La scelta terapeutica nel carcinoma ovarico avanzato guidata da istotipo e caratteristiche biomolecolari: novità e prospettive future

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La scelta terapeutica nel carcinoma ovarico avanzato guidata da istotipo e caratteristiche biomolecolari: novità e prospettive future

Dr.ssa Lorena Incorvaia

Tutor Roberto Sabbatini

Azienda Ospedaliera Universitaria Policlinco

«P.Giaccone» Palermo

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Ovarian Cancer: setting the scene

 5 Y survival <25% for stage III/IV

Minimal improvement in ovarian cancer mortality rates – no new front-line therapy for >20 years

(3)

Cisplatin

Cisplatin Paclitaxel

Carboplatin Paclitaxel

Platinum Paclitaxel Bevacizumab

0 5 10 15 20 25 30

1990 1993 1998 2013

DFS

Survie depuis rechute Survie globale

Survival from recurrence Overall survival

The overall survival increase in ovarian cancer is mainly due to the treatment of recurrent disease

Primary Treatment

Cytoreductive surgery + platinum based

Carboplatin-Paclitaxel PFS = 16-23 m OS = 31-65 m

Intraperitoneal Chemotherapy

PFS = + 5.5 m OS = + 15 m

Weekly Carboplatin- Paclitaxel

PFS = + 10.8 m

Carboplatin-Paclitaxel + bevacizumab

PFS = + 4 m

First line treatment options in advanced ovarian cancer at present

Karam A, et al. Annals of oncology 2017

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Recurrence very common: multiple ralapses

 75% of patients responde to first line platinum-based chemotherapy

 70% of them experience recurrences within 24 months

(5)

The platinum free interval dogma

Refractory Resistent

Partially sensitive Fully sensitive

Relapsed ovarian cancer categories

Choise of treatment: What did we know?

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Epithelial ovarian tumors: from singular to plural Choise of treatment: What do we know today?

The backstage….

(7)

Epithelial Ovarian cancer is not a unique disease

Epithelial ovarian tumors

(8)

Impact of histological subtype

(9)

Prognostic impact of separating HGSOC and LGSOC

(10)

Histology more important?

Relapsed ovarian cancer categories

Choise of treatment: What do we know today?

(11)

Treatment guidance by histologic type

WHO 2014 diagnostic criteria

(12)

Low grade serous cancer

- Young age at diagnosis - Chemoresistance

- Prolonged overall survival

- May arise de novo or following diagnosis of serous borderline tumor

- Aberrations within the MAP kinase signaling pathway

Farley et al. Lancet Oncol 2013 Friday et al. Cancer Res 2008

Ras

MEK

ERK

Other substrates Frequent

mutations in SBTs and

low-grade serous carcinomas

Raf

MAPK

P P P

P P

MAPK

Elk SA

P ^Target_genes

Nucleus

Y

Growth factor

SBT: serous borderline tumour

• Selumetinib, trametinib

– Potent – Selective

– Orally available

– Non-ATP competitive inhibitor of the mitogen-activated protein kinase (MAPK), MEK-1/2

(13)

Recurrent or persistent low-grade serous carcinomas of the ovary,

fallopian tube or primary peritoneum

MEK162

CT

(liposomal doxorubicin, Paclitaxel

or topotecan)

MILO Study

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Hormonal Maintenance Therapy for Women with Low-Grade Serous Carcinoma of the

Ovary or Peritoneum

David M. Gershenson, MD

• High frequency of ER and PR expression in LGSC

Wong et al. Int J Gynecol Pathol 2007

• Hormonal therapy for recurrent LGSC associated with ORR = 9%, SD = 66%, median PFS = 7.4 mo

Gershenson et al. Gynecol Oncol 2012

• LGSC similar to luminal breast cancer: Worse prognosis for women age < 35 y Gershenson et al. J Clin Oncol 2015

Rationale

(15)

Stage II- IV LGSC

Primary Cytoreductive

Surgery

Platinum- Based

Chemotherapy

Surveillance

N = 134

Hormonal

Maintenance

Therapy N = 70

David M. Gershenson, MD ASCO 2016

Hormonal Maintenance Therapy for Women with Low-Grade Serous Carcinoma of the

Ovary or Peritoneum

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Group Median PFS (mo)

95% CI P- Value

SURV

(n = 121) 29.9 24.5, 35.2

< .001

HMT

(n = 27) 81.1 55.2, 106.9

ALL

(N = 148) 33.0 28.4, 37.7

p<.001 Results: PFS in Patients NED at Completion of

Chemotherapy

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Results: OS in Patients NED at Completion of Chemotherapy

Group Median OS (mo)

95% CI P- Value

SURV

(n = 121) 106.8 72.8, 140.7

.04

HMT

(n = 27) 191.3 93.5, 289.1

ALL

(N = 148) 115.7 86.5, 144.9

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Choise of treatment: What do we know today?

From singular to plural

Molecular profile

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Epithelial Ovarian cancer: Molecular profiling

Epithelial ovarian tumors

(20)

What did we know? What do we know today?

Family history OC/BC Age at diagnosis BRCA1/BRCA2 Germline Mutations

BRCA mutation is not correlate to age and

family history

Beyond gBRCA1/BRCA2:

Not only germline mutations: somatic!

Not only BRCA: “HRD phenotype”

BRCA testing

prognostic and predictive value:

BIOMARKER!

Molecular Profiling of High-Grade Serous Ovarian Cancer

Surveillance program Prophylactic

surgery

(21)

• Approximately 35%-40% of BRCA 1-2 mutation carriers do not have a family history of cancer

BRCA mutation is not correlated to age and family history

• At least 25% of BRCA 1-2 mutation carriers are >60 yrs old

Available evidence

Median Age BRCA 1/2

Yrs

BRCA 1 + Yrs

BRCA 2 + Yrs

Alsop et al. 60 53 60

Soegaard et al. 61 49

Risch et al. 56 51 57

Malander et al. 59 57

Song et al. 59 52 57

Age is not a good predictor of BRCA mutation

BRCA Mutation Carriers Who Lack a Family History (%)

Walsh et al. 27

Soegaard et al. 54

Malander et al. 8

Risch et al. 37

Alsop et al. 44

Song et al. 39

Family history is not a good predictor of BRCA mutation

(22)

BRCA mutation is not correlated to histotype

Alsop K, et al. J Clin Oncol 2012; 30: 2654–63.

BRCA mutation in 14.1% of the studied population

 16.6% of serous histotype

 22.6% of high grade serous subtype

Available evidence

 6.3% of clear cell subtype

 8.4% of endometrioid subtype

(23)

Total population

(%)

Serous

(%) Endometrioid

(%) Clear Cell

(%) Mucinous

(%)

Alsop et al. 14.1 16.6 8.4 6.3 NA

Risch et al. 13.2 18.0 7.1 7.1 0

Soegaard et al. 5.8 5.4 5.4 9.1 0

Jacobi et al. 13.9 10.8 0 0 0

Malander et al. 8 7.6 13.0 12.5 0

Soergaard M. et al., Clin Cancer Rev. 2008; Risch HA et al., JNCI 2006; Alsop K et al., JCO 2012 Malander S. et al., EJC, 2004; Jacobi CE et al., Genet Med, 2007

Available evidence

Histotype is not a good predictor of BRCA mutation

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What did we know? What do we know today?

Family history OC/BC Age at diagnosis

BRCA1/BRCA2

Surveillance program

Prophylactic surgery

family history

Beyond BRCA1/BRCA2:

 “Beyond HR repair genes”

 “HRD phenotype”

BRCA test: prognostic and predictive value:

BIOMARKER!

(25)

1. Prognostic

Patients with BRCA mutated ovarian cancer show a significantly more favourable prognosis

BRCA: impact of germline mutations

Bolton KL, et al. JAMA. 2012;307(4):382-390. Zhong Q et al. Clin Cancer Res. 2014;21(1):211-220.

5-year survival:

•BRCA1 – 44%

•BRCA2 – 61%

•No mutation – 25%

Bolton KL, et al. JAMA. 2012;307(4):382-390. Zhong Q et al. Clin Cancer Res. 2014;21(1):211-220.

(26)

Pts with gBRCA mutations have a longer survival than in women with sporadic ovarian cancer

1. Prognostic

(27)

BRCA: impact on patient therapy 2. Predictive

Improved survival in BRCA-mutated ovarian

cancer patients treated with Intraperitoneal cisplatin and paclitaxel

Lesnock JL, Br J Cancer, 2013

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BRCA: impact on patient therapy

2. Predictive

(29)

BRCA: impact on patient therapy 2. Predictive

Trabectedin in patients with BRCA-mutated and BRCAness phenotype Advanced Ovarian Cancer (AOC): Phase II Prospective

MITO-15 Study

(30)

BRCA: impact on patient therapy 2. Predictive

Analysis of OV-301 according to BRCA status

Monk BJ Ann Oncol 2015

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Study 19: OLAPARIB. PFS by BRCAm status

0

Time from randomization (months)

0 1.0

Proportion of patients progression- free

3 6 9 12 15

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

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 Placebo Events: total pts (%) 26:74 (35.1) 46:62 (74.2) Median PFS, months 11.2 4.3

HR=0.18 95% CI (0.11, 0.31);

P<0.00001

BRCA: impact on patient therapy

2. Predictive

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SOLO-1, -2, -3

Randomized phase III studies of Olaparib in OC

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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

Progression-free survival (%)

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

Presented by Pujade-Lauraine at SGO 2017 annual meeting

SOLO 2, PFS by investigator assessment

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Abbreviations: MMR, mismatch repair; BER, base excision repair; NHEJ, nonhomologous end-

joining; HRR, homologous recombination repair; NER, nucleotide excision repair; TLJ, translesional joining.

Major interactive pathways involved in DNA damage and repair

(35)

Functioning PARP1

Single- strand

break PARP1

Repaired DNA Mutation in

BRCA1 or BRCA2 gene

Cell death PARP

1

PARP- inhibitor

No DNA repair Single-

strand break

Collapsed replication

fork Double-

strand break

No homologous recombination

No repair

PARPi- sensitive

PARP inhibitor and tumor selective synthetic lethality

PARP1

Incorvaia et Al, Oncotarget 2016

(36)

Age and family history are not sufficient criteria for BRCA testing

Histologic type (except mucinous) is not a sufficient criterio for BRCA testing

Key points

BRCA is predictive of PARP-inhibitor sensitivity

BRCA testing for all women with epitelial ovarian cancer, regardless of age,

histologic type and family history

(37)

What did we know? What do we know today?

Family history OC/BC Age at diagnosis

BRCA1/BRCA2

Surveillance program

Early diagnosis

Prophylactic surgery

Tumor risk reduction

family history

Beyond BRCA1/BRCA2:

 “Beyond HR repair genes”

 “HRD phenotype”

BRCA test: prognostic and predictive value

(38)

Beyond germline BRCA1/2 mutations

Not only germline mutations Not only BRCA mutations

(39)

HR gene mutations are not restricted to

BRCA

(40)

Sensitivity to DNA repair inhibitors?

BRCA-like signature

Beyond BRCA: “HRD phenotype”

BRCA germline mutation BRCA somatic

mutation HR mutation,

non-BRCA

(41)

Parp-inhibitor trials for sporadic, BRCA WT, ovarian cancer:

Do we have one?

Rucaparib, Ariel 3 trial

Niraparib, NOVA trial

2 Randomised maintenance trials following platinum-based chemotherapy in BRCAm and BRCAwt

gBRCAmut

Non-gBRCAmut gBRCAmut

BRCA-like

Biomarker negative

(42)

Homologous Recombination Deficiency (HRD) Assay Do we have one?

ARIEL 2, ASCO 2015 Biomarker

negative gBRCAmut

BRCA-like

ORR 80%

ORR 29%

ORR 10%

Rucaparib, Ariel 2 trial

(43)

McNeish IA, et al. J Clin Oncol. 2015;

Homologous Recombination Deficiency (HRD) Assay

Do we have one?

(44)

• Loss of heterozygosity (LOH)

• Telomeric allelic imbalance (TAI)

• Large-scale state transitions (LST)

HRD score is sum of LOH + TAI + LST scores

- Presented evidence of correlation between HRD score and in vitro/in vivo response to niraparib in 106 tumor samples

Thus:

- Two assays under further evaluation, as key elements in 2 randomized maintenance trials, with niraparib and rucaparib in sporadic and BRCAm- associated ovarian cancer

Developed HRD score in the NOVA trial incorporating 3 components:

Homologous Recombination Deficiency (HRD) Assay Do we have another?

Haluska P et al, NCI/EORTC/AACR 2014 (Eur J Cancer. 2014)

(45)

gBRCAmut Non-gBRCAmut

Non-gBRCAmut cohort, HRDpos group

NOVA trial, Niraparib PFS

Mirza MR et al. N Engl J Med. 2016

(46)

Germline

BRCA1/BRCA2 “HRD phenotype”

Olaparib Niraparib Rucaparib

…...

Molecular Profiling of High-Grade Serous Ovarian Cancer

(47)

Choise of treatment: What do we know today?

Molecular biology more important?

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Identifying the HR Deficiency Signature

Identifying the subset of BRCA-like tumors, which respond to HRR- directed therapy

OC and HR: How the debate is evolving?

Need for Biomarkers!

Panel testing:

Which molecular alterations most important?

Sensitivity to targeted therapy? Clinically relevant?

Heterogeneity!

How can we account for heterogeneity and dynamic changes that

occur in response to a given targeted therapy?

(49)

Tumor Heterogeneity

(50)

BRCA2 BRCA1 RAD51 BRIP EMSY FANCF TP53 CHECK2 ATM ATR

BRCA1/2

ATM/

ATR

BRCA1/2

Tp53

ATM/

ATR ATM/

ATR

ATM/

ATR

ATM/

ATR ATM/

ATR

ATM/

ATR ATM/

ATR

ATM/

ATR

ATM/

ATR

ATM/

ATR ATM/

ATR

BRCA1/2 BRCA1/2

BRCA1/2

BRCA1/2 Tp53

Tp53

Tp53 Tp53

Tp53

Tp53 Tp53

Tp53

Tp53 Tp53 Tp53

Tp53

Beltrame L et al., Ann Oncol 2015

BRCA1/2

ATM/

ATR

ATM/

ATR ATM/

ATR

ATM/

ATR

ATM/

ATR ATM/

ATR

ATM/

ATR

ATM/

ATR ATM/

ATR

ATM/

ATR

ATM/

ATR ATM/

ATR

BRCA1/2 BRCA1/2

BRCA1/2

Tp53 Tp53 Tp53

Tp53

Tp53 ATM/

ATR

AF=1%- 20%

AF=20%- 50%

AF=50%- 100%

Non HGS-EOC HGS-EOC

Inter-patients Heterogeneity

(51)

BRCA2 BRCA1 RAD51 BRIP EMSY FANCF TP53 CHECK2 ATM ATR

BRCA1/2 Tp53

BRCA1/2 BRCA1/2

BRCA1/2

BRCA1/2 Tp53

Tp53 Tp53

Tp53

Tp53 Tp53 ATM/

ATR

ATM/

ATR

BRCA1/2

Tp53

AF=1%-20% AF=20%-50% AF=50%-100%

BRCA1/2

BRCA1/2 BRCA1/2

BRCA1/2

Tp53

Tp53 Tp53

ATM/

ATR ATM/

ATR

BRCA1/2

BRCA1/2 Tp53

HGS-EOC Non- HGS-EOC

Spatial and Temporal Heterogeneity

(52)

Where to go next?

Until we identify actionable target, the severe genomic

instability found across HGSOC remains the fulcrum

(53)

HRD

Synthetic Lethality

iPARP

(54)

Leverage DNA damage

response (DDR)

New opportunities…..

Clinical Synthetic Lethality

Targeting the molecular and microenvironmental characteristics of tumor

Endogenous tumor factors HRD

TP53

Cell cycle regulation

Exogenous tumor factors Hypoxia

Immune activation Glucose metabolism

Chemical synthetic lethality

Contextual synthetic

lethality

+

(55)

Hypoxia

 Hypoxia downregulates key genes in the

homologous-

recomination and

mismatch-repair pathway (RAD 51, RAD 52,

BRCA, MSH2, and MSH6)

 Hypoxia is presumed to be generated locally by angiogenesis inhibitors

 Leveraging hypoxia to induce HRD-like environment

(56)

Testing the hypothesis: PARPi + VEGFRi

TP53

lethality

+

(57)

Olaparib + Cediranib

 Olaparib + Cediranib signifcantly increased PFS in patients without BRCA mutation

Sinergy between hypoxia and inhibition of DNA repair

Poster 5535 ASCO 2017

(58)

New opportunities…..

Clinical Synthetic Lethality

TP53

lethality

+

(59)

Targeting cell cycle to inhibit DDR

(60)

Cell cycle checkpoint abrogation:

CHK1/2 inhibitor

(61)

Cell cycle checkpoint abrogation:

Wee-1 inhibitor (AZ1775)

(62)

Wee-1i + Carboplatin/paclitaxel in TP 53 mut HGSOC

Oza and colleagues ASCO 2015

 In combination con carboplatin, promosing activity in “platinum-

resistant” disease with p53 mutations.

(63)

New opportunities…..

Clinical Synthetic Lethality

TP53

lethality

+

(64)

Ovarian Cancer

Immunogenic

T cell infiltration

affect outcome

(65)

Anti PD1/PDL1 -ORR 15%

-Very rarely long lasting responses Other Studies -Disis et Al, Avelumab: ORR 9.7%

-Brahmer et al, Nivolumab: 17 pts, 1 PR, 2 SD

(66)

Testing the hypothesis: PARPi + Immunotherapy

TP53

lethality

+

(67)

Why combine DDR inhibitors + immunotherapy

• HGSOC has intermediate mutational load with high genomic instability, causing neoantigen production

• Inhibition of DDR pathways would be expected to propagate DNA damage and thus increase neoantigen potential

Promising start!

J-m Lee et al, JCO 2017

(68)

On going Clinical Trials

(69)

The range of DNA

opportunities

Combine with other DNA repair targets

Cell cycle dysregulation Epigenetic

generation of HRD

Hypoxia

Immunotherapy combinations

(70)

?

? ?

?

Navigating the new information….

Options likely will increase in tandem with our understanding as long as we keep asking relevant

questions….

Is it possible to prospectively profile tumors to guide therapy choice?

Individualized Medicine in Ovarian Cncer: Are we there yet?

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