Cáncer de ovario y BRCA Abriendo un nuevo camino · Cáncer de ovario y BRCA Abriendo un nuevo...

Cáncer de ovario y BRCA

Abriendo un nuevo camino Dra. Yolanda García

Oncología Médica

Parc Taulí Sabadell. Hospital Universitari

Panticosa, 15 Mayo 2015

B-2 What Are the Promising Targets for Future Therapeutic Approaches?

• The most promising targets in clinical trials are Angiogenesis and Homologous recombination deficiency( HRD).

Int J Gynecol Cancer 2011: 21; 756-762

4th Ovarian Cancer Consensus Conference 25 – 27 June 2010

UBC Life Sciences Institute, Vancouver, British Columbia

BRCAness HDR

Letalidad sintética

Mecanismo de acción iparp

Iparp’s en cáncer de

ovario

Olaparib

Veliparib Niraparib Rucaparib

BMN 673

Logística

Guías

Futuro

BRCAness HDR

Letalidad sintética

Mecanismo de acción iparp

“Ovarian Cancer is erroneously regarded as a single disease”: Dualistic Model

apoptosis and induce angiogenesis. Nuclear localization

of activated phosphorylated STAT3 occurs in more than

70% of ovarian cancers and is associated with decreased

overall survival61. Activated STAT3 also translocates to

focal adhesion complexes and stimulates motility in

combination with SRC . In addition to antibodies against

IL-6 and inhibitors of JAK2 (REFS 62,63), new inhibitors

of STAT3 are being developed that might be used to tar-

get most ovarian cancers64.

Lysophosphatidic acid (LPA) is produced by the

phosphodiesterase autotoxin (ATX; also known as lyso-

phospholipase D). The G protein-linked LPA receptors

LPAR2 and LPAR3 are upregulated during the malignant

transformation of ovarian surface epithelial cells. LPAR3

responds to LPAs with unsaturated fatty acyl chains that

are produced by ovarian cancers. Interestingly, cyclic

phosphatidic acid blocks ATX, reducing LPA levels and

metastasis, but not the growth of primary cancers65. LPA-

neutralizing antibodies have been developed, and LPA

receptor inhibitors are being sought that might block the

proliferation of ovarian cancer cells66.

The NF-κB transcription factor is constitutively acti-

vated in more than half of ovarian cancers67,68 through

signalling initiated by several cytokines (IL-1 and TNFα)

and growth factors (EGF). Inactive NF-κB is complexed

with inhibitor of NFκB (IκB) and is generally activated

by the IκB kinase (IKK) complex, which contains two

kinase subunits (IKKα and IKKβ) and a regulatory

subunit (IKKγ)69. MEKK3 is one of several kinases that

can activate the IKK complex70,71 and is overexpressed

in >50% of ovarian cancers. The resultant activation of

NF-κB upregulates anti-apoptotic genes (for example,

CFLAR), antioxidant proteins (superoxide dismutase or

ferritin heavy chain), growth regulatory cytokines (IL-6

or growth regulated-α (GRO1)) and angiogenic factors

(IL-8)71. Selective inhibition of NF-κB has been difficult

to achieve, but gene therapy with adenoviral E1A reduces

NF-κB signalling and increases sensitivity to paclitaxel in

xenograft models, which has prompted a clinical trial at

the University of Texas M. D. Anderson Cancer Center of

liposomal E1A in combination with paclitaxel in patients

with intra-abdominal recurrence of ovarian cancer.

Tumour biologyProliferation. The fraction of cycling cells in different

ovarian cancers varies over a wide range from 1% to 79%

(REF. 72). Upregulation of cyclin D1 or E1, E2F1 or cyclin-

dependent kinases (CDK2), and downregulation of CDK

inhibitors (p16, p21 and p27) have been observed in a

fraction of ovarian cancers, and the levels of cyclins and

CDKs correlate with prognosis73,74. In addition to intrin-

sic deregulation of checkpoints in the cell cycle, a range of

autocrine and paracrine growth factors stimulate ovarian

cancer proliferation, including EGF, transforming growth

factor-α (TGFα), amphiregulin, heregulin, VEGFA, insu-

lin-like growth factor 1 (IGF1), IL-6 and LPA.

In normal ovarian surface epithelial cells, autocrine

growth inhibition is maintained by TGFβ75. In approxi-

mately 40% of ovarian cancers, expression of or respon-

siveness to TGFβ is lost. Although mutation of SMAD4

is sometimes observed, TGFβRI and TGFβRII receptors

are generally intact, as is Smad signalling downstream of

the receptors. Loss of growth inhibition and increased

invasiveness might relate to ecotropic viral integration

Box 3 | Molecular classif icat ion of epithelial ovarian cancers

PTEN α PIK3CA

KRAS BRAF CTNNB1 TP53

TP53

BRCA1 BRCA2

Type Histology Precursor Molecular features

I Low-grade serous carcinoma

Cystadenoma–borderline tumour–carcinoma sequence

Mutations in KRAS and/or BRAF

I Low-grade endometrioid carcinoma

Endometriosis and endometrial cell-like hyperplasia*

Mutations in CTNNB1, PTEN and PIK3CA with microsatellite instability

I Mucinous carcinoma Cystadenoma–borderline tumour–carcinoma sequence; metastases from bowel

Mutations in KRAS; TP53 mutation associated with transition from borderline tumour to carcinoma

I Clear cell carcinoma Endometriosis PTEN mutation or loss of heterozygosity; PIK3CA mutation‡

II High-grade serous carcinoma

De novo in epithelial inclusion cysts; fallopian tube

TP53 mutation (up to 80%) and BRCA1 dysfunction

II High-grade endometrioid carcinoma

Epithelial inclusion glands or cysts TP53 mutation and BRCA1 dysfunction; PIK3CA mutation

* Endometriosis and adjacent low-grade endometrioid carcinoma share common genetic events such as loss of heterozygosity at the same loci involving the same allele (for example, PTEN). By contrast, high-grade and poorly differentiated endometrioid carcinomas are similar to high-grade serous carcinomas. ‡ PIK3CA at 3q26 encodes the p110 catalytic subunit of PI3K19.

REVIEWS

422 | JUNE 2009 | VOLUM E 9 www.nature.com/reviews/cancer

Bast RC; Nature Reviews; Vol 9; June 2009

TCGA – Potential target pathways

TCGA – Potential target pathways

Log-rank P value=0.0002).

Breast tumours • higher histological grade

• basal like

• triple negative receptor status

• more aggressive

• poor prognosis

• platinum sensitive

• visceral metastases

Ovarian tumours • higher histological grade

• serous histology

• improved prognosis

• platinum sensitive

• visceral metastases

• Due to defective BRCA1

– mutational/epigenetic mechanisms

http://img.medscape.com/article/709/904/709904-fig3.jpg

http://blogs.nejm.org/now/wp-content/uploads/2010/11/Picture22-300x235.jpg

http://www.glowm.com/resources/glowm/graphics/figures/v4/0290/011f.jpg

Triple negative BrCa

Triple negative BrCa

Serous Ovca

BRCAness

http://blogs.nejm.org/now/wp-content/uploads/2010/11/Picture15.jpg

BRCAness BRCAness ~ HR deficiency in high grade serous ovarian cancer, not in TNBC

The Cancer Genome Atlas Molecular profiling of serous ovarian cancer

D. Levine (2011)

Gelmon KA, Lancet Oncol 2011

Non HR deficient HR deficient

Base excision

repair

Type of damage:

Bulky adducts

Insertions & deletions

O6- alkylguanine

Repair pathway:

Nucleotide- excision

repair

Mismatch repair

Direct reversal

Repair enzymes:

Double- strand breaks (DSBs)

Single- strand breaks (SSBs)

PARP

Recombinational repair

ATM DNA-PK

HR NHEJ

XP, poly-

merases

MSH2, MLH1

AGT

Types of DNA damage and repair

BRCA

PARP recruitment PARP

DNA damage

PARP activation and

assembly of repair factors

NAD+

poly (ADP-ribose) PARP

PAR degradation via PARG

PARG

PARP

End processing,

gap filling, and ligation PNK 1

XRCC1 LigIII

pol β

XRCC1 LigIII

PNK 1

Vergote, ND; Khanna et al, 2001; Sanchez-Perez, 2006; Kennedy et al, 2006.

PARP and Base Excision Repair

In normal cells, both base-excision repair and homologous recombination are available for the repair of damaged DNA.


In cells that have lost either BRCA1 or BRCA2, homologous recombination is nonfunctional, and base-excision repair and other DNA-repair processes can compensate for the loss of homologous recombination.

In cells that have lost base-excision repair function because of PARP1 inhibition but retain at least one functioning copy of BRCA1 and BRCA2), homologous recombination is intact and can repair DNA damage,including damage left unrepaired because of the loss of base-excision repair

In the cancer cells of mutation carriers, all BRCA1 or BRCA2 function is absent, and when PARP1 is inhibited, cancer cells are unable to repair DNA damage by homologous recombination or base-excision repair, and cell death results.


In cells that have lost either BRCA1 or BRCA2, homologous recombination is nonfunctional, and base-excision repair and other DNA-repair processes can compensate for the loss of homologous recombination.

In cells that have lost base-excision repair function because of PARP1 inhibition but retain at least one functioning copy of BRCA1 and BRCA2), homologous recombination is intact and can repair DNA damage,including damage left unrepaired because of the loss of base-excision repair

SYNTHETIC LETHALITY

“Situation when a mutation in one of two gens individually has no effect but combining the mutations leads to cell death”.

T Dobzhansky, Genetics 1946

PARP Inhibitor Mechanism of Action

PARP Inhibitor Mechanism of Action

• Inhibition of PARP blocks PARylation requiered for SSB

• Trapping: PARPi trap PARP1,2 on DNA . DNA and HR/NHEJ activation.

• Loss of PARP-1 activates NHEJ via DNA PK

1. Patel et al, PNAS 2011; 2. Murrai et al, Cancer Research 2012

Tres mecanismos citotóxicos de la inhibición de parp

Tres mecanismos citotóxicos de la inhibición de parp

Homologous Recombination • BRCA1/2 • Rad51 • FA proteins • XRCC3 • Others (PTEN)

Error-free Repair

Cell Survival

NHEJ • DNA-PK

Error-prone Repair

Cell Death

• Genomic Instability

• Chromosome rearrangement

DN

A D

amag

e

PARP1

Modified from Patel, et al., PNAS (2011)

PARPi


ovario


BMN 673

Olaparib

Agent Administration Phase*

Comments

Olaparib

(AZD-2281)

Oral I, II, III Single Agent and Combination, BRCA and non-BRCA, Platinum-sensitive and resistant, Primary and Recurrent

SOLO-1;SOLO-2

AZD-2461 Oral I, II FIH, Solid Tumors

Veliparib

ABT-888

Oral I, II, III Single Agent and Combination, BRCA and non-BRCA, Platinum-sensitive and resistant, Primary and Recurrent

(GOG-9923, PIS1004, GOG-280)

BMN 673 Oral I, II BRCA mutation carriers, Platinum Sensitive

CEP-9722 Oral I Combination, Solid Tumors

Niraparib

(MK4827)

Oral I, II, III Single Agent and Combination, BRCA and non-BRCA, Platinum-sensitive and resistant : NOVA Trial

Rucaparib

(CO-338)

Oral I, II, III BRCA mutation carriers and no carriers, Platinum Sensitive: ARIEL-2, ARIEL-3

AG014699 IV II Single Agent, BRCA, Platinum-sensitive and resistant

*Available at: http://www.clinicaltrials.gov.

PARP Inhibitors in Clinical Trials

Tumor Type

Cell Line BRCA Status

CO-338 (Rucaparib)

EC50 (µM)

MK-4827 (Niraparib)

EC50 (µM)

AZD22881 (Olaparib)

EC50 (µM)

BMN-673 EC50 (µM)

ABT-888 (Veliparib)

EC50 (µM)

Ovary

UWB1.289+BRCA1 Wild-type 5.4 1.8 8.2 0.2 20

UWB1.289 BRCA1 mut 0.4 0.2 0.6 0.01 4.3

MCA S BRCA2 mut 3.4 2.6 7.0 0.3 19.3

OAW-28 Wild-type 5.7 2.8 11.1 0.7 20

PA-1 Wild-type 0.5 0.2 0.7 0.007 2.2

Rucaparib at least as potent as Olaparib and Niraparib (MK-4827) BioMarin BMN-673 is the most potent PARP inhibitor in vitro Veliparib is the least potent PARP inhibitor in vitro

PARP Inhibitors in Clinical Trials

Dr. Coleman´s Courtesy

Olaparib Phase I and BRCA

mutation expansion studies in ovarian cancer patients1

Olaparib multicenter Phase II BRCA mutation ovarian cancer study2

Olaparib multicenter Phase II BRCA+/– study

(ovarian cancer patients)3

Olaparib patients n=50 n=33 n=64

Olaparib dose 200 mg bid 400 mg bid 400 mg bid

RECIST response (CR + PR)

28% 33% BRCA+ 41% BRCA– 24%

Disease control rate*

34% 69% BRCA+ 76% BRCA– 62%

Median duration of response

7.0 months 9.5 months Not reported

Complete response (CR) + partial response (PR) + stable disease (SD)

1.Fong PC et al. J Clin Oncol 2010;28:2512–2519; 2. Audeh MW et al. Lancet 2010;376:245–251; 3. Gelmon KA et al. Lancet Oncol 2011;12:852–861

Provides clinical evidence of activity in ovarian cancer patients with and without BRCA1/2 mutations

Olaparib( AZD2281): an orally active PARP inhibitor in ovarian cancer

• Primary- End Point: 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

Stratification Factors: - Jewish Heritage - Best Response to Platinum - Platinum Free Interval

• Interim OS analysis (38% maturity): HR=0.94; 95% CI, 0.63–1.39; P=0.75

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

ility

of

p

rogr

ess

ion

-fre

e s

urv

ival

Time from randomization (months)

Primary analysis (58% maturity; n=154/265)

PFS hazard ratio=0.35 (95% CI, 0.25–0.49)

P<0.00001

Randomized treatment*

Placebo (n=129)

Olaparib 400 mg bd monotherapy (n=136)

Study 19: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer

Ledermann J et al. N Engl J Med 2012;366:1382–1392 *Patients were treated until disease progression

• Patients were randomized after response to platinum-based chemotherapy

Interim overall survival (OS) subgroup analysis* (38% maturity)

Hypothesis: olaparib maintenance therapy may lead to a greater PFS and OS benefit vs placebo in patients with a known BRCAm

HR (olaparib:placebo) and 95% CIs

Favours olaparib

• BRCA1/2 mutation (BRCAm) status was not required for study entry, but was known for 97/265 patients (36.6%)

Size of circle is proportional to number of events Purple band represents 95% CI for overall population

Overall

gBRCA positive

gBRCA negative

gBRCA status unknown

Olaparib 400 mg bd

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%)

0.125 0.25 0.5 1.0 2.0 4.0 8.0 16.0

*Subgroup analysis pre-specified in study protocol gBRCAm, germline BRCA1/2 mutation

Presented by: Jonathan Ledermann Abstract 5505; ASCO 2013

Methods: BRCAm testing

• Germline BRCAm (gBRCAm) status was determined retrospectively in an additional 121 patients (218 in total)

‒ The diagnostic assay (Myriad Genetics) used blood samples collected before randomization from consenting patients

• Since patients without an inherited gBRCAm can develop somatic mutations, tumour BRCAm (tBRCAm) status was also determined in 209/265 patients

‒ Archival tumour samples were analyzed by Foundation Medicine


Results: BRCA testing

tBRCA

Mutated Wild type* Not available TOTAL gB

RC

A Mutated 71 3 22 96

Wild type* 20 79 23

Not available 20 16 11

265

*Wild-type group includes patients with no known BRCAm or a mutation of unknown significance (a non-deleterious mutation)

• The number of patients with a known BRCAm status increased from 97 (36.6%) to 254 (95.8%) out of 265

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

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

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


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

PFS by BRCAm status

0


0

1.0

Pro

po

rtio

n o

f p

atie

nts

pro

gre

ssio

n-

fre

e

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


PFS by BRCAm status

0


0

1.0

Pro

po

rtio

n o

f p

ati

en

ts

pro

gre

ss

ion

-fre

e

3 6 9 12 15

Olaparib BRCAm

Olaparib BRCAwt

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

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

Olaparib Placebo Olaparib Placebo

Events: total pts (%) 26:74 (35.1) 46:62 (74.2) 32:57 (56.1) 44:61 (72.1)

Median PFS, months 11.2 4.3 5.6 5.5

HR=0.18

95% CI (0.11, 0.31);

P<0.00001

HR=0.53

95% CI (0.33, 0.84);

P=0.007

Placebo BRCAm

Placebo BRCAwt

Number at risk

Olaparib BRCAm

Olaparib BRCAwt

Placebo BRCAm

Placebo BRCAwt

74 59 33 14 4 0

57 44 17 9 2 0

62 35 13 2 0 0

61 35 10 4 1 0

BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance)


Study 19 updated overall survival: all patients


0


0 48

1.0

Pro

po

rtio

n o

f p

atie

nts

aliv

e

3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Number at risk

129 1 127 120 111 108 96 87 81 71 59 55 51 37 23 6 1 Placebo

136 132 129 124 117 109 97 87 78 73 61 57 39 18 9 Olaparib 400 mg bd

Randomized treatment

Placebo

Olaparib 400 mg bd

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

Overall population (n=265)

Olaparib 400 mg bd Placebo

Deaths: total pts (%) 77:136 (56.6) 77:129 (59.7)

Median OS, months 29.8 27.8

HR=0.88

95% CI (0.64, 1.21); 80% CI (0.72, 1.09)

P=0.438

• At the interim OS data cut-off (26 Nov 2012), 154/265 (58.1%) patients had died

OS in BRCAm patients

0


0 48

1.0

Pro

po

rtio

n o

f p

atie

nts

aliv

e

3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Number at risk

62 62 58 52 50 46 39 36 33 29 29 27 21 12 4 Placebo BRCAm

74 71 69 67 65 62 57 54 50 48 39 36 26 12 7 Olaparib BRCAm

Randomized treatment

Placebo BRCAm

Olaparib BCRAm

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

BRCAm (n=136)

Olaparib Placebo

Deaths: total pts (%) 37:74 (50.0) 34:62 (54.8)

Median OS, months 34.9 31.9

HR=0.74

95% CI (0.46, 1.19)

P=0.208

• OS in BRCAwt patients: HR=0.98; 95% CI, 0.62–1.55; P=0.946 ‒ Median OS: olaparib, 24.5 months; placebo, 26.2 months

• 14/62 (22.6%) placebo patients switched to a PARP inhibitor

Ledermann J, ASCO 2013 #5505; Ledermann J Lancet Oncol 2014

Time to second subsequent therapy (PFS2)

0


0

1.0

Pro

po

rtio

n o

f p

atie

nts

re

ceiv

ing

stu

dy

tre

atm

en

t o

r fi

rst

sub

seq

ue

nt

the

rap

y

10 20 30 40

Olaparib BRCAm

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

Placebo BRCAm

Number at risk

Olaparib BRCAm

Placebo BRCAm

74

62

5 15 25 35 45

70

60

65

46

50

31

38

21

33

18

30

11

23

9

9

2

0

0

BRCAm (n=136)

Olaparib Placebo

Events: total pts (%) 42:74 (56.8) 49:62 (79.0)

Median PFS, months 23.8 15.3

HR=0.46

95% CI (0.30, 0.70);

P<0.0003


Time to second subsequent therapy (PFS2)

0


0

1.0

Pro

po

rtio

n o

f p

ati

en

ts r

ec

eiv

ing

stu

dy t

rea

tme

nt

or

firs

t

su

bs

eq

ue

nt

the

rap

y

10 20 30 40 50

Olaparib BRCAm

Olaparib BRCAwt

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

Placebo BRCAm

Placebo BRCAwt

Number at risk

Olaparib BRCAm

Olaparib BRCAwt

Placebo BRCAm

Placebo BRCAwt

74

57

62

61

5 15 25 35 45

70

56

60

58

65

48

46

48

50

34

31

28

38

20

21

18

33

16

18

8

30

14

11

6

23

11

9

4

9

3

2

2

0

0

0

1

0

0

0

0

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

Olaparib Placebo Olaparib Placebo

Events: total pts (%) 42:74 (56.8) 49:62 (79.0) 42:57 (73.7) 55:61 (90.2)

Median PFS, months 23.8 15.3 17.1 14.7

HR=0.46

95% CI (0.30, 0.70);

P<0.0003

HR=0.64

95% CI (0.42, 0.96);

P=0.032

BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance)


Duration of treatment and tolerability

• As of 23 May 2013, 26 patients remain on study treatment (olaparib, n=23; placebo, n=3)

• 33/136 patients (24%) have received >3 years of olaparib treatment, of whom 22 had a known BRCAm

• Olaparib tolerability was similar in patients with a BRCAm and the overall population

‒ The most common AEs in patients with a BRCAm were low-grade nausea (73%) and fatigue (54%)


Conclusions

• Olaparib maintenance therapy led to the greatest clinical benefit, compared with placebo, in patients with a BRCAm

‒ PFS median improvement of 6.9 months; HR=0.18 (95% CI, 0.11–0.31)

‒ PFS2 median improvement of 8.5 months; HR=0.46 (95% CI, 0.30–0.70)

‒ OS median improvement of 3.0 months; HR=0.74 (95% CI, 0.46–1.19)

• No significant OS benefit was observed in the overall patient population

‒ The final OS analysis will be performed at ~85% maturity (after ~222 deaths)

• As a result of these compelling data, Phase III confirmatory trials in patients with a BRCA mutation had been completed. Results pending.


300 mg bid tablets (equivalent 400 mg bid cps)

®

Olaparib y quimioterapia

Olaparib vs QT

Kaye S, JCO 2012

Oza A, ASCO 2012 # 5001; Oza A et al, Lancet Oncol 2014

Oza A, ASCO 2012 # 5001


ovario

Olaparib


BMN 673

In Study CO-338-010, rucaparib has demonstrated robust clinical activity in platinum-sensitive OC patients with gBRCA1/2 mutations

48 | Confidential

Overall Response Rates, n/N (%) Disease Control Rates, n/N (%)

RECIST & CA-125 RECIST CR, PR or SD

>12 weeks

CR, PR or SD

>24 weeks

15/20 (75%) 13/20 (65%) 16/18 (89%)* 13/15 (87%)†

CR, complete response; PR, partial response; SD, stable disease

*2 patients w/SD have not reached 12 weeks; †5 patients w/SD have not reached 24 weeks

• Response and disease control rates

– 75% ORR

– 87% disease control rate (DCR) at 24 weeks

• Rucaparib is well-tolerated at the recommended Phase 2 dose (600 mg BID)

– The most frequent adverse events (AEs) are primarily mild to moderate and include gastrointestinal toxicities, fatigue/asthenia, AST/ALT elevation, and myelosuppression

– AEs are manageable and no patients have discontinued due to an AE

Annals of Oncology ,Vol 25 | Supplement 4 | September 2014

In Study CO-338-010, Rucaparib has demonstrated robust clinical activity in platinum-sensitive OC patients with gBRCA1/2 mutations

ARIEL2 will evaluate Rucaparib in relapsed, platinum sensitive, high-grade ovarian cancer

Key Eligibility:

• High-grade ovarian

(serous or

endometrioid), fallopian

tube or primary

peritoneal cancer

• ≥1 prior platinum

• Last tx = platinum-

based; must have

sensitive disease

• Documented radiologic

relapse

• Adequate screening

tumor tissue

• No prior PARPi

N = 180

Primary EP: ORR by RECIST and GCIG CA-125 criteria in HRD subgroups Secondary EPs: DOR

PFS

Safety

Steady state PK

600 mg BID rucaparib until disease progression by RECIST

• CA-125 every 4 wks

• CT scans every 8 wks

49 | Confidential ClinicalTrials.gov Identifier:NCT01891344

ARIEL2 : preliminary data 26th EORTCSC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics- Barcelona, Spain-Nov 2014

• Test to detect LOH and BRCA 1/2 mutations

• N: 121 • 25% BRCA1/2 m+

• 42% high genomic LOH

• 33% none

• 61 evaluable patients

• ORR: 38% all patients

• 77% CB

• BRCA1/2m+: (61-70% ORR)

• LOH : 32-40%

ARIEL 3: Rucaparib as Switch Maintenance in Patients who Respond to Platinum-based Treatment for Relapsed Disease

ClinicalTrials.gov Identifier:NCT01968213

Key Eligibility: • High-grade serous or

endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer

• Received ≥ 2 prior platinum-based regimens; up to 1 non-platinum permitted

• Sensitive disease to penultimate platinum

• RECIST CR or PR or CA-125 response to last platinum regimen (≥ 4 cycles);

• CA-125<ULN

• Available archival tumor tissue for HRD classification

N = 540 pts Up to 150 gBRCA Up to 200 tBRCA

Stratify: • HRD classification (tBRCA,

nbHRD, biomarker negative) • Response to platinum

regimen (CR or PR) • TFI after penultimate

platinum (6-12 or >12 mo)

8 wks from last dose to randomization

2:1

R A N D O M I Z A T I O N

Rucaparib

Placebo

ARIEL 3: Rucaparib as Switch Maintenance in Patients who Respond to Platinum-based Treatment for Relapsed Disease

Study drug bid

continuously until

disease progression

by RECIST

• CTs and CA-125

every 12 wks

• PRO (FOSI-18,

EQ-5D) every 4 wks

Primary EP: PFS by Investigator Secondary EPs: PFS by IRR

FOSI-18 (disease symptom subscale and total score)

OS

Safety

Population PK

Subsequent

Treatments

Overall

Survival

(every 12

weeks)

Treatment Phase Long-term

Follow Up

2:1

R A N D O M I Z A T I O N

Rucaparib

Placebo

ClinicalTrials.gov Identifier:NCT01968213

GOG 280:A Phase II Evaluation of the Potent, Highly Selective PARP Inhibitor Veliparib in the Treatment of Persistent or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Patients Who Carry a Germline BRCA1 or BRCA2 Mutation – a Gynecologic Oncology Group Study

1 cycle = 28 days Treat until

progression, toxicity, voluntary withdrawal

ClinicalTrials.gov identifier: NCT01540565

Recurrent EOC, FT, PPT BRCA1/2 deficient 1-3 prior regimens Measureable disease PS 0-2

Veliparib 400 mg po BID

Primary Endpoints: RR (RESIST v1.1), Tolerability (CTCAE v.4)

Secondary Endpoints: PFS, OS, EFS@6 mos

Opened: 4-09-2012 • First stage closed: 7-23-12 • Second stage open: 10-15-12 Closed: 11-15-12

Study Sample: N=50 toxicity/efficacy

Coleman RL et al

Phase II Veliparib: Results

Characteristic Response No Response Total (N) %

Platinum Resistant 6 24 30 20%

Platinum Sensitive 7 13 20 35%

Total N 13 37 50 26%

Fis

her’s

Exact P

= 0

.33

Characteristic Response No Response Total (N) %

BRCA1 10 29 39 26%

BRCA2 3 8 11 27%

Total N 13 37 50 26%

Fis

her’s

Exact P

= 1

.0

Niraparib: NOVA TESARO- ENGOT-OV16

• PFS endpoint primario • Ongoing, pendiente valoración de test predictivo de respuesta en

HRD, Myriad diagnostics presentado en Barcelona 2014

Iparp inhibitors and safety

Olaparib y antiangiogénicos

Presented By Joyce Liu at 2014 ASCO Annual Meeting

Liu J et al, Lancet Oncology 2014

Cediranib and olaparib have synergistic activity in vitro


Study Design


Primary Outcome: Cediranib/olaparib significantly increased PFS compared to olaparib alone


Secondary Outcome: Cediranib/olaparib significantly increased overall response rate (ORR) compared to olaparib alone


Cediranib/olaparib significantly increased PFS in patients without a BRCA mutation


Treatment-related Adverse Events


Estudio PAOLA: olaparib + bevacizumab

Logística

Guías

Futuro

Results of the Royal Marsden pilot

114 ovarian cancer patients selected for BRCA testing (regardless of BRCA risk) –

from July to December 2013

Oncologist trained to explain the implications of BRCA testing without entering into lengthy discussions

Oncologists explained the test and secured patients’ consent, usually during the first consultation

All 114 women took up the offer of the test

All patients thought they had been given sufficient information on which to base their

decision to undergo the test – no patients referred to Genetics for extra discussion

None of the patients who tested positive reported undue distress in informing their

relatives about the risk

Women testing positive given the result by their clinician and

referred for genetic counselling

Aire S. BMJ 2014;348:g1179

Results of the Royal Marsden pilot

114 ovarian cancer patients selected for BRCA testing (regardless of BRCA risk) –

from July to December 2013

Oncologist trained to explain the implications of BRCA testing without entering into lengthy discussions

Oncologists explained the test and secured patients’ consent, usually during the first consultation

All 114 women took up the offer of the test

All patients thought they had been given sufficient information on which to base their

decision to undergo the test – no patients referred to Genetics for extra discussion

None of the patients who tested positive reported undue distress in informing their

relatives about the risk

Women testing positive given the result by their clinician and referred for

genetic counselling

Aire S. BMJ 2014;348:g1179

Logística

Guías

Futuro

BRCA and high grade epitelial ovarian cancer: Who should be tested?

Logística

Guías

Futuro

Cuestiones por resolver….

• Administración: monoterapia vs combinación

• Biomarcadores de HRD ‒ gBRCA mut BIOMARCADOR ESTABLECIDO BENEFICIO IPARP ‒ ARIEL 2 LOH + BRCAm+ ‒ Mutaciones somáticas BRCA

• ¿Cuándo realizar tests genéticos?

• ¿Quién y cómo?

• Mecanismos de resistencia Iparp y respuesta a QT posterior

• ¿Adyuvancia/Quimioprevención en pacientes con mutación germinal?

Conclusiones

• Los inhibidores de PARP marcan un nuevo hito en el tratamiento del cáncer de ovario

‒ Olaparib indicación en mantenimiento tras recaida sensible a platinos y mutación BRCA

• Beneficio claro en pacientes con déficit de recombinación homóloga

‒ Mutación germinal BRCA biomarcador establecido

GRACIAS POR LA ATENCIÓN [email protected]

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