solo-1€¦ · solo-1 is the first phase iii trial to investigate maintenance therapy with a parp...

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SOLO-1Olaparib maintenance therapy in patients with newly diagnosed advanced

ovarian cancer following platinum-based chemotherapy

SOLO-1

There remains a significant unmet need for newly diagnosed ovarian

cancer1

1. Ledermann, J. A. et al. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 24 Suppl 6, vi24-32 (2013) 2. Bookman, M. A. et al. J. Clin. Oncol. 27, 1419–1425 (2009); 3. Burger, R. A. et al. N. Engl. J. Med. 365, 2473–2483 (2011); 4. Perren, T. J. et al. N. Engl. J. Med. 365, 2484–2496 (2011); 5. de Angelis R et al. Lancet Oncol 2014;15:23-34.

There is a significant need for better frontline treatment to improve

outcomes for women with ovarian cancer1-5

~70% of women relapse within 3

years of first line treatment1

38%5-year survival rate5

10-18 monthsMedian progression-free

survival2,3,4

Platinum-based

chemotherapy

Bevacizumab

4

20 months

Cure Goal Palliation

HighToxicity

acceptanceLow

Less important Convenience More important

Treatment considerations

First-line treatment Recurrent disease

15% still alive, disease free, at 10 years

When a women is diagnosed with advanced epithelial ovarian

cancer, the goal of firstline treatment is to achieve a cure

SOLO-1 is the first Phase III trial to investigate maintenance therapy

with a PARP inhibitor in newly diagnosed ovarian cancer

*Upfront or interval attempt at optimal cytoreductive surgery for stage III disease and either biopsy and/or upfront or interval cytoreductive surgery for stage IV diseaseBICR = blinded independent central review; ECOG = Eastern Cooperative Oncology Group; FACT-O = Functional Assessment of Cancer Therapy – Ovarian Cancer; FIGO = International Federation of Gynecology and Obstetrics; HRQoL = health-related quality of life; PFS = progression-free survival; PFS2 = time to second progression or death; RECIST = Response Evaluation Criteria in Solid Tumours; TOI = Trial Outcome Index; PARP = poly (ADP-ribose) polymerase; BRCAm = BRCA gene mutationhttps://clinicaltrials.gov/ct2/show/NCT01844986 (accessed October 2018)

SOLO-1 is a global randomised multicentre placebo controlled Phase III study

• Newly diagnosed, FIGO

stage III–IV, high-grade

serous or endometrioid

ovarian, primary

peritoneal or fallopian tube

cancer

• Germline or somatic

BRCAm

• ECOG performance status

0–1

• Cytoreductive surgery*

• In clinical complete

response or partial

response after platinum-

based chemotherapy

Olaparib 300 mg bid

(N=260)

Placebo

(N=131)

2:1 randomisation

• Study treatment

continued until

disease progression

• Patients with no

evidence of disease

at 2 years stopped

treatment

• Patients with a

partial response at 2

years could

continue treatment

Primary endpoint

• Investigator-assessed PFS

(modified RECIST 1.1)

Secondary endpoints

• PFS using BICR

• PFS2

• Overall survival

• Time from randomisation to first

subsequent therapy or death

• Time from randomisation to

second subsequent therapy or

death

• HRQoL (FACT-O TOI score)

Stratified by response

to platinum-based

chemotherapy

2 years’ treatment if no evidence of disease

Ad esclusivo uso interno Medical Affairs

Analysis

• Prespecified analysis at 206 PFS events

• 90% power at a two-sided significance level of 5%

• Target HR for PFS of 0.62 (median of 21 months

[olaparib] vs. 13 months [placebo])

Protocol amended due to slower than projected

event rate – primary PFS analysis conducted

after ≈196 events OR last patient randomised

had the opportunity to be on study for ≥36

months

Patients in SOLO-1 had a minimum follow-up of 3 years

HR = hazard ratio; PFS = progression-free survival

Moore K et al. Oral presentation LBA7_PR, ESMO (2018)

2013 2014 2015 2016 2017 2018

First patient in:

3 Sep 2013Last patient in:

6 Mar 2015

Data cut-off:

17 May 2018

Minimum follow-up period of 3 years

Baseline characteristics were well balanced between treatment groups

*Clinical complete response was defined as no evidence of (RECIST) measurable or non-measurable disease on the post-treatment scan and a normal CA-125 level.†Partial response was defined as a ≥30% reduction in tumour volume from the start to the end of chemotherapy or no evidence of disease on the post-treatment scan, but with a CA-125 level which had not decreased to within the normal range‡Other includes ovary, fallopian tube, peritoneum, and omentum (N=1), ovary and peritoneum (N=1) and tubo-ovary (N=1)ECOG = Eastern Cooperative Oncology Group; FIGO = International Federation of Gynecology and ObstetricsMoore K et al. N. Engl. J. Med. (2018) ePub ahead of print

Characteristic Olaparib (N=260) Placebo (N=131)

Median age, years (range) 53.0 (29–82) 53.0 (31–84)

Response after platinum-based chemotherapy, N (%)

Clinical complete response*

Partial response†

213 (81.9)

47 (18.1)

107 (81.7)

24 (18.3)

ECOG performance status, N (%)

0

1

Missing

200 (76.9)

60 (23.1)

0

105 (80.2)

25 (19.1)

1 (0.8)

Primary tumour location, N (%)

Ovary

Fallopian tubes

Primary peritoneal

Other‡

220 (84.6)

22 (8.5)

15 (5.8)

3 (1.2)

113 (86.3)

11 (8.4)

7 (5.3)

0

FIGO stage, N (%)

III

IV

220 (84.6)

40 (15.4)

105 (80.2)

26 (19.8)

8

More than 50% of patients in the olaparib arm completed protocol-

defined treatment

DCO: May 2018IQR = interquartile range 1. Moore K et al. N. Engl. J. Med. (2018) ePub ahead of print; 2. Moore K et al. N. Engl. J. Med. (2018) ePub ahead of print [supplementary appendix]

Olaparib Placebo

Randomised, N 260 131

Treated, N 260 130

Discontinued treatment before 2 years

Completed treatment at 2 years per protocol, N (%)

Continued treatment beyond 2 years

Still receiving treatment at data cut-off, N (%)

111 (42.6)

123 (47.3)

26 (10.0)

13 (5.0)

92 (70.7)

35 (26.9)

3 (2.3)

1 (0.8)

Median (mean) total treatment duration (months) 24.6 (052.0) 13.9 (0.245.6)

Median (IQR) duration of follow-up, months40.7

(34.9–42.9)

41.2

(32.2–41.6)

The most common reason for discontinuation was disease

progression

*Other includes study-specific discontinuation criteria, severe non-compliance to protocol and lost to follow-up, among other reasonsDCO: May 2018; Median duration of treatment: olaparib 24.6 months; placebo 13.9 monthsIQR = interquartile range1. Moore K et al. N. Engl. J. Med. (2018) ePub ahead of print; 2. Moore K et al. Oral presentation LBA7_PR, ESMO (2018)

Olaparib Placebo

Randomised, N 260 131

Treated, N 260 130

Discontinued treatment other than protocol defined

stopping rule, N (%)

Objective disease progression

Adverse event

Patient decision

Other*/unknown reason

124 (47.7)

51 (19.6)

30 (11.5)

22 (8.5)

21 (8.1)

94 (72.3)

78 (60.0)

3 (2.3)

2 (1.5)

11 (8.5)

Olaparib reduced the risk of progression or death by 70% vs.

placebo1

DCO: May 2018; Median FU: olaparib, 40.7 months placebo, 41.2 months

Analysis was performed after 198 progression events had occurred (in 50.6% of patients)

PFS = progression-free survival; DCO = data cut-off; HR = hazard ratio; CI = confidence interval

1. Moore K et al. N. Engl. J. Med. (2018) ePub ahead of print; 2. Moore K et al. Oral presentation LBA7_PR, ESMO (2018)

After a median follow-up of 41 months, the median PFS had not been reached in the olaparib

arm (vs. 13.8 months in the placebo arm)1

0 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

0

10

20

30

40

50

60

70

80

90

100

3

Inve

sti

ga

tor-

as

se

ss

ed

pro

gre

ss

ion

-fre

e s

urv

iva

l (%

)

Months since randomisation

260

131

229

103

221

82

212

65

201

56

194

53

184

47

172

41

149

39

138

38

133

31

111

28

88

22

45

6

36

5

4

1

3

0

0

0

0

0

0

0

Olaparib

Placebo

240

118

No. at risk

Olaparib

Placebo

Primary endpoint:

investigator-assessed

PFS

Olaparib Placebo

Events, N (%) 102 (39.2) 96 (73.3)

Median PFS

(months)NR 13.8

HR=0.30

95% CI: 0.23, 0.41

p<0.001

Stima PFS: 49.8 mesi vs 13.8 mesi: ∆36 mesi

Olaparib reduced the risk of progression or death by 70% vs.

placebo1


Analysis was performed after 198 progression events had occurred (in 50.6% of patients)

PFS = progression-free survival; DCO = data cut-off; HR = hazard ratio; CI = confidence interval


0 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

0

10

20

30

40

50

60

70

80

90

100

3

Inve

sti

ga

tor-

as

se

ss

ed

pro

gre

ss

ion

-fre

e s

urv

iva

l (%

)

Months since randomisation

260

131

229

103

221

82

212

65

201

56

194

53

184

47

172

41

149

39

138

38

133

31

111

28

88

22

45

6

36

5

4

1

3

0

0

0

0

0

0

0

Olaparib

Placebo

240

118

No. at risk

Olaparib

Placebo

Primary endpoint:

investigator-assessed

PFS

Olaparib Placebo

Events, N (%) 102 (39.2) 96 (73.3)

Median PFS

(months)NR 13.8

HR=0.30

95% CI: 0.23, 0.41

p<0.001

60.4% progression

free at 3 years

26.9% progression

free at 3 years

A 3 anni solo il 40% delle pazienti trattate con olaparib ricade, contro il 70% delle pazienti

trattate con placebo

A consistent benefit was seen across all PFS subgroups1,2


ECOG = Eastern Cooperative Oncology Group; ULN = upper limit of normal; PFS = progression-free survival; CA-125 =

cancer antigen 125; DCO = data cut-off; HR = hazard ratio


All patients

Response to previous chemotherapy

Complete response

Partial response

ECOG performance status at baseline

Normal activity

Restricted activity

Baseline CA-125 value

≤ULN

>ULN

gBRCA mutation type by Myriad testing

BRCA1

BRCA2

BRCA1/2 (both)

Negative

Age

<65 years

≥65 years

Stage of disease at initial diagnosis

Stage III

Stage IV

Following debulking surgery prior to study entry

Residual macroscopic disease

No residual macroscopic disease

102/260 (39.2)

73/213 (34.3)

29/47 (61.7)

75/200 (37.5)

27/60 (45.0)

92/247 (37.2)

10/13 (76.9)

84/188 (44.7)

15/62 (24.2)

0/3

3/7 (42.9)

85/225 (37.8)

17/35 (48.6)

83/220 (37.7)

19/40 (47.5)

29/55 (52.7)

70/200 (35.0)

96/131 (73.3)

73/107 (68.2)

23/24 (95.8)

76/105 (72.4)

20/25 (80.0)

89/123 (72.4)

7/7 (100.0)

69/91 (75.8)

26/39 (66.7)

0/0

1/1 (100.0)

82/112 (73.2)

14/19 (73.7)

79/105 (75.2)

17/26 (65.4)

23/29 (79.3)

69/98 (70.4)

0.30 (0.23, 0.41)

0.35 (0.26, 0.49)

0.19 (0.11, 0.34)

0.33 (0.24, 0.46)

0.38 (0.21, 0.68)

0.34 (0.25, 0.46)

NC

0.40 (0.29, 0.56)

0.20 (0.10, 0.38)

NC

0.33 (0.24, 0.45)

0.45 (0.22, 0.92)

0.32 (0.24, 0.44)

0.49 (0.25, 0.94)

0.44 (0.25, 0.77)

0.33 (0.23, 0.46)

Subgroup

Olaparib 300 mg bid Placebo bidHR (95% CI)

0.2500 0.5000 1.0000 2.00000.0625 0.1250

Olaparib better Placebo better

Number of patients with events/total number of patients (%)

A 50% reduction in the risk of second progression or death was

observed in SOLO-11,2


Data maturity at 30.9%

PFS2 = progression-free survival 2; DCO = data cut-off; HR = hazard ratio; PARP = poly (ADP-ribose) polymerase


This demonstrates that olaparib maintenance does not diminish the benefit conferred by

subsequent therapy

14

Olaparib Placebo

Events, N (%) 69 (26.5) 52 (39.7)

Median PFS2

(months)NR 41.9

HR=0.50

95% CI: 0.35, 0.72;

p<0.001

0 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

0

10

20

30

40

50

60

70

80

90

100

3

Inve

sti

ga

tor-

as

se

ss

ed

pro

gre

ss

ion

-fre

e s

urv

iva

l (%

)

Months since randomisationNo. at risk

Olaparib

Placebo

Olaparib

Placebo

260

131

239

122

231

113

229

108

225

100

216

92

204

88

194

79

177

73

168

68

163

63

140

55

111

44

61

18

48

11

13

3

5

1

0

0

0

0

0

0

246

126

In 2nd line, PARP inhibitor was

used in 33/94 (35%) and 10/91

(11%) of patients who received a

subsequent therapy in the placebo

and olaparib arms respectively

Efficacy of olaparib was observed beyond a range of efficacy

endpoints vs. placebo1,2

*Time from randomisation to second progression or death; in second line, a PARP inhibitor was used in 33/94 (35%) patients in the placebo arm and 10/91 (11%)

patients in the olaparib arm

DCO: May 2018

PFS2 = progression-free survival 2; DCO = data cut-off; HR = hazard ratio; CI = confidence interval

1. Moore K et al. N. Engl. J. Med. (2018) ePub ahead of print 2. Moore K et al. Oral presentation LBA7_PR, ESMO (2018)

0 10 20 30 40 50 60

Olaparib (N=260) Placebo (N=131)

Data are immature

40.7

Median not reached

15.1

51.8

51.8Median not reached

41.9

Median overall survival

(21.0% maturity)

HR 0.95

95% CI 0.60, 1.53;

p=0.89

Median time to

second subsequent

therapy or death

Median time to first

subsequent

therapy or death

Median PFS2*

(30.9% maturity)

HR 0.50

95% CI 0.35, 0.72;

p<0.001

HR 0.45

95% CI 0.32, 0.63;

p<0.0001

HR 0.30

95% CI 0.22, 0.40;

p<0.0001

Adverse events were mostly mild or moderate in the olaparib arm1,2

DCO: May 2018A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose. results in death, is life-threatening. requires inpatient hospitalisation or causes prolongation of existing hospitalisationAE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; DCO = data cut-off; SAE = serious adverse event1. Moore K et al. N. Engl. J. Med. (2018) ePub ahead of print; 2. Moore K et al. Oral presentation LBA7_PR, ESMO (2018)

Grade ≥3 AEs occurred in 39% of patients in the olaparib arm vs. 19% in the placebo arm


Median duration of treatment, months (range) 24.6 (0-52.0) 13.9 (0.2-45.6)

Any AE, N (%) 256 (98.5) 120 (92.3)

Any AE of CTCAE Grade ≥3, N (%) 102 (39.2) 24 (18.5)

Any SAE, N (%) 54 (20.8) 16 (12.3)

16

Most interventions were managed through dose modifications

without the need for discontinuation1,2

DCO: May 2018

AE = adverse event; DCO = data cut-off

1. Moore K et al. N. Engl. J. Med. (2018) ePub ahead of print [supplementary appendix]; 2. Moore K et al. Oral presentation LBA7_PR, ESMO (2018)

11.5% of patients in the olaparib arm discontinued treatment due to an AE

17


Any AE leading to a dose interruption, N (%) 135 (51.9) 22 (16.9)

Any AE leading to a dose reduction, N (%) 74 (28.5) 4 (3.1)

Any AE leading to discontinuation of treatment, N (%) 30 (11.5) 3 (2.3)

• The most common treatment-emergent AEs leading to discontinuation were

– Nausea (2.3% in the olaparib group vs. 0.8% in the placebo group)

– Anaemia (2.3% in the olaparib group vs. 0% in the placebo group)

The most common AEs reported in patients on olaparib in

SOLO-1 were gastrointestinal disturbances, fatigue and anaemia

*Grouped term

AE = adverse event

1. Moore K et al. Oral presentation LBA7_PR, ESMO (2018)

11,5

26,9

3,8

19,2

24,6

10

14,6

41,5

37,7

23,1

25,4

26,2

27,7

34,2

38,8

40.0

63,5

77,3


Adverse events (%)

Constipation

Dysgeusia

Neutropenia*

Nausea

Fatigue/asthenia*

Vomiting

Diarrhoea

Arthralgia

100 75 50 25 0 0 25 50 75 100

Anaemia*

0.8

3.8

0.4

21.5

3.1

8.5 4.6

1.5

0.8

1.5

All grades (frequency ≥25%)

Grade ≥3 (frequency ≥5%)

All grades (frequency ≥25%)

Grade ≥3 (frequency ≥5%)

The most common haematological AEs were anaemia and

neutropenia1,2

*Grouped term

AE = adverse event

1. Moore K et al. N. Engl. J. Med. (2018) ePub ahead of print; 2. AstraZeneca data on file (2018)

This is consistent with previous trials of olaparib in ovarian cancer

19

Olaparib 300mg bid

(N=260)Placebo (N=130)

Adverse events, % Any grade Grade ≥3 Any grade Grade ≥3

Anaemia* 38.8 21.5 10.0 1.5

Neutropenia* 23.1 8.5 11.5 4.6

Thrombocytopenia* 11.2 0.8 3.8 1.5

The safety and tolerability profile for olaparib in SOLO-1 is consistent

with previous knowledge despite longer duration of therapy

*Grouped term

PSR = platinum-sensitive relapse; CTCAE = Common Terminology Criteria for Adverse Events; AE = adverse event

1. Moore K et al. N. Engl. J. Med. (2018) ePub ahead of print; 2. Pujade-Lauraine E, et al. Lancet Oncol 2017:18(9)1274–1284

SOLO-1 (newly diagnosed BRCAm)1 SOLO-2 (PSR BRCAm)2

Olaparib tablet (N=260) Placebo (N=130) Olaparib tablet (N=195) Placebo (N=99)

Adverse events, % All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade ≥3

Anaemia* 39 22 10 2 43 19 8 2

Neutropenia* 23 9 12 5 20 5 6 4

Thrombocytopenia* 11 1 4 2 13 1 2 1

Nausea 77 1 38 0 76 3 33 0

Fatigue/asthenia 64 4 42 2 66 4 39 2

Vomiting 40 0.4 15 0.8 38 3 19 1

Diarrhoea 34 3 25 0 33 1 20 0

CTCAE Grade ≥3 39 19 36 18

% with AE leading to dose

interruption52 17 45 18

% with AE leading to dose reduction 29 3 25 3

% with AE leading to discontinuation 12 2 11 2

Conclusions

PFS = progression-free survival; AE = adverse event; HRQoL = health-related quality of life; HR = hazard ratio; BRCAm = BRCA gene mutation


Maintenance olaparib led to a substantial, unprecedented improvement in PFS in patients with

newly diagnosed, advanced ovarian cancer and a BRCAm, with a difference in median PFS

estimated to be in the region of 3 years1,2

21

A 70% reduction in risk of disease progression or death was observed for olaparib vs. placebo-treated

patients (HR 0.30; p<0.001)1

• After a median follow up of 41 months, median PFS was not reached on the olaparib arm vs. 13.8 months

for placebo with PFS at 3 years: 60.4% vs. 26.9% for olaparib vs placebo1

A reduction in the risk of second progression or death was observed demonstrating that olaparib maintenance

does not diminish the benefit conferred by subsequent therapy1

The safety profile is consistent with previous olaparib data with most AEs being mild or moderate in

severity and generally not leading to dose reduction or permanent discontinuation1

There was no decrease in HRQoL from baseline for olaparib-treated patients over the 24-month treatment

period and no clinically important differences in HRQoL compared with placebo-treated patients1

Ad esclusivo uso interno Medical Affairs

solo-1€¦ · solo-1 is the first phase iii trial to investigate maintenance therapy with a parp...

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