CÁNCER DE OVARIO Y BRCA:

MUTACIÓN SOMÁTICA O GERMINAL

ENFOQUE TERAPÉUTICO

RAQUEL BRATOS HOSPITAL MD ANDERSON

MADRID

OUTLINE

1. INTRODUCTION

2. BEYOND BRCA1 AND BRCA2 IN OVARIAN CANCER

3. PREDICTIVE AND PROGNOSTIC FACTOR

4. BRCA TESTING: WHO, HOW AND WHEN?

5. PARP INHIBITORS

6. CONCLUSIONS

1. INTRODUCTION

OVARIAN CANCER

• Approximately 14% of high grade ovarian cancers are attributable to germline mutations in BRCA1 and BRCA2. However, most ovarian cancer can be attributable to a growing number of somatic abberations

• Germline and somatic mutations in HR genes occur in

approximately 31% of patients with ovarian carcinoma – Of these, 75% of germline HR mutations and 71% of

somatic HR mutations are typically in BRCA

• Identification of BRCA ½ mutations is relevant for…

– Prognosis – Therapeutic decission making – Cancer risk assessment

• Estimation of the lifetime risk of cancer in a individual and/or her family • Identification of individuals at sufficient risk to consider enhanced screening

or other prevention strategies

Cancer Genome Atlas Research Network. Nature 2011;474:609–615. Pennington K et al. Clin Cancer Res, 2014, 20: 764–775. Bolton K et al. JAMA 2012; 307:382-390. Vencken PM et al. Ann Oncol 2011; 22: 1346-1352. Audeh MW et al. Lancet 2010; 376:245-251. Balmaña J. J Natl Cancer Inst 2015; 107 (11):djv262

2. BEYOND BRCA ½ IN OV. CA

Walsh T et al. Proc Natl Aca Sci USA 2011; 108: 18032-18037

360 carcinomas Unselected by age or family history

24% germline mut. 31% NO prior BC or family history 37% diagnosed >60y

11,1%

6,1%

6%

BEYOND BRCA ½ IN Ov. Ca.

Pennington K et al. Clin Cancer Res 2014; 20: 764-775

390 carcinomas (367 individuals)

BEYOND BRCA ½ IN Ov. Ca.

Mucinous, n=16 no mutations

Norquist B et al. JAMA Oncol 2016; 2: 482-490

1915 individuals: -570 University of Washington -788 GOG 218 -557 GOG 262 Enrolled at diagnosis, unselected by age or

family history Mutation frequencies were compared with the

National Heart, Lung and Blood Institute GO Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC)

18% carried a germline mutation:

-14,6% in BRCA1 (9,5%) or BRCA2 (5,1%)

-3,3% in BRIP1, RAD51C, RAD51D, PALB2, BARD1 (Anemia Fanconi-BRCA pathway)

-0,4% in a MMR gene (MSH2, MLH1, PMS2 and MSH6)

No more mutation in OvC: CHEK2, NBN, RAD50, FAM175A and MRE11A

ATM and TP53: NS

BEYOND BRCA ½ IN Ov. Ca.

GENOMIC SCARS

3. PREDICTIVE AND PROGNOSTIC FACTOR

80%

92%

60%

66m

59m

41m

70m

59m 41m

Pennington K et al. Clin Cancer Res 2014; 20: 764-775

PREDICTIVE AND PROGNOSTIC F.

PREDICTIVE AND PROGNOSTIC F.

4. BRCA TESTING:

WHO, HOW AND WHEN?

WHO? gBRCA Study Population BRCA1/2 prevalence BRCA1/2 frequency by

subtype

Hirsh-Yechezkel, 2003, Israel

(3 Founder Mut)

EOC (896:779 invasive C+117 BOT)

Non EOC (40)

PPC (68)

Invasive C: 29,4%

Non-EOC: 5%

PPC:27,9%

Invasive C: 29,4%

Non-EOC: 5%

PPC:27,9%

Malander, 2004, Sweden EOC (161) 17/161 (10,5%) Serous: 7,6%; Endometrioid: 13%; Clear cell:12,5; Mucinous: 0%

Risch, 2006, Canada EOC (1171:977 invasive+194 BOT)

129/977 (13,2%) Serous: 18%; Endometrioid/Clear cell: 7,1%; Mucinous: 0%

Zhang, 2011, Canada Invasive OvC (1342) 176/1342 (13,3%) Serous: 18%; Endometrioid: 9,1%; Clear cell:2,2%; Mucinous: 0%; Ca-Sa/Not specified:7/15,2%

Jacobi, 2007, Netherlands Invasive OvC (85) 5 Pat. mutations:6,1%

6 Unclassified v:7,3%

Serous: 10,8%; Endometrioid, clear cell and mucinous: 0%

Soegaard, 2008, Denmark Invasive OvC (445) 26/445 (5,8%) Serous: 5,4%; Endometrioid: 5,3%; Clear cell:9%; Mucinous: 0%

TCGA, 2011 HGSOvCa (316) 14% High grade Serous:14%

Alsop, 2012, Australian Non-mucinous OvC (1001) 141/1001 ( (14,1%) Serous: 16,6%; Endometrioid: 8,4%; Clear cell:6,3%

Pennington, 2014,

Washington

Invasive carcinoma (367) 66/367 (18%) Serous: 20%; Endometrioid: 7,6%; Clear cell: 0%; Mucinous: 0%

Approximately 35% of BRCA1/2 mutation carriers do not have a family history

sBRCA

Study Population sBRCA1/2 frequency

Hennessy, 2010 235 unselected ovarian carcinoma 4,8%

TCGA, 2011 489 high grade serous ovarian carcinoma 6,3%

Alsop, 2012 1001 non-mucinous ovarian carcinoma 6%

Pennington, 2014 390 invasive carcinoma 6,8%

Ledermann, 2014

265 recurrent high grade serous ovarian carcinomas, platinum- sensitive

7%

Hennessy B et al. J Clin Oncol 2010; 28:3570-3576. Cancer Genome Atlas Research Network. Nature 2011;474:609-615. Alsop K et al. J Clin Oncol 2012;30:2654-2663. Pennington K et al. Clin Cancer Res 2013; 20:764-775. Ledermann J et al. Lancet Oncol 2014; 15:852-861.

HOW?

• Samples:

– Blood/ mucosal membrane/ buccal swab

– Tumor tissue

• Molecular techniques:

– Direct sequencing

– Next generation sequencing. Multigene panels

– MLPA (Multiplex ligation-dependent probe amplification)

gBRCA testing

sBRCA testing

wtBRCA

gBRCA wt sBRCA+

No BRCA

sBRCA+

gBRCA+

wt

+

wt

+

PRESENT FLOW DIAGRAM

sBRCA testing at Dº

Directed

gBRCA testing

(GC)

sBRCA+ gBRCA+

gBRCA wt sBRCA+

gBRCA+

sBRCA+

wt BRCA

+

-

+

wt

PROPOSED FLOW DIAGRAM

WHEN?

• EOC SURGICAL MANAGEMENT: – Surgery stage IV EOC: indication for more aggressive surgery

in gBRCA carriers? • gBRCA more prone to be stage IV • Stage IV <1 cm: better prognosis

– Secondary cytoreduction: DESKTOP III trial translational analysis

– Surgery advanced EOC

• FIRST-LINE SYSTEMIC TREATMENT: – Intraperitoneal chemotherapy – Standard CT – Trials (SOLO-1, PAOLA-1, PRIMA…)

Gourley C K et al. J Clin Oncol 2010; 28: 2505-2511. Ataseven B et al. Gynecol Oncol 2016; 140: 215-220. Riester M et al. J Natl Cancer Inst 2014; 106. Lesnock JL. Br J cancer 2013; 108:1231-1237

WHEN?

• SECOND LINE TREATMENT – Bevacizumab-Carboplatin-

Gemcitabine – Olaparib maintenance after

platinum-based chemo – Pegilated lyposomal doxorubicin-

trabectedin

• RETREATMENT WITH PLATIN

REGIMEN AFTER PROGRESSION < 6 m

– Treatment response was based on a 50% decrease in Ca 125 for 28 d

– 25% (4/16) of responders to platinum on a third occasion had a

sBRCA mutation

Alsop K et al. J Clin Oncol 2012; 30: 2654-2663

5. PARP inh.

PARP

DNA damage (SSBs)

DNA replication (accumulation of DNA DSBs)

Normal cell with functional HR

pathway

HR-deficient tumor

cell. HRD

Cell survival Cell death

HR-mediated DNA repair Impair HR -mediated DNA repair

Tumor-selective cytotoxicity

PARP inhibitor agents

Farmer H et al. Nature 2005;434:917–921 Bryant HE et al. Nature 2005;434:913–917 McCabe N et al. Cancer Res 2006;66:8109–8115

ACTION MECHANISM

Courtesy Dr. A. González-Martín

PARP inh. AGENTS

• Treatment until disease progression

Olaparib 400 mg po bid (n=136)

Placebo po bid (n=129)

Primary endpoint PFS

Pre-specified exploratory

analysis of all efficacy

end-points according to BRCA status

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

N = 265

Platinum-sensitive high grade serous ovarian

cancer

>/= 2 previous platinum regimens

Last chemotherapy was platinum-based to wich

they had a mantained PR or CR prior to enrolment

Stable Ca 125

STUDY 19

0

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

Pro

bab

ilit

y o

f

pro

gressio

n-f

ree s

urviv

al

Time from randomization (months)

Hazard ratio 0.35,

(95% CI, 0.25–0.49); P<0.00001

Randomized treatment

Placebo

Olaparib 400 mg bid monotherapy

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

4.8 mos

• Interim OS analysis: HR=0.94; (95% CI, 0.63–1.39); p=0.75 (29.7 mos vs 29.9 mos)

8.4 mos

STUDY 19: PFS

STUDY 19: PFS by BRCAm status

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

7,4

STUDY 19: FINAL OS ANALYSIS

Gourley Ch. et al. ASCO 2017; Abstact 5533. Poster 355 Ledermann J et al. Lancet Oncol 2016; 17: 1579-1589

STUDY 19: OS BRCAm patients

Time to first subsequent therapy or death significantly

improved with olaparib

Time to second subsequent therapy or death significantly

improved with olaparib

Represents the time

women are

free from next line

of chemotherapy

Can demonstrate benefit

beyond the next line

of chemotherapy; helps

address the confounding

impact of crossover

15,6 vs 6,2 m HR 0.32

95% CI 0.22-0.48

p < 0.00001

22 vs 15,3 m HR 0.41

95% CI 0.26-0.62

P = 0.00001

STUDY 19: BRCAm patients. TFST & TSST

STUDY 19: RETROSPECTIVE

BIOMARKER ANALYSIS

Gourley Ch. et al. ASCO 2017; Abstact 5533. Poster 355

PROTOCOL 42

Ovarian cohort (Ov C+ FTC +PPC) : 193 •gBRCA1m:77% •gBRCA2m:23% •PS (28%), PR (56%) y PRf (10%) •Mean prior regimens: 4,3 (1-14) •Prior platinum therapy •Platinum resistant or ”no suitable for further platinum therapy”

Kauffman B et al. J Clin Oncol 2015; 33: 244-250

PROTOCOL 42

Kauffman B et al. J Clin Oncol 2015; 33: 244-250

OLAPARIB

December 2014

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*)

Olaparib 300 mg bid (n=196)

Placebo bid (n=99)

Primary endpoint

Investigator-assessed PFS

N = 295

BRCA1/2 mutation

Platinum-sensitive relapsed ovarian cancer

At least 2 prior lines of

platinum therapy

CR or PR prior to most recent platinum therapy

SOLO-2. ENGOT-Ov21

*Primary endpoint for HRQoL was trial outcome index (TOI) of the FACT-O (Functional Assessment of Cancer Therapy – Ovarian)

Characteristic Olaparib (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)

SOLO-2: baseline characteristics

Pujade-Lauraine E. Annual meeting on women´s cancer. March 2017 Slides are the property of AZ

No. at risk

Olaparib Placebo

196 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

gressio

n-f

ree s

urviv

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

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

SOLO-2: PFS by investigator assessment

Pujade-Lauraine E. Annual meeting on women´s cancer. March 2017 Slides are the property of AZ

Months since randomization

Pro

gressio

n-f

ree s

urviv

al

(%

)

100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12 15 18 21 24 27 33

30.2 5.5

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)

Median PFS, months 30.2 5.5

HR 0.25

95% CI 0.18 to 0.35

P<0.0001

Olaparib

Placebo

SOLO-2: PFS sensitivity analysis using BICR

Pujade-Lauraine E. Annual meeting on women´s cancer. March 2017 Slides are the property of AZ

27.9

7.1

18.4

Not reached

18.2

PFS2

0 10 20 30

Median (months)

Olaparib

Placebo

Data immature Overall survival

Time to first subsequent

therapy, or death (TFST)

Time to second subsequent

therapy, or death (TSST)

HR 0.28

95% CI 0.21- 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

SOLO-2: Secondary efficacy endpoints

Pujade-Lauraine E. Annual meeting on women´s cancer. March 2017 Slides are the property of AZ

Swisher E et al. Lancet Oncol 2017; 18: 75-87

Key Eligibility (N=206)

•High-grade serous or endometrioid OvC

(Known germline BRCA enrollment capped at

N=15)

•≥1 prior platinum CT

•Platinum-sensitive, relapsed, measurable

disease

•Tumor tissue (screening biopsy and

archival)

tBRCAmut

tBRCA-like (LOH high)

Biomarker Negative

(LOH low)

600 mg BID rucaparib until

disease progression

NGS of tumor tissue allows patients to be

classified

Primary endpoint: PFS

Unclassified 6%

(n=12) tBRCAmut* 20%

(n=40)

tBRCA-like

40% (n=82)

Biomarker negative

34% (n=70)

59% 1 platinum line 41% > 2 platinum lines

ARIEL-2 (Part 1)

CD Test: Foundation Medicine T5 NGS-based. FFPE BRCAt status & % genomic LOH (>16%)

Courtesy Dr. A. González-Martín

41

tBRCAmut 40 (0) 40 (0) 38 (1) 38 (1) 36 (3) 36 (3) 32 (5) 31 (5) 25 (9) 22 (10) 18 (12) 13 (13) 13 (15) 8 (15) 6 (16) 6 (16) 1 (18)

tBRCA-like 82 (0) 75 (3) 59 (13) 54 (17) 46 (25) 42 (27) 34 (35) 29 (37) 25 (40) 21 (44) 14 (45) 10 (46) 6 (47) 4 (48) 2 (48) 2 (48) 2 (48) 1 (49) 1 (49) 0 (50)

Biomarker negative

70 (0) 68 (0) 52 (15) 46 (17) 33 (29) 32 (29) 22 (37) 20 (38) 13 (44) 11 (45) 5 (49) 4 (49) 2(51) 1 (51) 0 (51)

Available (endpoint reached)

16 10 11

tBRCAmut

tBRCA-like Biomarker negative

0 1 2 3 4 5 6 7 8 9 12 Time (months)

PFS

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

13 14 15

Subgroup comparison

HR (95% CI) p-value

tBRCAmut vs

Biomarker negative 0.22 (0.12, 0.40) <0.0001

tBRCA-like vs

Biomarker negative 0.67 (0.45, 0.99) 0.0445

Median PFS (95% CI)

12.8 (9.0, 14,7 )

5.7 (5.2, 7.6)

5.3 (3.5, 7.1)

HRD molecular subgroup

ORR RECIST , % (N)

Median DoR, mo (95% CI)

tBRCAmut 75 (30/40) 9.5 (7.4, 12.9)

tBRCA-like 36 (28/77) 8.2 (5.6, 10.8)

Biomarker negative 16 (11/68) 5.5 (2.1, 7.4)

Swisher E et al. Lancet Oncol 2017; 18: 75-87

ARIEL-2: PFS in tBRCAmut and tBRCA-like vs biomarker negative

Courtesy Dr. A. González-Martín

FDA approval of Rucaparib

• ARIEL2 (part 2) and ARIEL3 will prospectively validate the assay in a different cohort of patients

ARIEL2 Part 2 (N=300)

Single arm in HGOC (S, R, Rf) patients who have

received 3-4 prior chemotherapy regimens

(NCT01891344)

ARIEL3 (N=540)

Randomized maintenance study rucaparib vs placebo in HGOC patients who have

received ≥2 platinum regimens (NCT01968213)

The HRD algorithm will be applied prospectively to two ongoing trials

Prospective validation of HRD assay defined by LOH

gBRCAmut 203

Treat until Progression of

Disease

Niraparib 300 mg

once daily

Placebo

Non-gBRCAmut 350

Treat until Progression of

Disease

Niraparib 300 mg

once daily Placebo

2:1 Randomization 2:1 Randomization

Platinum-Sensitive Recurrent High Grade Serous Ovarian Cancer

Response to Platinum Treatment

Treatment with 4-6 Cycles of Platinum-based Therapy

553

ENGOT-OV16: NOVA

CD Test: Myriad “MyChoice” HDR NGS-based BRCA status & HDR score (TAI+LOH+LST >42)

PFS: gBRCAmut

Treatment

PFS Median (95%

CI) (Ms)

Hazard Ratio

(95% CI) p-value

% of Patients without

Progression or Death

12 mo

18 mo

Niraparib

N=138

21.0 (12.9, NR)

0.27

(0.173, 0.410)

p<0.0001

62% 50%

Placebo

(N=65)

5.5 (3.8, 7.2)

16% 16%

PFS was analyzed using a 2-sided log-rank test using randomization stratification factors, and summarized using the Kaplan-Meier methodology. Hazard ratios with 2-sided 95% confidence intervals were estimated using a stratified Cox

proportional hazards model, with the stratification factors used in randomization.

NR=not reached

Mirza MR et al. N Engl J Med 2016; 375: 2154-2164 Presidential Symposium, ESMO 2016

Courtesy Dr. A. González-Martín

Treatment

PFS Median (95%

CI) (Months

)

Hazard Ratio

(95% CI) p-value

% of Patients without

Progression or Death

12 mo

18 mo

Niraparib

(N=106)

12.9 (8.1, 15.9)

0.38

(0.243, 0.586)

p<0.0001

51% 37%

Placebo

(N=56)

3.8 (3.5, 5.7)

13% 9%

PFS: non-gBRCAmut, HRD positive

Mirza MR et al. N Engl J Med 2016; 375: 2154-2164 Presidential Symposium, ESMO 2016

Courtesy Dr. A. González-Martín

Treatment

PFS Median (95%

CI) (Months

)

Hazard Ratio

(95% CI) p-value

% of Patients without

Progression or Death

12 mo

18 mo

Niraparib

N=234

9.3 (7.2, 11.2)

0.45

(0.338, 0.607)

p<0.0001

41% 30%

Placebo

N=116

3.9 (3.7, 5.5)

14% 12%

PFS: non-gBRCAmut

Mirza MR et al. N Engl J Med 2016; 375: 2154-2164 Presidential Symposium, ESMO 2016

BRCAwt

Treatment

PFS Median (95%

CI) (Month

s)

Hazard Ratio (95%

CI) p-value

% of Patients without

Progression

or Death 12 mo

18 mo

Niraparib

(N=71)

9.3 (5.8, 15.4)

0.38

(0.231, 0.628)

p=0.0001

45%

27%

Placebo

(N=44)

3.7 (3.3, 5.6)

11%

6%

Treatment

PFS Median (95%

CI) (Month

s)

Hazard Ratio (95%

CI) p-value

% of Patients without

Progression

or Death 12 mo

18 mo

Niraparib (N=35)

20.9 (9.7, NR)

0.27

(0.081, 0.903)

p=0.0248

62%

52%

Placebo (N=12)

11.0 (2.0, NR)

19%

19%

sBRCAmut

Treatment

PFS Media

n (95%

CI) (Mont

hs)

Hazard Ratio (95%

CI) p-value

% of Patients without

Progression or Death

12 mo

18

mo Niraparib

(N=92) 6.9 (5.6, 9.6)

0.58

(0.361, 0.922)

p=0.0226

27%

19%

Placebo

(N=42) 3.8 (3.7, 5.6)

7% 7%

HRD-positive HRD-negative

Exploratory Analysis: PFS in subgroups of Non-gBRCAmut Cohort

Mirza MR et al. N Engl J Med 2016; 375: 2154-2164 Presidential Symposium, ESMO 2016 Courtesy Dr. A. González-Martín

FDA approval of Niraparib

Summary approved PARPinh

OLAPARIB RUCAPARIB NIRAPARIB

Indication Maintenance BRCA relapsed Pt-sensitive Ov Ca (EMA)

BRCAmut Ov Ca with 3 or more prior lines (FDA)

BRCAmut Ov Ca with 2 or more prior lines (FDA)

Maintenance with recurrent Ov Ca in CR or PR to platinum-based chemo (FDA)

Phase II/III II III

Dose reduction 42 % / 25% 39% 66,5%

Main Toxicity Anemia Anemia > neutrop > thrombopenia

Thrombo> anemia > neutropenia

MDS/AML 2 (1.4%) /4 (2.1%) 0 5 (1,4%)

PFS gBRCAmut 19,1 vs 5,5 m ; HR:0.3 30,2 vs 5,5 m; HR:0,25

12,8 m 21 vs 5,5 m HR:0,27

5. CONCLUSIONS

MESSAGES TO HOME

• Time has come for incorporation of genetics into the practice of ovarian cancer

• BRCAmut Ov Ca. is a distinct entity

• Recommendations are in favour of… • Early testing, at best at initial diagnosis for all non-mucinous epithelial

OvC independently of age and family history

• BRCA testing in healthy individuals is an opportunity for cancer prevention

• Several PARP inhibitors are disponible in our clinical practice

• Genomic scars (HRD signatures) require further validation for routine clinical use

QUESTIONS…???

GRACIAS

rbratosl@mdanderson.es