treatment with olaparib monotherapy in the -...

Eric Pujade-Lauraine,1 Jonathan A Ledermann,2 Richard T Penson,3 Amit M Oza,4 Jacob Korach,5

Tomasz Huzarski,6 Andrés Poveda,7 Sandro Pignata,8 Michael Friedlander,9 and Nicoletta Colombo10

1Université Paris Descartes, AP-HP, Paris, France; 2University College London, London, UK; 3Massachusetts General Hospital and

Harvard University, Boston, USA; 4Princess Margaret Cancer Centre, Toronto, Canada; 5Sheba Medical Center, Tel Aviv University,

Tel Hashomer, Israel; 6Pomeranian Medical University, Szczecin, Poland; 7Instituto Valenciano de Oncología, Valencia, Spain; 8Istituto

Tumori Pascale di Napoli, Naples, Italy; 9University of New South Wales Clinical School, Prince of Wales Hospital, Randwick, Australia; 10University of Milan-Bicocca and Istituto Europeo Oncología (IEO), Milan, Italy

Funded by AstraZeneca; ClinicalTrials.gov number NCT01874353

Treatment with olaparib monotherapy in the

maintenance setting significantly improves

progression-free survival in patients with

platinum-sensitive relapsed ovarian cancer:

Results from the Phase III SOLO2 study

Verbal disclosure

• Eric Pujade-Lauraine reports advisory board membership and honoraria from AstraZeneca, and advisory board membership,

honoraria, and speaker’s bureau membership from Roche

• Jonathan A Ledermann reports honoraria from AstraZeneca, honoraria from Pfizer, and advisory roles from AstraZeneca,

Clovis Oncology, Pfizer, and Roche

• Richard T Penson reports honoraria, a consulting and advisory role, and receipt of research funding from AstraZeneca

• Amit M Oza reports a non-compensated advisory role and investigator role for AstraZeneca, Clovis Oncology, Tesaro, and

Pfizer

• Jacob Korach reports no disclosures

• Tomasz Huzarski reports no disclosures

• Andrés Poveda reports consulting and advisory roles from Advaxis, AstraZeneca, PharmaMar, and Roche

• Sandro Pignata reports honoraria from AstraZeneca, Roche, and PharmaMar

• Michael Friedlander reports honoraria and advisory roles from AstraZeneca, and Pfizer

• Nicoletta Colombo reports honoraria and advisory roles from AstraZeneca, Pfizer, Clovis Oncology, Roche, PharmaMar, and

Immunogen

AcknowledgmentsThe 295 patients and their families, and…

IDMC

R Ozols, J Vermorken

M Buyse

QoL Committee

E Pujade-Lauraine, F Hilpert,

M Friedlander, L Wenzel, E Lowe,

F Joly, V Gebsky, S Garnett, N Le Fur,

D Eek, R Bloomfield, T Morris,

A Fielding

Trial Steering Committee

E Pujade-Lauraine, P Harter, A Poveda,

R Penson, M Friedlander, G Sonke, N Colombo,

S Pignata, A Oza, K Fujiwara, G Girotto,

J Ledermann, I Vergote, J Korach, J-W Kim,

O Mikheeva, V Gebsky, E Lowe, A Fielding,

R Bloomfield

Study Sponsor:

AstraZeneca

P Pautier N Colombo A Clamp R Penson A Oza J Korach T Huzarski A Poveda Velasco

M Roigues S Pignata C Parkinson J Cosin D Ovencher A Amit M Sikorska A Prat Aparicio

J-P Lotz G Scambia J Ledermann R Penson M Plante L Helpman A Słowińska N Laínez Milagro

I Ray-Coquard M Nicoletto S Williams D O'Malley A Covens M Bidziński MP Barretina Ginesta

J Ioni R Sabbatini S Banerjee P Timmins H Hirte M Miedzińska A Tibau Martorell

C Dubot F Cognetti C Poole D Warshal S Welch A Casado Herraez

M-C Kaminsky E Dickson-Michelson P Bessette C Mendiola Fernández

A Lortholary N McKenzie MJ Rubio Pérez

F Joly G Roiguez JA Pérez Fidalgo

A Floquet D Armstrong

L Gladieff E Chalas

S Hamizi P Celano

K Behbakht

C Leath III

J Chan

MA Crispens

Australia Japan Germany Russia Netherlands South Korea Brazil Belgium

M Friedlander P Harter K Tamura A Lisyanskaya G Sonke J-H Kim E Filho I Vergote

C Scott T-W Park-Simon K Matsumoto S Tjulandin I Boere J-H Nam R Hegg H Denys

A Linda Mileshkin M Gropp-Meier M Mandai O Mikheeva P Ottevanger C-H Choi L Costa

A El-Balat T Saito R Lalisang J-W Kim G Queiroz

S Rothe K Takehara F Franke

T Reimer T Enomoto R Pereira

B Schmalfeldt H Watari G Borges

L Hanker Y Hirashima

F Thiel K Fujiwara

ARCAGYB Voltan, N Le Fur

Background

1. Ledermann JA et al 2012; 2. Ledermann JA et al 2014

• Olaparib is the first-in-class PARP inhibitor

• In a Phase II trial (Study 19), olaparib maintenance therapy (capsules) provided a

significant progression-free survival (PFS) improvement over placebo in all-comer

patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer1

– The PFS benefit was greatest for patients with a BRCA1/2 mutation2

• SOLO2/ENGOT-Ov21 (NCT01874353) was a Phase III trial to confirm findings from

Study 19 in the BRCA1/2 mutation subgroup using the olaparib tablet formulation

SOLO2/ENGOT-Ov21: study design

Placebo

n=99

Olaparib

300 mg bid

n=196

Patients

• BRCA1/2 mutation

• Platinum-sensitive relapsed

ovarian cancer

• At least 2 prior lines of

platinum therapy

• CR or PR to most recent

platinum therapy

Ra

nd

om

ize

d

2:1

CR, complete response; PR, partial response


Placebo

n=99

Olaparib

300 mg bid

n=196Primary endpoint

Investigator-assessed

PFS

Patients



ovarian cancer


platinum therapy


platinum therapy

Ra

nd

om

ize

d

2:1

CR, complete response; PR, partial response

*Primary endpoint for HRQoL was trial outcome index (TOI) of the

FACT-O (Functional Assessment of Cancer Therapy – Ovarian)

Sensitivity analysis: PFS by blinded independent central review (BICR)

• Key secondary endpoints:– Time to first subsequent therapy or death (TFST), time to second progression (PFS2),

time to second subsequent therapy or death (TSST), overall survival (OS)

– Safety, health-related quality of life (HRQoL*)


Placebo

n=99

Olaparib

300 mg bid

n=196Primary endpoint

Investigator-assessed

PFS

Patients



ovarian cancer


platinum therapy


platinum therapy

Ra

nd

om

ize

d

2:1

CharacteristicOlaparib

(n=196)

Placebo

(n=99)

Age, median (range) 56 (28–83) 56 (39–78)

Primary tumor type, n (%)

Ovarian 162 (82.7) 86 (86.9)

Fallopian tube or primary peritoneal 31 (15.8) 13 (13.1)

Other/missing 3 (1.5) 0

Prior platinum regimens, n (%)

2 lines 110 (56.1) 62 (62.6)

3 lines 60 (30.6) 20 (20.2)

≥4 lines 25 (12.8) 17 (17.2)

Platinum-free interval, n (%)6–12 months 79 (40.3) 40 (40.4)

>12 months 117 (59.7) 59 (59.6)

Response to platinum therapy, n (%)Complete response 91 (46.4) 47 (47.5)

Partial response 105 (53.6) 52 (52.5)

Demographic and baseline characteristics

No. at risk

Olaparib

Placebo196

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

100

90

80

70

60

50

40

30

20

10

0

Pro

gre

ssio

n-f

ree

su

rviv

al (%

)

Months since randomization

0 3 6 9 12 15 18 21 24 27 30 33 36

19.1

Olaparib

Placebo

5.5

Olaparib

(n=196)

Placebo

(n=99)

Events (%) 107 (54.6) 80 (80.8)

Median PFS, months 19.1 5.5

HR 0.30

95% CI 0.22 to 0.41

P<0.0001

PFS by investigator assessment

Median follow-up was 22.1 months in the olaparib group and 22.2 months for placebo


Pro

gre

ssio

n-f

ree

su

rviv

al (%

)100

90

80

70

60

50

40

30

20

10

00 3 6 9 12 15 18 21 24 27 33

30.25.5

30

No. at risk

Olaparib

Placebo

196

99

176

62

148

26

128

18

112

16

103

14

88

14

82

11

30

6

28

5

3

0

1

0

Olaparib

(n=196)

Placebo

(n=99)

Events (%) 81 (41.3) 70 (70.7)


HR 0.25

95% CI 0.18 to 0.35

P<0.0001

PFS sensitivity analysis using BICR

Olaparib

Placebo

Secondary efficacy endpoints

27.9

7.1

18.4

Not reached

18.2

PFS2

0 10 20 30Median (months)

Olaparib

PlaceboData immatureOverall survival

Time to first

subsequent therapy,

or death (TFST)

Time to second

subsequent therapy,

or death (TSST)

HR 0.28

95% CI 0.21 to 0.38

P<0.0001

HR 0.50

95% CI 0.34 to 0.72

P=0.0002

HR 0.37

95% CI 0.26 to 0.53

P<0.0001

Median not reached

Median not reached

Characteristic, n (%)Olaparib

(n=195)

Placebo

(n=99)

Any AE 192 (98.5) 94 (94.9)

Any AE grade ≥3 72 (36.9) 18 (18.2)

Any SAE 35 (17.9) 8 (8.1)

Any AE leading to dose reduction 49 (25.1) 3 (3.0)

Any AE leading to discontinuation of study treatment 21 (10.8) 2 (2.0)

Any AE with an outcome of death 1 (0.5) 0

Total adverse events

AE, adverse event; SAE, serious adverse event

Most common hematologic adverse events

Event, n (%) Olaparib (n=195) Placebo (n=99)

All grades Grade ≥3 All grades Grade ≥3

Anemia* 85 (43.6) 38 (19.5) 8 (8.1) 2 (2.0)

Neutropenia* 38 (19.5) 10 (5.1) 6 (6.1) 4 (4.0)

Thrombocytopenia 16 (8.2) 0 3 (3.0) 1 (1.0)

MDS/AML: 4 cases in olaparib group (2.1%), including one case of CMML

4 cases in placebo group (4.0%)

*Grouped terms

Most common non-hematologic adverse events

All grades (frequency ≥20%)

Olaparib Placebo

100 75 50 25 0 0 25 50 75 100

Adverse events (%)

Dysgeusia 7.126.7

Headache 13.125.1

Decreased appetite 11.122.1

Nausea 33.375.9

Fatigue/asthenia 39.465.6

Vomiting 19.237.4

Constipation 23.220.5

Diarrhea 20.232.8

Abdominal pain 31.324.1

Grade ≥3 (frequency ≥2.5%)

Other AEs of interest

Elevated ALT: 10 patients in olaparib group (5.1%) vs 4 patients in placebo group (4.0%)

Elevated AST: 4 patients in olaparib group (2.1%) vs 4 patients in placebo group (4.0%)

2.6

1.02.6

2.04.1

3.0

1.0

2.6 3.0

0.5

Health-related quality of life: TOI of the FACT-O

TOI over first 12 months Olaparib (n=185) Placebo (n=94)

Change from baseline, adjusted mean −2.90 −2.87

TOI, trial outcome index;

FACT-O, Functional Assessment of Cancer Therapy – Ovarian

Estimated difference in adjusted means = −0.03 (95% CI −2.19 to 2.13, P=0.98)

Conclusions

• SOLO2 demonstrated a statistically significant PFS improvement in patients receiving

olaparib, by investigator assessment and BICR

• The PFS benefit was supported by a significant delay in TFST, PFS2 and TSST in the

olaparib group

• With the exception of anemia, toxicity was mostly low grade

• SOLO2 is the first Phase III trial of olaparib tablets as maintenance treatment and

showed a significant benefit in patients with platinum-sensitive, relapsed ovarian

cancer and a BRCA1/2 mutation

Additional slides

Olaparib better Placebo better

Subgroup analysis of PFSHazard ratio (95% CI)Subgroup

No. at risk

Olaparib

Placebo

196

99182

78

156

44

139

26

122

22

110

19

100

17

93

14

60

9

37

6

16

2

4

0

TDT: time to treatment discontinuation, or death

100

90

70

60

50

40

30

20

10

0

Pro

po

rtio

n o

f p

atie

nts

eve

nt

fre

e (

%)


0 3 6 9 12 15 18 21 24 27 30 33

80

5.6 19.4

Olaparib

Placebo

Olaparib

(n=196)

Placebo

(n=99)

Events (%) 112 (57.1) 86 (86.9)


HR 0.31

95% CI 0.23 to 0.42

P<0.0001

TFST: time to first subsequent therapy, or death

Months since randomizationNo. at risk

Olaparib

Placebo196

99

190

92

176

65

155

33

139

26

130

23

122

20

107

19

64

11

40

6

16

2

4

0

100

90

80

70

60

50

40

30

20

10

0

No

t o

n f

irst su

bse

qu

en

t th

era

py (

%)

0 3 6 9 12 15 18 21 24 27 30 33

27.97.1

Olaparib

Placebo

Olaparib

(n=196)

Placebo

(n=99)

Events (%) 92 (46.9) 79 (79.8)


HR 0.28

95% CI 0.21 to 0.38

P<0.0001

PFS2: time to second progression, or death


Olaparib

Placebo

196

99

191

95

180

84

167

71

152

59

132

47

114

38

100

28

39

13

30

7

3

0

2

0

Pro

gre

ssio

n-f

ree

su

rviv

al 2

(%

)

Olaparib

Placebo

18.4

100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12 15 18 21 24 27 30 33

18.4

Olaparib

(n=196)

Placebo

(n=99)

Events (%) 70 (35.7) 49 (49.5)

Median PFS, months Not reached 18.4

HR 0.50

95% CI 0.34 to 0.72

P=0.0002

100

90

70

60

50

40

30

20

10

0

0 3 6 9 12 15 18 21 24 27 30 33 36

18.2

80

TSST: time to second subsequent therapy, or death

No

t o

n s

eco

nd

su

bse

qu

en

t th

era

py (

%)


Olaparib

Placebo

196

99

194

95

190

90

181

81

169

67

155

51

141

43

123

30

75

17

43

10

17

2

4

0


Olaparib

(n=196)

Placebo

(n=99)

Events (%) 68 (34.7) 60 (60.6)

Median PFS, months Not reached 18.2

HR 0.37

95% CI 0.26 to 0.53

P<0.0001

0

0

Olaparib

Placebo

Hierarchy of statistical testing

• PFS is tested first using the full alpha. Subsequently, PFS2 is testedonly if PFS is statistically significant

• If PFS2 is significant at either the interim or final analyses, the fullalpha will be carried forward to OS

• Statistical significance will be declared at the interim analysis for PFS2if the one-sided P<0.0125

• Statistical significance will be declared at the interim analysis for OS if

the null hypothesis for PFS2 is rejected at the PFS analysis and the

observed P value for OS is P<0.0001

PFS

PFS2

OS

Multiple testing procedure

Supportive secondary endpoints: TDT, TFST, TSST

TDT, time to treatment discontinuation or death;

TFST, time to first subsequent therapy or death;

TSST, time to second subsequent therapy or death

Proportion of patients event free after 18 months and

after 24 months on treatment

Study endpoint Patient statusOlaparib

(n=196), %

Placebo

(n=99), %

PFS

(investigator assessed)

Progression free, 18 months


51.1

43.0

16.2

15.1

PFS

(BICR)



58.7

52.7

21.7

19.9

TDTDiscontinuation free, 18 months

Discontinuation free, 24 months

51.8

44.8

17.2

13.1

PFS2Second progression free, 18 months

Second progression free, 24 months

71.8

59.2

52.4

37.3

TFSTFirst subsequent therapy free, 18 months

First subsequent therapy free, 24 months

65.0

54.1

21.8

17.3

TSSTSecond subsequent therapy free, 18 months

Second subsequent therapy free, 24 months

75.8

65.7

50.7

33.0

Key study dates

Study event Date

First subject in (FSI) 3 September 2013

Last subject in (LSI) 21 November 2014

Database lock (DBL) 19 October 2016

treatment with olaparib monotherapy in the -...

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