Inhibidores de PARP

Juan de la Haba Rodríguez

Servicio de Oncología Médica

Hospital Universitario Reina Sofía

Córdoba

Structures of PARP Inhibitors in Clinical Development

Veliparib

Niraparib

FDA approved

Rucaparib

FDA approved

Talazoparib

FDA approved

E7016

Pommier. Sci Transl Med. 2016;8:362ps17.

Olaparib

FDA/EMEA approved

PARP Inhibitors Target Tumors With Defects in Homologous Recombination

PARP trapped on DNA by PARPi; more trapping more potent

Lord. Science. 2017;355:1152.

Talazoparib Niraparib Rucaparib Olaparib Veliparib> > >≈

Preclinical PARP trapping potency (high to low)

Early PARP Inhibitor Trials in Breast Cancer

Study Treatment N BRCA1/2 Mutation Status TNBC, % Response

Fong[1]

Olaparib (phase I; multiple tumor

types)60 BRCA1/2: 37% N/A

CBR: 63% (in 19 patients with BRCA-associated

cancers)

ICEBERG 1[2]Olaparib 400 mg

PO BID27 BRCA1/2: 67%/33% 50 41%

Isakoff[3]Veliparib +

temozolomide41 BRCA1/2: 7.3%/12.0% 56

BRCA1/2: 37.5%WT BRCA: 0%

Kaufman[4]Olaparib 400 mg

PO BID62 BRCA1/2: 60%/40% 48

Tumor response: 12.9%

Gelmon[5]

Olaparib 400 MG PO BID

26TNBC: 16

gBRCA: 10

gBRCA: 50%WT BRCA: 100%

WT BRCA: 0%

1. Fong. NEJM. 2009;361:123. 2. Tutt. Lancet. 2010;376:235. 3. Isakoff. ASCO 2010. Abstr 1019. 4. Kaufman. JCO. 2015;33:244. 5. Gelmon. Lancet Oncol. 2011;12:852.

How Common Are BRCA Mutations?

• General population: ~ 1 in 400 (~ 0.25%)– Women with breast cancer (any age): 1 in 50 (2%)

– Women with breast cancer (younger than 40 yrs): 1 in 10 (10%)

– Men with breast cancer (any age): 1 in 20 (5%)

– Women with ovarian cancer (any age): 1 in 8 to 1 in 10 (10% to 15%)

EVIDENCIAS

OlympiAD: Olaparib vs Chemotherapy in HER2-Negative MBC

• Randomized, open-label phase III study

• Primary endpoint: PFS

• Secondary endpoints: time to second progression/death, OS, ORR, safety, tolerability, global HRQoL

Robson. NEJM. 2017;377:523. Robson. AACR 2018. Abstr CT038.

Patients with HER2-negative MBC with deleterious or suspected deleterious gBRCA mutation; previous anthracyclineand taxane, ≤ 2 previous lines of CT* for metastatic disease; if HR+, not suitable for ET or progressed on ≥ 1 ET

Until PD or unacceptable AEs

Olaparib† 300 mg PO BID(n = 205)

CT‡ on 21-day cycles(n = 97§)

Stratified by HR status (ER+ and/or PgR+ vs TNBC), prior CT for metastases (yes vs no), prior platinum tx (yes vs no)

N: 302

OlympiAD: PFS by BICR (Primary Endpoint)

HR: 0.58 (95% CI: 0.43-0.80; P < .001)

Olaparib

CT

MosPatients at Risk, nOlaparib

CT

10090

80

70

60

50

40

30

20

10

0

PFS

(%

)

0 2 6 84 10 12 16 1814 20 22 26 2824

205

97

177

63

154

44

107

25

9421

6911

408

234

214

111

41

31

21

10

00

Median PFS, Mos

7.0

4.2

Robson. NEJM. 2017;377:523.

OlympiAD: Final OS Analysis*

Pro

bab

ility

of

OS

Mos

1.0

0

0.9

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0 4 8 12 16 20 24 28 32 36 40

20597

19985

17874

14662

12448

9240

5530

2315

115

62

00

Patients at Risk, nOlaparib

CT

HR: 0.90 (95% CI: 0.66-1.23; P = .513)

Olaparib

CT

Deaths,n (%)

19.3

17.1

18-Mo OS,%

54.1

48.0

6-Mo OS,%

93.1

85.8

Median OS, Mos

130 (63)

62 (64)

Robson. AACR 2018. Abstr CT038.

Median F/u,Mos

18.9

15.5

*64% maturity. Study not powered for OS difference.

0.9

Prior Chemotherapy for MBCNo Prior Chemotherapy for MBC

0 4 8 12

16

20

24

28

32

36

40

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Mos From Randomization

0 4 8 12 16 20 24 28 32 36 400

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

1.0

Mos From Randomization

Pro

bab

ility

of

OS

Olaparib TPC

Deaths, n (%) 30 (50.8) 21 (75.0)

Median OS, mos 22.6 14.7

HR 0.51 (95% CI: 0.29-0.90; P = .02)

Alive at 6 mos, % 93.2 88.5

Alive at 18 mos, % 62.1 46.2

Median follow-up, mos 25.5 26.9

Olaparib TPC

Deaths, n (%) 100 (68.5) 41 (59.4)

Median OS, mos 18.8 17.2

HR 1.13 (95% CI: 0.79-1.64; P = NS)

Alive at 6 mos, % 93.1 84.9

Alive at 18 mos, % 50.8 48.8

Median follow-up, mos 25.2 26.0

OS by Prior Chemotherapy With Olaparib vs CT in HER2-Negative MBC With gBRCA Mutation (OlympiAD)

Robson. AACR 2018. Abstr CT038.

OlympiAD: Overall Response by BICR

Olaparib(n = 167)

CT(n = 66)

Median TTR, days 47 45

Median DoR, mos (IQR)

6.4(2.8-9.7)

7.1 (3.2-12.2)

Robson. NEJM. 2017;377:523.

Re

spo

nse

Rat

e (

%)

60%

9%

29%

2%0

10

20

30

40

50

60

70

ORR CR

Olaparib CT100

90

80

OlympiAD: Adverse Events

Any-Grade AEs in ≥ 10% of Patients* Grade ≥ 3 AEs in ≥ 2% of Patients

Robson. AACR 2018. Abstr CT038.

OlaparibCT

OlaparibCT

Nausea

Anemia

Vomiting

Fatigue

Neutropenia

Cough

Decreased appetite

Back pain

Increased ALT

Increased AST

Alopecia

Hand–foot syndrome

75

AEs (%)50 25 0 755025

35.2

26.4

15.4

24.2

49.5

6.6

12.1

8.8

17.6

16.5

13.2

20.9

58.0

40.0

32.2

29.8

27.3

17.1

17.1

14.6

11.7

9.8

3.4

0.5

Anemia

Neutropenia

White blood cell count decreased

Fatigue

Platelet count decreased

AST increased

Leukopenia

γ-Glutamyltransferase

Back pain

Dyspnea

Headache

Hand–foot syndrome

75

AEs (%)50 25 0 755025

4.4

26.4

9.9

1.1

1.1

0

3.3

1.1

1.1

2.2

2.

2

2.2

16.1

9.3

3.4

3.4

2.4

2.4

2.4

2.0

2.

01.0

1.0

0

*AEs with ≥ 5% difference in frequency between arms.

EMBRACA: Talazoparib vs Chemotherapy in Advanced BRCA1/2-Positive, HER2-Negative Breast Cancer

▪ Randomized, open-label phase III study conducted at 145 sites in 16 countries

▪ Primary endpoint: PFS by BICR

▪ Secondary endpoints: ORR, OS, safety,

▪ Investigational endpoints: DoR, QoL

Litton. NEJM. 2018;379:753.

Patients with HER2-negative LA/MBC with deleterious or suspected

deleterious germline BRCA1/2 mutation ; previous anthracycline and/or taxane,

≤ 3 previous lines of CT* for adv disease(N = 431)

Until PD or unacceptable AEs

Talazoparib 1.0 mg PO QD(n = 287)

Physician’s Choice of Chemotherapy†(n = 144) 

Stratified by HR status (ER+ and/or PgR+ vs TNBC), prior chemo regimens (0 vs ≥ 1), history of CNS metastases (yes vs no)

21-day cycles

*Previous platinum-based therapy for EBC permitted if DFI ≥ 6 mos†Physician’s choice of: capecitabine 1250 mg/m2 PO BID Days 1-14; eribulin 1.4 mg/m2 IV Days 1, 8; gemcitabine 1250 mg/m2 IV Days 1, 8; or vinorelbine 30 mg/m2 IV Days 1, 8, and 15.

▪ Median follow-up time: 11.2 mos

EMBRACA: PFS by BICR (Primary Endpoint)

Litton. NEJM. 2018;379:753.

PFS OutcomeTalazoparib

(n = 287)Standard CT

(n = 144)

PFS events, % 186 (65) 83 (58)

Median PFS, mos (95% CI)

8.6 (7.2-9.3) 5.6 (4.2-6.7)

HR (95% CI) 0.54 (0.41-0.71); P < .001

1-yr PFS, % 37 20

Mos

0 423 6 12 15 18 21 24 27 30 33 36 399

100

90

80

70

60

50

40

30

20

10

0

PFS

(%

)

TalazoparibStandard therapy

TalazoparibStandard CT

EMBRACA: Interim OS Analysis (Secondary Endpoint)

Litton. NEJM. 2018;379:753.

OS OutcomeTalazoparib

(n = 287)Standard CT

(n = 144)

OS events, n (%) 108 (38) 55 (38)

Median OS, mos (95% CI) 22.3 (18.1-26.2) 19.5 (16.3-22.4)

HR (95% CI) 0.76 (0.54-1.06); P = .105

24-mo OS, % (95% CI) 45 (36.7-53.5) 37 (24.1-49.1)

36-mo OS, % (95% CI) 34 (25.3-43.7) 0

Mos

0 423 6 12 15 18 21 24 27 30 33 36 399

100

90

80

70

60

50

40

30

20

10

0

Ove

rall

Surv

ival

(%

)

Adverse Event, n (%) Talazoparib (n = 286) Standard CT (n = 126)

Any Grade 3/4 Any Grade 3/4

Hematologic 194 (67.8) 157 (54.9) 63 (50.0) 48 (38.1)

Anemia 151 (52.8) 112 (39.2) 23 (18.3) 6 (4.8)

Neutropenia 99 (34.6) 60 (21.0) 54 (42.9) 44 (34.9)

Thrombocytopenia 77 (26.9) 42 (14.7) 9 (7.1) 2 (1.6)

Leukopenia 49 (17.1) 19 (6.6) 17 (13.5) 11 (8.7)

Nonhematologic 282 (98.6) 91 (31.8) 123 (97.6) 48 (38.1)

Fatigue 144 (50.3) 5 (1.7) 54 (42.9) 4 (3.2)

Nausea 139 (48.6) 1 (0.3) 59 (46.8) 2 (1.6)

Headache 93 (32.5) 5 (1.7) 28 (22.2) 1 (0.8)

Vomiting 71 (24.8) 7 (2.4) 29 (23.0) 2 (1.6)

Diarrhea 63 (22.0) 2 (0.7) 33 (26.2) 7 (5.6)

Back pain 60 (21.0) 7 (2.4) 20 (15.9) 2 (1.6)

PPE 4 (1.4) 5 (1.7) 28 (22.2) 3 (2.4)

EMBRACA: Safety

Litton. NEJM. 2018;379:753.

Meta-analysis of Phase III Trials of PARP Inhibitors vs Single-Agent CT in MBC: Survival Outcomes

PFS

Poggio. ESMO Open. 2018;3:e000361.

OS

▪ Pt population: BRCA-mutant positive/HER2-negative MBC

Trial name HR (95% CI)

OlympiAD

EMBRACA

Random effect (I-squared = 0%, P = .756)

0.58

(0.43-0.80)

0.54

(0.41-0.79)

0.56

(0.45-0.70)

0.41 1 2.44Favors PARPi Favors controls

Trial name HR (95% CI)

OlympiAD

EMBRACA

Random effect (I-squared = 0%, P = .501)

0.90

(0.63-1.29)

0.76

(0.54-1.06)

0.82

(0.64-1.05)

0.54 1 1.85Favors PARPi Favors controls

Response Rates Across Randomized Phase III Trials of PARP Inhibitors in MBC

Trial Measurable Disease, %

PARPi Overall

Response, %

CT OverallResponse, %

Odds Ratio P Value

OlympiAD (olaparib)

77.1 59.9 28.8 3.67

EMBRACA (talazoparib)

77.3 62.6 27.2 4.47

Overall 61.4 27.8 4.15 < .001

Robson. NEJM. 2017;377:523. Litton. NEJM. 2018;379:753. Poggio. ESMO Open. 2018;3:e000361.

Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V1.2019. © National Comprehensive Cancer Network, Inc 2019. All rights reserved. Accessed March 18, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org.

Conclusión:

Los inhibidores de PARP (Olaparib y Talazoparib) son activos

en el tratamiento del cáncer de mama avanzado con mutación

en BRCA con unos resultados mejorables.

Propuestas…

Propuestas… 1.- ¿Son todos los iPARP iguales?

Propuestas… 2.- ¿Sólo para BRCA mutadas?

Propuestas… 2.- ¿Sólo para BRCA mutadas?

Propuestas… 2.- ¿Solo para BRCA mutadas?

Propuestas… ¿Mejor en combinación?