA-1) and with niraparib in recurrence ENGOT AVANOVA)

• Cediranib & olaparib versus chemotherapy in platinum-sensitive recurrent ovarian cancer ( NCI)

• Cediranib & olaparib maintenance versus cediranib maintenance after platinum-based chemotherapy and cediranib for platinum-sensitive ovarian cancer ( ICON9)

WHAT ARE THE KEY ISSUES?

• Implementation in routine practice requires more comprehensive

population testing for BRCAmut

• No routine strategy for somatic mutation testing ( ~3-6 % HGSOC)

• How will results of NOVA and ARIEL 3 trial play into this?- HRD

testing will become established

• If SOLO-1 is positive- how will this affect use in recurrent disease?

– How to compare the benefit of either approach?

• Later-line use? What are the merits of this versus maintenance?

• Is there a role for PARP inhibitors in platinum-resistant disease?

• Combination studies with VEGF and other signalling inhibitors-

where do these fit in?

PARP inhibition in ovarian cancer · 2 2 RELEVANT DISCLOSURES •Advisory Boards ( no personal...

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