Nuevas estrategias de tratamiento en tumores con mutaciones de BRCA

Emilio Alba UGCI Oncología

Hospital Universitario Regional y Virgen de la Victoria

Facultad de Medicina. Málaga

IBIMA

ÍNDICE DE LA PRESENTACIÓN

Mecanismo de acción

Magnitud del problema: frecuencia y penetrancia de BRCA

Cáncer de mama

Cáncer de ovario

Otros tumores

Conclusiones y perspectivas

Mechanisms of Action of Olaparib

Survival

Normal cell

Repair by Homologous Recombination

No effective repair

(No HR pathway)

Cell death

Cancer cell with HRD

SSBs increased by dacarbazine, temozolomide and topotecan

DSBs increased by platinums

Mechanism 1:

Tumor specific killing

by olaparib

PARP

Replicating cells

olaparib

Mechanism 2: Potentiation

The Concept of Synthetic Lethality

(PARP) (BRCA)

Ashworth, A. J Clin Oncol; 26:3785-3790 2008

Riesgo de cáncer en personas con mutaciones de los genes BRCA 1/2

BRCA 1 BRCA 2

Mama 65-71% 45-84%

Ovario 12-63% 7-27%

Mama-varón 3-10% 7%

Próstata ? 5.2-7.5%

Páncreas 1.2% 1.5-4%

Levy-Lahad E. BJC 2007

Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA)

Couch FJ et al. PLoS Genet 9 (3): e1003212

Chemotherapeutic Agents: Double Strand DNA Breaks

Kennedy R et al. JNCI 2004; 96:1659-1668

Alkylators DNA interstrand cross-links double strand (DS) DNA breaks

Cyclophosphamide

Platinums Forms adducts with DNA Cisplatin Carboplatin Oxaliplatin

Topoisomerase I poisons

Arrest of DNA replication forks

Etoposide Irinotecan Topotecan Mitoxantrone

Topoisomerase II poisons

DNA interstrand cross-linking, generation of O2 free radicals

Doxorubicin Epirubicin

Bleomycin Directly damages DNA DS DNA breaks

TNBC Shares Clinical and Pathologic Features with BRCA-1-Related Breast Cancers (“BRCAness”)

3Sorlie et al. Proc Natl Acad Sci U S A 2001;98:10869-74 4 Miyoshi et al. Int J Clin Oncol 2008;13:395-400

1Perou et al. Nature. 2000; 406:747-752 2Cleator et al.Lancet Oncol 2007;8:235-44

Characteristics Hereditary BRCA1 Triple Negative/Basal-Like1,2,3

ER/PR/HER2 status Negative Negative

TP53 status Mutant Mutant

BRCA1 status Mutational inactivation* Diminished expression*

Gene-expression pattern Basal-like Basal-like

Tumor histology Poorly differentiated

(high grade)

Poorly differentiated

(high grade)

Chemosensitivity to DNA-

damaging agents Highly sensitive Highly sensitive

*BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID44

Regimen No. pts No. of pCRs % pCRs

CMF 14 1 7

AC 23 5 22

FAC 28 6 21

AT 25 2 8

Cisplatin 12 10 83

J Clin Oncol 2009;28:375-9

pCR rate: 22%

Predictors of response to cisplatin therapy in triple-negative/basal-like tumors

Copyright © American Society of Clinical Oncology

Silver, D. P. et al. J Clin Oncol; 28:1145-1153 2010

Phase I Trial of Olaparib in Patients with Solid Tumors

• Escalation and expansion phase, n = 60

• Recommended phase II dose: 400 mg PO BID

• Toxicities

– Nausea (32%), fatigue (30%), vomiting (20%), taste alteration (13%), anorexia (12%), anemia (5%)

• Clinical activity = 12/19 patients with BRCA mutations

Tumor BRCA No. of pts Response

Breast 2 2 1 CR, 1 SD

Ovarian 1 or 2 8 8 PRs

Fallopian tube 1 1 PR

Prostate 2 1 PR

Fong PC et al. N Engl J Med 2009; 361:123-134

Olaparib in BRCA-deficient Metastatic Breast Cancer: Results

ITT cohort 400 mg BID

N = 27

100 mg BID

N = 27

ORR 11 (41%) 6 (22%)

CR 1 (4%) 0

PR 10 (37%) 6 (22%)

Median PFS 5.7 mo

(4.6-7.4)

3.8 mo

(1.9 – 5.6)

Tutt A et al. J Clin Oncol 2009;27(18S):803s (abstr CRA501)

Best percent change from baseline in target lesions by genotype Median 3 prior lines of therapy

Objective Response Rate (by RECIST)

Gelmon KA et al. Proc ASCO 2010;Abstract 3002.

BRCA Mutation-Positive BRCA Mutation-Negative

Ovarian 7/17 (41.2%) 11/46 (23.9%)

Breast 0/8 (0) 0/15 (0)

Final Results: Phase II: Gem Carbo +/- Iniparib in TNBC

O’Shaughnessy J et.al. NEJM 2011

Efficacy Endpoints Overall Survival (OS) – ITT Population

With permission from O’Shaughnessy J et al. Proc ASCO 2011;Abstract 1007.

Pro

bab

ility

of

Surv

ival

Prespecified alpha = 0.04

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 2 4 6 8 10 12 14 16

OS GC

(N = 258) GCI

(N = 261) HR p-value

Median OS 11.1 mos 11.8 mos 0.88 0.28

Months

Ovarian Cancer Survival: Effect of BRCA Mutations

Cass et.al. Cancer May 2003

BRCAness and Response to Chemotherapy

Konstantinopoulos PA, et al. J Clin Oncol. 2010;28:3555.

Disease Free Survival Overall Survival

34 v 15 mo P = 0.01

72 v 41 mo P = 0.006

Prior response to platinum may predict response to olaparib in BRCA mutated Ovarian Cancer

Gelmon K, et al J Clin Onc 2010

Phase II: BRCA Mutation Ovarian Cohort

Audeh et al, 2009.

Niraparib: Phase 1/2 Ovarian Cancer Anti-tumor Activity

Michie Co et al. J Clin Oncol 31, 2013 (suppl; abstr 2513)

At recommended dose (290/300 mg), 3/4 (75%) platinum sensitive patients achieved RECIST response RECIST response rate in platinum-sensitive patients was 46% (6/13) Response rate (by RECIST and/or GCIG Ca125 criteria) in evaluable platinum-resistant patients was 22% (6/27)

* BRCA1/2 mutation carriers † Reduction in overall sum of measurable disease but new lesion seen (overall: PD) -Refractory patient (BRCA mutated) not included

-100

-80

-60

-40

-20

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20

40

60

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Platinum Resistant Platinum Sensitive Platinum Sensitive @ Recommended Dose

*

*

* * * *

*

* *

*

*

* *

* * * *

*

*

† †

Study 19: Progression-free survival

Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003); N Engl J Med. 2012 Apr 12;366(15):1382-92.

0

Time from randomization (months)

136 104 51 23 6 0 0

129 72 23 7 1 0 0

At risk (n)

Olaparib

Placebo

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

No. of events: Total patients (%) Median PFS (months)

Olaparib 60:136 (44.1) 8.4

Placebo 93:129 (72.1) 4.8

Hazard ratio 0.35 (95% CI, 0.25–0.49) P<0.00001

Olaparib 400 mg bid

Placebo Randomized treatment

Pro

po

rtio

n o

f p

atie

nts

pro

gre

ssio

n

fre

e

Study 19: PFS by BRCAm status

Presented by: Jonathan Ledermann et al at ASCO 2013

0 Time from randomization (months)

0

1.0

Pro

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n o

f p

atie

nts

p

rogr

ess

ion

-fre

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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)

Progression-Free Survival

Olaparib 200 mg: 6.5 (5.6-8.0) months

Median PFS (80% CI)

Olaparib 400 mg: 8.8 (6.3-9.2) months PLD 50 mg/m2: 7.1 (5.5-7.8) months

HR* vs PLD (80% CI) Olaparib 200 mg: 0.91 (0.60-1.39); P = 0.78

Olaparib 400 mg: 0.86 (0.56-1.30); P = 0.63

Olaparib 200 mg + 400 mg: 0.88 (0.62-1.28); P = 0.66

Time From Randomization (months)

Pro

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n o

f P

atie

nts

Pro

gre

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n F

ree

0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0 12 10 8 6 4 2

*HR < 1 favors olaparib.

32 0 3 8 13 21 24 32 0 1 12 17 21 28 33 0 3 8 15 18 25

Number of patients at risk: Olaparib 200 mg Olaparib 400 mg PLD

Stats: HR 0.55 (median PFS of 4 to 7.3 mos) N planned: 90 (30/arm)

Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol. 2012 Feb 1;30(4):372-9.

Summary: PARPi in Phase III Development as Maintenance Therapy in Ovarian Cancer

1. AZD 2281 (KU-0059436) = Olaparib – SOLO-1 = Front-line HGS maintenance in BRCAmut

– SOLO-2 = Platinum sensitive HGS maintenance in BRCAmut

2. MK-4827 = Niraparib – NOVA = Platinum sensitive HGS maintenance in BRCAmut and

BRCAwt

3. CO-338 (AG014699, PF-01367338) = Rucaparib – ARIEL-3 = Platinum sensitive HGS and endometrioid maintenance

in BRCAmut and BRCAwt

PARPi in Phase III Development in Ovarian Cancer

1. AZD 2281 (KU-0059436) = Olaparib

2. MK-4827 = Niraparib

3. CO-338 (AG014699, PF-01367338) = Rucaparib

Others with randomized trials in devleopment ABT-888 = Veliparib

BMN 673

No direct clinical comparisons!

Olaparib in BRCA-deficient Metastatic Breast Cancer: Select Toxicities

Tutt A et al. J Clin Oncol 2009;27(18S):803s (abstr CRA501)

Olaparib 400 mg BID (n = 27)

Olaparib 100 mg BID (n = 27)

Grade 1/2 Grade 3 Grade 1/2 Grade 3

Fatigue 15 (56) 4 (15) 15 (56)

2 (7)

Nausea 11 (41)

5 (19) 15 (56) 0

Vomiting 7 (26) 3 (11) 6 (22) 0

Headache 10 (37) 0 5 (19) 1 (4)

Constipation 6 (22) 0 8 (30) 0

Kaufman B et al. JCO 2015; 33(3)

Tumor Response Rates

Kaufman B et al. JCO 2015; 33(3)

Platinum – Sensitive Relapse: Cediranib + Olaparib

Phase II open-label randomised study -1:1 randomisation to cediranib/olaparib combination or single-agent olaparib - Platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer

Liu J et al. JCO 2014; 32(5S): AbstractLBA5500.

Primary Outcome: Cediranib/Olaparib Significantly Increased PFS Compared to Olaparib Alone

Liu J et al. JCO 2014; 32(5S): AbstractLBA5500.

Cediranib/Olaparib Significantly Increased PFS in Patients Without a BRCA Mutation

Liu J et al. JCO 2014; 32(5S): AbstractLBA5500.

Response to Chemotherapy Post PARP Inhibitors in BRCA-Carrier Ovarian Cancer – Retrospective Study

78 patients (median 3 lines chemotherapy pre-olaparib) - Response rate RECIST 36%, PFS 17 weeks; OS 34 weeks

Responses to platinum post olaparib - Response rate RECIST 40%, PFS 22 weeks; OS 45 weeks

Responses observed regardless of pre-PARP

platinum-sensitivity

Platinum-to-platinum interval associated with response

to post-PARP platinum

In 6 cases tested, secondary mutations not observed

Ang JE et al. Clin Cancer Res 2013; 19(19): 5485-5493.

RESISTANCE TO PARP INHIBITORS

• Secondary mutations of BRCA genes altering the reading frame to wild-type

1.-Selection of pre-existing resistance clones 2.-Mutations acquired during treatment in cells genetically unstable due

to the lack of HR

Mechanisms of PARP Inhibitor Resistance

Restoration of HR

Drug Efflux

PARP1 Loss

BRCA Reversion

or P53BP1 loss

Upregulation of

P-glycoprotein

Mechanism

Unknown

PARPi Resistance

NEED BIOPSIES TO CLARIFY CLINICAL SIGNIFICANCE

CONCLUSIONES

• BRCA es un biomarcador diferente (riesgo+predictivo)

• Es necesario una mejor definición del significado de la mutación germinal versus somática

• Las sales de platino (alquilantes?) parecen ser mas efectivas en presencia de mutación de BRCA

• Los inhibidores de PARP son eficaces en presencia de mutaciones de BRCA

• No es conocido si la eficacia es organodependiente

• Inhibidores de PARP+ QT+ farmacos antidiana +RT

• Adyuvancia/neoadyuvancia

• Toxicidad tardía

Might Platinum Response Be Predictor of Germline BRCA Mutation?

Alsop K, et al. JCO 2012; 30 (21): 2654-63

Maintenance PARP Inhibitors: Current Trials