Carcinoma mammario metastatico BRCA mutato: quale ruolo per i PARP-I?

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(1)

Carcinoma mammario

metastatico BRCA mutato:

quale ruolo per i PARP-I?

Prof.ssa Valentina Guarneri Università di Padova

IOV - IRCCS

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OlympiAD study design and patients population

• HER2- MBC

• gBRCAmut

• <2 prior lines of CT for MBC

• HR+ progressed on >1 line of ET

• If platinum use: no PD during treatment in MBC

• >12 mos since neo/adj treatment

Olaparib 300 mg bid

TPC:

Capecitabine Eribulin Vinorelbine

Robson M et al, N Engl J Med 2017

Olaparib n=205 TPC n=97

Age (median) 44 45

BRCA1 BRCA2

117 (57) 84 (41)

51 (53) 46 (47) HR+

TN

103 (50) 102 (50)

49 (51) 48 (49)

New MBC 26 (13) 12 (12)

Previous CT for MBC 146 (71) 69 (71) Previous platinum 60 (29) 26 (27)

>2 met sites 159 (78) 72 (74)

Bone only 16 (8) 6 (6)

A/T PRETREATED

MOST pts RECEIVED CT FOR MBC TN: NON-PLATINUM RESISTANT

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OlympiAD primary end point PFS

Robson M, NEJM 2017

Median 7.0 vs 4.8 months HR 0.58, 95% CI 0.43-0-80 P<0.001

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OlympiAD Final Overall Survival

Robson M, Ann Oncol 2019

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Median response onset

Olaparib: 47 days

TPC: 45 days

Median best % change from baseline (target lesions)

Olaparib: – 45.1%

TPC: –14.8%

Median duration

• Olaparib: 6.2 (4.6–7.2)

• TPC: 7.1 (2.8–12.2)

37.9 25.1

33.3

15.0

0 20

40 60

80

Stable disease

27.3

50.9

1.5

9.0

0 20 40 60

Partial response Complete response

Olaparib 300 mg bd (n=167)

Non-response Response

Patients, % Chemotherapy TPC

(n=66)

15 25 51

27 38

33

9

1.5

PD SD PR CR

PD SD PR CR

N=233 pts evaluable for ORR RECIST 1.1 (blinded independent central review)

OlympiAD - ORR

Robson M et al, N Engl J Med 2017

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EMBRACA study design and patients population

Litton JK, NEJM 2018

Talazoparib n=287 TPC n=144

Age (median) 45 50

BRCA1 BRCA2

133 (46) 154 (54)

63 (44) 81 (56) HR+

TN

157(55) 130 (45)

84 (58) 60 (42) Previous CT for MBC 176 (61) 90 (62) Previous platinum 46 (16) 30 (21) Visceral disease 200 (70) 103 (72) History of CNS mets 43 (15) 20 (14)

A/T PRETREATED, no more than 3 lines of CT

Platinum sensitivity

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EMBRACA primary end point: PFS

Litton JK, NEJM 2018

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EMBRACA interim OS analysis

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N=333 pts evaluable for ORR RECIST 1.1 (blinded independent central review)

EMBRACA - ORR

Litton KD, NEJM 2018

TALA n=219 TPC n=114

Complete Response (CR) 12 (5.5%) 0

Partial Response (PR) 125 (57%) 31 (27.2%)

Stable Disease (SD) 46 (21%) 36 (31.6%)

Progressive Disease (PD) 4 (1.8%) 19 (16.7%)

Overall Response Rate (CR+PR) 62.6% vs 27.2%, OR 4.99 (p<.0001)

CBR at 24 weeks 68.6% vs 36.1%, OR 4.2 (p<.0001)

Median DOR, mos 5. 4 3.1

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HER2- metastatic BRCA-mut BC

HR- HR+

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n Brain Liver Lung Bone Distant

Nodal

Pleural/

peritoneal

Other

Luminal A 458 7.6 28.6 23.8 66.6 15.9 28.2 13.5 Luminal B 378 10.8 32.4 30.4 71.4 23.3 35.2 19.3 Luminal/HER2 117 15.4 4.4 36.8 65 22.2 34.2 13.7 HER2 enriched 136 28.7 45.6 47.1 59.6 25 31.6 16.9 Basal Like 159 25.2 21.4 42.8 39 39.6 29.6 23.9 TN non basal 109 22 32.1 35.8 43.1 35.8 28.4 25.7 p <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.32 0.006

Kennecke H, JCO 2010 Gong Y, Sci Rep 2017

Metastatic BC according to molecular subtype

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Seah DSE, J Natl Compr Canc Netw 2014

Lines of chemotherapy and duration according to BC subtype

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13

ORR

Study Drug Setting All/ Unselected BRCA wt BRCA mut

TBCR0091 Cisplatin or Carboplatin 1-2 line 26% 20% 54.5%

BALI2 Cisplatin 1-2 line 10% -- --

Byrski3 Cisplatin 1-2 line -- -- 80%

1. Isakoff SJ, J Clin Oncol 2015; 2. Baselga J et al, J Clin Oncol 2013; 3. Byrski T et al, Breast Cancer Res 2012

Platinum for gBRCAmut metastatic TNBC

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Tutt A et al, Nature Medicine 2018

TNT phase III trial for TN metastatic BC

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Tutt A et al, SABCS 2014

TNT phase III trial for TN metastatic BC

Carbo BRCAmut: median PFS 6.8 mos Carbo BRCAwt: median PFS 3.1 mos Doc BRCA mut: median PFS 4.8

Doc BRCAwt: median PFS 4.6 mos

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• Based on available data it is reasonable to consider platinum-containing regimens as a valid option as 1st line treatment for BRCAmut mTNBC

• Subgroup analysis of OlympiAD suggests OS benefit for olaparib in 1st line pts

• However:

• Carboplatin inclusion in CT regimens for early disease will likely increase

• No head to head comparison PARPi vs platinum salts

• For 2nd line and further:

• Unknown efficacy of PARPi in MBC “platinum resistant” disease

• Eribulin prolongs OS vs capecitabine or TPC in pretreated MBC patients, markedly in TNBC

…but PFS ~3 months and no specific data for gBRCAmut

• PARPi prolong PFS vs TPC including eribulin for gBRCAmut mTNBC

• Other critical endpoints for MBC: ORR, safety, HRQoL

Attempt to design a treatment algorithm for

gBRCAmut mTNBC

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HRQoL in the OlympiAD trial

Robson M, ESMO 2017

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HRQoL in the EMBRACA trial

Litton J, SABCS 2017, NEJM 2018

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Olaparib in the treatment algorithm for gBRCAmut HR+/HER2- MBC

• Crowded scenario dominated in first lines by endocrine Tx

• OlympiAD suggests more limited benefit of olaparib vs TPC in HR+ disease

• EMBRACA does not confirm this observation

• Better HRQoL with PARPi, but TPC alltogether (vs capecitabine?)

• Disease course is longer than TNBC: a sequence strategy that includes olaparib among the options at some point as an additional line of therapy is feasible

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• Efficacy of PARPinh for BRCA mut BC demonstrated in phase III trials

• New class of agents with efficacy demonstrated in a genomic-defined subset of patients

• Especially attractive for TNBC, with limited options

• Comparison with platinum salts and efficacy in platinum refractory/resistant patients needs to be further assessed

• Correct positioning: maintenance, earlier lines (incl. delay of CT in HR+)

PARPi for gBRCAmut HER2- MBC

Figure

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