I tumori mammari metastatici BRCA-mutati:
quali opzioni?
Giuseppe Curigliano, MD, PhD
University of Milano and Istituto Europeo di Oncologia
Milano, Italy
• Who should be tested for BRCA mutation?
• Management of BRCA mutated MBC
• Evidences from clinical trials
• Open questions
Outline
Factors for Consideration of Genetics Evaluation and Testing
• Known mutation in at least one blood relative
• Breast cancer diagnosis ≤35 years
• Familial clustering of BR and/or OV cancers
• Triple-negative breast cancer diagnosis ≤ 60 years
• Male breast cancer
• Ovarian cancer, especially papillary serous
̵ Pancreatic and related malignancies in the family
̵ Castrate-resistant prostate cancer
̵ Results of tumor (somatic) genetic analysis
• Per guidelines ̵ Not yet finalized on guidelines
OV, ovarian
TNT Trial: Objective Response by BRCA1/2 Status
17/25 (68.0%)
6/18 (33.3%)
0 20 40 60 80 100
Carboplatin
Docetaxel
Percentage with OR at cycle 3 or 6 (95% CI)
4
Absolute difference (C-D) 34.7% (95% CI 6.3–63.1)
Exact P = .03 Germline BRCA1/2
mutation (n = 43)
Interaction: Randomized treatment & BRCA1/2 status: P = .01
0 20 40 60 80 100
Carboplatin
Docetaxel
Percentage with OR at cycle 3 or 6 (95% CI)
NO Germline BRCA1/2 mutation (n = 273)
Absolute difference (C-D) -8.5% (95% CI -19.6–2.6)
Exact P = .16
36/128 (28.1%)
53/145 (36.6%)
Tutt A, et al. Nat Med. 2018;24(5):628-637.
OR, overall response
Lig3 XRCC1
Polß PNK
Poly(ADP-ribose) polymerase (PARP)
• A key regulator of DNA damage repair processes
• Involved in DNA base-excision repair (BER)
• Binds directly to DNA damage (spontaneous and therapeutic)
• Produces large branched chains of poly(ADP-ribose)
• Attracts and assists BER repair effectors
Specific tumor cell killing
H R rep ai r
Few normal tissue effects Normal tissue cells
DNA repair
DNA repair
Base excision DNA repair
Homologous recombination (HR) repair
BRCA1/BRCA2 deficient Tumor cells
HR r ep ai r
PARP inhibitor
Base excision DNA repair
PARP inhibitor
Base excision DNA repair
H R rep ai r
Tutt and Ashworth Cold Spring Harb Symp Quant Biol 2005;70:139–148; McCabe N et al. Cancer Res 2006;66:8109–8115
The principle of synthetic lethal tumour targeting
Tutt et al The Lancet 2010 376(9737):235-44
To assess the efficacy and tolerability of oral olaparib in BRCA1/ BRCA2 mutation carriers with breast cancer
Proof-of-concept phase II study, single-arm sequential cohort design
Confirmed BRCA1 or BRCA2 mutation Advanced refractory breast cancer
(stage IIIB/IIIC/IV) after failure of ≥1 prior chemotherapy for advanced disease
Olaparib 400 mg po bid (MTD) 28-day cycles; n = 27
Olaparib 100 mg po bid 28-day cycles; n = 27
Cohort 2
Cohort 1 (enrolled first)
400 mg BD 100 mg BD
Efficacy in BRCA1/2 breast cancer
ORR 41% ORR 22%
Tutt et al The Lancet 2010 376(9737):235-44
Single agent olaparib in ovarian cancer
Moore K et al October 21, 2018 DOI: 10.1056/NEJMoa1810858
PARP inhibitors with DNA damaging agents in
breast cancer
OlympiAD
• * Tablet formulation (2 tablets twice daily)
• M=metastatic breast cancer, HER2=human epidermal growth factor 2, TNBC=triple negative breast cancer, TPC=treatment of physician’s choice, OS=overall survival, PFS=progression-free survival,
PFS2=progression-free survival 2, ORR=objective response rate, HRQoL=health-related quality of life, FSI=first subject in, RECiST= Response Evaluation Criteria in Solid Tumors, ER=oestrogen receptor, PR=progresterone receptor, ECOG PS= Eastern Cooperative Oncology Group Performance Status, gBRCAm=germline BRCA mutation; po=oral
• 1. https://clinicaltrials.gov/ct2/show/NCT02000622; 2. Robson et al. Poster OT1-1-04, San Antonio Breast Cancer Symposium 2014; 3. AZ data on file (2017), 4. Robson et al. N Engl J Med. 2017; 377:523-533
Olaparib 300mg*po bid
Treatment of Physician’s Choice (TPC)
• gBRCAm mBC
• TNBC or HER2-negative, ER/PR positive
• ≤2 prior chemotherapy lines for mBC
• Previous treatment must include anthracycline and taxane
• Hormone receptor positive (HR+) disease progressed on ≥1 endocrine therapy, or not suitable
• If patients have received platinum therapy there should be:
• No evidence of progression during treatment in the advanced setting
• At least 12 months since (neo)adjuvant treatment and randomisation
• ECOG PS 0-1
• At least one lesion that can be assessed by RECIST v1.1
Randomise 2:1 N=302
4Stratification by
2• Prior chemotherapy regimens for metastatic breast cancer
• Hormonal receptor (HR) status
• Prior platinum therapy
Primary endpoint
• PFS (RECIST 1.1, Independent Review)
Secondary endpoints
• OS
• PFS2
• ORR
• PFS, PFS2 and OS based on Myriad gBRCAm status
• HRQoL (EORTC-QLQ-C30)
• Safety and tolerability FSI May 2014
3Global Study in 19 countries
and approximately 141 sites
1Robson et al. N Engl J Med. 2017; 377:523-533
Patient characteristics
Olaparib n=205
n (%)
TPC n=97 n (%)
Total n=302
n (%)
Median age (min, max) 44 (22, 76) 45 (24, 68) 44 (22, 76)
Male 5 (2.4) 2 (2.1) 7 (2.3)
ECOG PS
0 148 (72.2) 62 (63.9) 210 (69.5)
1 57 (27.8) 35 (36.1) 92 (30.4)
Race
White 134 (65.4) 63 (64.9) 202 (66.9)
Asian 66 (32.2) 28 (28.9) 94 (31.1)
Other 5 (2.4) 6 (6.2) 11 (3.6)
Olaparib n=205
n (%)
TPC n=97
n(%)
Total n=302
n (%) Received previous
chemotherapy for mBC
Yes 146 (71.2) 69 (71.1) 215 (71.2)
No 59 (28.8) 28 (28.8) 87 (28.8)
Hormonal receptor status HR+ 103 (50.2) 49 (50.5) 152 (50.3)
TNBC 102 (49.8) 48 (49.5) 150 (49.7)
Received prior platinum therapy for breast cancer
Yes 60 (29.3) 26 (26.8) 86 (28.4)
No 145 (71) 71 (73) 216 (71.5)
Patient characteristics
Robson et al. N Engl J Med. 2017; 377:523-533
Patient characteristics
Robson et al. N Engl J Med. 2017; 377:523-533
Olaparib n=205
n (%)
TPC n=97
n(%)
Total n=302
n (%) Number of metastatic
sites
1 46 (22.4) 25 (25.8) 71 (23.5)
2 or more 159 (77.6) 72 (74.2) 231 (76.5)
Sites of metastatic lesions
Bone & locomotor
only 16 (7.8) 6 (6.2) 22 (7.3)
CNS 17 (8.3) 8 (8.2) 25 (8.3)
BRCA mutation status
BRCA1 117 (57.1) 51 (52.6) 168 (55.6)
BRCA2 84 (41.0) 46 (47.4) 130 (43.0)
Both 4 (1.9) 0 4 (1.3)
De novo metastatic BC 26 (12.7) 12 (12.4) 38 (12.6)
Progressive disease at randomisation 159 (77.6) 73 (75.3) 232 (76.8)
Patient characteristics
Robson et al. N Engl J Med. 2017; 377:523-533
Olaparib n=205
n (%)
TPC n=97
n(%)
Total n=302
n (%)
Received prior endocrine therapy* †
Adjuvant/neoadjuvant 71 (68.9) 36 (73.5) 107 (70.4)
Metastatic 66 (64.1) 28 (57.1) 94 (61.8)
Total 97 (94.2) 45 (91.8) 142 (93.4)
Lines of previous cytotoxic chemotherapy for
metastatic breast cancer
0 68 (33.2) 31 (32.0) 99 (32.8)
1 80 (39.0) 42 (43.3) 122 (40.4)
2 57 (27.8) 24 (24.7) 81 (26.8)
Received prior platinum therapy for BC †
Metastatic 43 (21.0) 14 (14.4) 57 (18.9)
Adjuvant/neoadjuvant 15 (7.3) 7 (7.2) 22 (7.3)
Patient characteristics
Robson et al. N Engl J Med. 2017; 377:523-533
Olaparib n=205
n (%)
n=97 TPC n (%)
Total n=302
n (%)
Full analysis set (randomised, ITT) 205 (100) 97 (100) 302 (100)
Patients who received study treatment 205 (100) 91 (93.8) 296 (98.0)
Number who received olaparib 205 (100) - 205 (67.9)
Number who received capecitabine - 41 (42.3) 41 (13.6)
Number who received eribulin - 34 (35.1) 34 (11.3)
Number who received vinorelbine - 16 (16.5) 16 ( 5.3)
Safety
Robson et al. N Engl J Med. 2017; 377:523-533
21 17
18 18 12
21 7
15 22
50 23
15
26 35
1 9 11 14 16
16 17 20 21 27 29 30 40 58
0 25 50 75
75 50 25
Adverse events (%) Nausea
Anemia Vomiting Fatigue Neutropenia Diarrhea Headache Cough
Decreased appetite Pyrexia
Increased ALT Increased AST Hand-foot syndrome
Olaparib 300 mg bd (N=205)
Chemotherapy TPC (N=91)
Decreased white blood cells
Safety
Robson et al. N Engl J Med. 2017; 377:523-533
2 2 3 0 1 3 1
10
26 4
0 1 1 2 2 2 3 3 9
Anemia
16Fatigue Neutropenia
Increased AST
Hand-foot syndrome Dyspnea
Decreased platelet count Leukopenia
0 25 50 75
75 50 25
Headache
Adverse events (%)
Olaparib 300 mg bd (N=205)
Chemotherapy TPC (N=91)
Decreased white blood cells
Progression free survival
Robson et al. N Engl J Med. 2017; 377:523-533
177 83
159 46
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
P rob abil it y of pr og re ss ion -f re e surv iv al
Time from randomisation (months) 14
12 10 8
6 4 2
0 16 18 20 22 24 26 28
23 4 40
8 69 11 94 21 107
25 154
44 205
97
21 4
11 1
4 1
3 1
2 1
1 0
0 0 21
4 36
7 61 11 73 13 100
24 129
29 201
88
11 1
11 1
3 1
2 1
1 0
1 0 Olaparib
TPC
Number of patient’s at risk
Median PFS was improved by 69% with olaparib treatment compared to
standard of care chemotherapy
Olaparib TPC
n 205 97
Events (%) 163 (79.5%) 71 (73.2%)
Median (m) 7.0 4.2
HR = 0.58 95 % CI (0.43, 0.80)
p=0.0009
PFS free at 6m (%) 54.1 32.9
PFS free at 12m (%) 25.9 15.0
Olaparib 300 mg bd (N=205)
TPC (N=97)
Response rate
Robson et al. N Engl J Med. 2017; 377:523-533
Olaparib TPC
Response Evaluable Population, n 167 66
ORR, n (%) 100 (59.9) 19 (28.8)
Complete Response, n (%) 15 (9.0) 1 (1.5)
Partial Response, n (%) 85 (51.0) 18 (27.3)
Median Duration of Response, months (95%CI) 6.4 (2.9-9.7) 7.1 (3.2-12.2)
Median Time to Onset of Response, days 47 45
Summary of efficacy data
Robson et al. N Engl J Med. 2017; 377:523-533
– OlympiAD showed a statistically significant improvement in PFS* (HR=0.58 (95% CI 0.43-0.80), p=0.0009) with a median PFS of 7.0 months in the olaparib arm
compared to 4.2 months in the TPC arm
– Treatment with olaparib increased PF2, demonstrating a continued and consistent clinical benefit beyond progression with olaparib (HR: 0.57, 95% CI 0.40-0.83,
p=0.0033)
– Median OS in the olaparib arm was 19.3 months compared to 17.1 months in the TPC arm, (HR= 0.9 (95% CI 0.66-1.23)); the difference did not reach statistical
significance p=0.51
– Patients treated with olaparib had a significantly better HRQoL compared with
those on TPC, a clinically meaningful benefit for patients
Talazoparib
BRCA=breast cancer susceptibility gene; CR=complete response; ECOG=Eastern Cooperative Oncology Group; HA=alternate hypothesis; H0=null hypothesis;
ORR=objective response rate; PR=partial response; QD=once daily; RECIST=Response Evaluation Criteria in Solid Tumors; 3L=third-line.
Turner NC, et al. Abstract 1007. ASCO 2017.
Patients with advanced breast cancer with germline BRCA mutation
• ECOG ≤ 1
• Measurable disease by RECIST v1.1
Cohort 1 (Prior Platinum) n=49
PR or CR to last platinum-containing regimen for metastatic disease with disease progression >8 weeks following the last
dose of platinum
Cohort 2 (3L+, No Prior Platinum) n=35
3 or more prior cytotoxic regimens for metastatic disease No prior platinum for metastatic disease
Phase 2, 2-Stage, 2-Cohort Study
Talazoparib
Primary Endpoint
•Confirmed ORR by central independent radiology facility using RECIST v1.1 Secondary Endpoints
•Clinical benefit rate lasting ≥24 weeks
•Duration of response
•Progression-free survival
•Overall survival
•Safety
2-stage design for each cohort separately:
• Stage 1: enrollment of 35 patients in each cohort
• If ≥ 5 responses seen in 1 cohort Stage 2: enrollment of 35 patients
• Designed to compare H
A30% versus H
015% response rate (90% power; alpha=0.05)
Note: enrollment discontinued at 84 pts
Talazoparib
Turner NC, et al. Abstract 1007. ASCO 2017.
Cohort 1 Cohort 2
*
* *
*
*
*
*
*
BRCA1+
BRCA2+
Unknown
BRCA1+
BRCA2+
Overall ORR for BRCA1=23% and for BRCA2=33%
EMBRACA: Study Design
Phase 3, international, open-label study randomized 431 patients in 16 countries and 145 sites Patients with locally advanced or
metastatic HER2-negative breast cancer and a germline BRCA1 or BRCA2 mutation*†
Stratification factors:
• Number of prior chemo regimens (0 or ≥1)
• TNBC or hormone receptor positive (HR+)
• History of CNS mets or no CNS mets
Talazoparib 1 mg PO daily
Physician's choice of therapy (PCT)‡:
capecitabine, eribulin, gemcitabine,
or vinorelbine R
2:1
*Additional inclusion criteria included: no more than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease;
prior treatment with a taxane and/or anthracycline unless medically contraindicated.
†HER2-positive disease is excluded.
‡Physician's choice of therapy must be determined prior to randomization.
CNS=central nervous system; EORTC=European Organisation for Research and Treatment of Cancer; HER2=human epidermal growth factor receptor 2;
mets=metastases; PO= by mouth; QLQ-BR23=Quality of Life Questionnaire breast cancer module; QLQ-C30=Quality of Life Questionnaire Core 30; R=randomized;
RECIST=Response Evaluation Criteria In Solid Tumors version 1.1;
TNBC=triple-negative breast cancer.
Litton J, et al. N Engl J Med 2018; 379:753-763.
Primary endpoint
• Progression-free survival by RECIST by blinded central review
Key secondary efficacy endpoints
• Overall survival (OS)
• Objective response rate (ORR) by investigator
• Safety
Exploratory endpoints
• Duration of response (DOR) for objective responders
• Quality of life (QoL; EORTC QLQ-C30, QLQ-BR23)
Treatment (21-day cycles) continues until progression or
unacceptable toxicity
TALA (n=287)
Overall PCT (n=144)
Age, median (range), y 45 (27.0-84.0) 50 (24.0-88.0)
<50 y, no. % 182 (63.4) 67 (46.5)
Gender, % female 98.6 97.9
ECOG = 0 / 1 / 2, % 53.0 / 44.0 / 2.0 58.0 / 40.0 / 1.0
Measurable disease by investigator, no. (%) 219 (76.3) 114 (79.2)
History of CNS metastasis, no. (%) 43 (15.0) 20 (13.9)
Visceral disease, no. (%) 200 (69.7) 103 (71.5)
Hormone receptor status, no. (%)
TNBC 130 (45.3) 60 (41.7)
HR+ 157 (54.7) 84 (58.3)
BRCA status, no. (%)
BRCA1+ 133 (46.3) 63 (43.8)
BRCA2+ 154 (53.7) 81 (56.3)
Disease free interval (initial diagnosis to aBC)
<12 months 108 (37.6) 42 (29.2)
Patient characteristics
TALA (n=287)
Overall PCT (n=144) Patients, no (%)
Prior adjuvant/neoadjuvant therapy 238 (82.9) 121 (84.0)
Prior hormonal therapy 161 (56.1) 77 (53.5)
Prior platinum therapy 46 (16.0) 30 (21.0)
No. of prior cytotoxic regimens for aBC
0 111 (38.7) 54 (37.5)
1 107 (37.3) 54 (37.5)
2 57 (19.9) 28 (19.4)
≥3 12 (4.2) 8 (5.6)
aBC=advanced breast cancer; PCT=physician’s choice of therapy; TALA=talazoparib.
Patient characteristics
Litton J, et al. N Engl J Med 2018; 379:753-763.
Safety
Litton J, et al. N Engl J Med 2018; 379:753-763.
TALA (n=286)
Overall PCT (n=126)
All Grade Grade 3 Grade 4 All Grade Grade 3 Grade 4 No. of patients with ≥1 AE,
no. (%) 194 (67.8) 140 (49.0) 17 (5.9) 63 (50.0) 29 (23.0) 19 (15.1) Anemia 151 (52.8) 110 (38.5) 2 (0.7) 23 (18.3) 5 (4.0) 1 (0.8) Neutropenia 99 (34.6) 51 (17.8) 9 (3.1) 54 (42.9) 25 (19.8) 19 (15.1) Thrombocytopenia 77 (26.9) 32 (11.2) 10 (3.5) 9 (7.1) 2 (1.6) 0
Lymphopenia 21 (7.3) 9 (3.1) 0 4 (3.2) 0 1 (0.8)
Febrile neutropenia 1 (0.3) 0 1 (0.3) 1 (0.8) 0 1 (0.8)
Safety
Litton J, et al. N Engl J Med 2018; 379:753-763.
TALA (n=286)
Overall PCT (n=126)
All Grade Grade 3 Grade 4 All Grade Grade 3 Grade 4 No. of patients with ≥1 nonhematologic AE, no.
(%) 282 (98.6) 91 (31.8) 123 (97.6) 48 (38.1)
Fatigue 144 (50.3) 5 (1.7) 0 54 (42.9) 4 (3.2) 0
Nausea 139 (48.6) 1 (0.3) 0 59 (46.8) 2 (1.6) 0
Headache 93 (32.5) 5 (1.7) 0 28 (22.2) 1 (0.8) 0
Alopecia 72 (25.2) ‒ ‒ 35 (27.8) ‒ ‒
Vomiting 71 (24.8) 7 (2.4) 0 29 (23.0) 2 (1.6) 0
Diarrhea 63 (22.0) 2 (0.7) 0 33 (26.2) 7 (5.6) 0
Constipation 63 (22.0) 1 (0.3) 0 27 (21.4) 0 0
Decreased appetite 61 (21.3) 1 (0.3) 0 28 (22.2) 1 (0.8) 0
Back pain 60 (21.0) 7 (2.4) 0 20 (15.9) 2 (1.6) 0
Dyspnea 50 (17.5) 7 (2.4) 0 19 (15.1) 3 (2.4) 0
Progression free survival
Litton J, et al. N Engl J Med 2018; 379:753-763.
Overall survival
Litton J, et al. N Engl J Med 2018; 379:753-763.
Response rate
Litton J, et al. N Engl J Med 2018; 379:753-763.
Summary of efficacy data
– Talazoparib resulted in prolonged progression-free survival vs physician’s choice of therapy by blinded central review HR: 0.54 (95% CI: 0.41, 0.71); P<0.0001
– Overall survival is immature (51% of projected events); HR: 0.76 (95% CI: 0.54, 1.06); P=0.105
– Global Health Status/Quality of Life showed overall improvement from baseline and a delay in the time to clinically meaningful deterioration in patients
receiving talazoparib HR: 0.38 (95% CI: 0.26, 0.55); P<0.0001
– Talazoparib was generally well tolerated, with minimal nonhematologic toxicity and few adverse events resulting in treatment discontinuation
Litton J, et al. N Engl J Med 2018; 379:753-763.