Carcinoma mammario
metastatico BRCA mutato:
quale ruolo per i PARP-I?
Prof.ssa Valentina Guarneri Università di Padova
IOV - IRCCS
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
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
OlympiAD Final Overall Survival
Robson M, Ann Oncol 2019
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
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
EMBRACA primary end point: PFS
Litton JK, NEJM 2018
EMBRACA interim OS analysis
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
HER2- metastatic BRCA-mut BC
HR- HR+
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
Seah DSE, J Natl Compr Canc Netw 2014
Lines of chemotherapy and duration according to BC subtype
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
Tutt A et al, Nature Medicine 2018
TNT phase III trial for TN metastatic BC
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
• 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
HRQoL in the OlympiAD trial
Robson M, ESMO 2017
HRQoL in the EMBRACA trial
Litton J, SABCS 2017, NEJM 2018
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
