management of brca mutation carriers...physician's choice of therapy must be determined prior to...
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Management of BRCA mutation carriers
Shani Paluch-Shimon, MBBS, MScDirector, Division of OncologyDirector, Breast Oncology Unit & the Talya Centre for young women with breast cancerShaare Zedek Medical Centre, Jerusalem, Israel
ESMO Breast Cancer Preceptorship – June 2019
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Disclosures
Roche: Speakers bureau, honoraria, consultancyAstra Zeneca: Speakers bureau, honoraria,
consultancyNovartis: Speakers bureau, honoraria, consultancy
Pfizer: Speakers bureau, honoraria, consultancyNanostring: Speakers bureau, honoraria
Teva: Speakers bureau, honoraria
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Nielsen et al Nature Reviews Cancer 2016
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Background
• Germline mutations in BRCA1/2 account for majority of hereditary breast cancer (BC) & ~5-10% of all BC
• BRCA1/2 mutations - ↑ prevalence in younger women with BC, TNBC, FHx of BC or Ovarian cancer (+ other malignancies) and in certain ethnic groups (Ashkenazi Jewish)
• A mutation in BRCA1/2 confers a lifetime risk of 35-90% of BC• In most studies, similar prognosis for BRCA1/2+ & sporadic BC
Tung et al JCO 2016Kuchenbacker et al JAMA 2017Goodwin et al 2012Copson E et al, Lancet Oncology, 2018
BC=Breast Cancer TNBC=Triple Negative Breast Cancer
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BRCA-associated Breast Cancer
BRCA1 BRCA2Age of onset Earlier Slightly older than with BRCA1Subtype Most often “triple negative” Most often hormone positiveRisk of other malignancies
Ovarian cancer Ovarian cancer, Pancreatic cancer, Melanoma (and in males – breast cancer, prostate cancer)
Other features High grade, medullary subtype, pushing margins, lymphocytic infiltrate
Sensitivity to DNA damage
Many similarities, but they are distinct entitiesand BRCA1 and BRCA2 cancers may not respond
Identically to treatment
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IMAGING FOR SCREENING AND DIAGNOSIS IN BRCA1/2
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Screening & Diagnosis: MRI in women with high risk of breast cancer
Exclusively BRCA+ cohort
American Cancer Society Guidelines, 2007
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Why is MRI superior to mammography in BRCA+?
• BRCA+ breast tumors are:- often in younger women with dense breasts – sensitivity of
mammography inversely related to breast density- with “pushing margins” rather then scirrhous, irregular
margins, giving a more “benign” appearance on mammography
- Less-often associated with DCIS (which often have micro-calcifications that are detected on mammography) – especially true for BRCA1
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Impact of a BRCA1/2 mutation on treatment decisions
• Local management- Lumpectomy vs mastectomy- Bilateral mastectomy?• Systemic therapy- No EBM to change adjuvant chemotherapy, conflicting evidence re: NAST- Evidence to support use of DNA cross-linking agents & alkylating agents:- Platinum agents, Mitomycin ,CMF (Cyclophosphamide/MTX/5FU)- PARPi• Reproductive considerations• Ongoing follow-up
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LOCAL THERAPY CONSIDERATIONS
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BCS vs Mastectomy• BCS is a legitimate and safe choice• Therapeutic radiation is safe:- Reduces local ipsilateral recurrence- Does not increase contra-lateral disease• Contralateral radiation?
• Contralateral mastectomy – some studies suggest that there may be a long term survival benefit
• Decision must be tailored to individual’s needs
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Does CRRM improve survival?
Stage 1 & 2 at DxMost were
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WHY DOES PRESENCE OF A BRCA1/2 MUTATION HAVE AN IMPACT ON SYSTEMIC THERAPY?
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DNA REPAIR IS MORE ERROR-PRONE WHEN BRCA1 OR BRCA2 PROTEINS ARE DEFICIENT
BER = base excision repair; HRR = homologous recombination repair; NHEJ = non-homologous end-joining.
Single-Strand Breaks (SSBs)
Double-Strand Breaks (DSBs)
DNA Damage
Proteins
BERRepair Mechanism HRR NHEJ
PARP1XRCC1LIGASE 3
BRCA1BRCA2PALB2ATM
CHEK1CHEK2RAD51
KU70/80CAN-PK
3. Curtin N. Nat Rev Cancer. 2012;12:801-17.4. Frey MK, Pothuri B. Gynecol Oncol Res Pract. 2017;4:4.
1. Homologous Recombination Repair (HRR)
• Non-functioning HRR may be due to BRCA 1 or BRCA 2 deficiency
2. Non-Homologous End-Joining (NHEJ)
• Less precise, more error-prone
Non-functioning HRR results in:• Accumulation of additional mutations• Chromosomal instability • Increased risk for malignant transformation
Two Major Mechanisms for the Repair of DNA Double-Stranded Breaks
1. Lord CJ, Ashworth A. Nature. 2012;481:287-94.2. Marquard AM, et al. Biomarker Res. 2015;3:9
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SYSTEMIC THERAPIES IN BRCA1/2+ BREAST CANCER
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Chemotherapy
• Pre-clinical studies - ↑ sensitivity to DNA damaging agents that interferes with DNA replication forks & require DNA repair by homologous recombination
• Early clinical data in neo-adjuvant setting - platinum sensitivity• ↑sensitivity to chemotherapy doesn’t necessarily prognosticate for BRCA1/2
associated BCSilver et al JCOBysrki et al JCO 2014Paluch-Shimon et al BCRT 2016Fasching et al JCO 2018
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Platinum in the neo-adjuvant setting for BRCA+Study Protocol pCR DFS (med f/u – 35 months)
GeparSixto Liposomal Doxorubicin+ Paclitaxel+/-Carboplatin*
wtBRCA(n=241)
36.4% vs 55%p=0.004
73.5% vs 85.3%p=0.04
BRCA+(n=50)
66.7% vs 65.4% p=0.92
82.5% vs 86%NS
* Also randomization to bevacizumab
BrighTNessPaclitaxel+/-Carboplatin+/-Veliparib→ ACx4
No outcome data
Hahnen et al, JAMA Oncology, 2017
Loibl et al, Lancet Oncology, 2018
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Platinum in BRCA+ in ABCPhase ORR (%) PFS (months)
TNT III Carboplatin vs Docetaxel in BRCA-wtCarboplatin vs Docetaxel in BRCA+
28% vs 36% (p=0.16)68% vs 33% (p=0.03)
3.1 vs 4.56.8 vs 4.8
TBCRC009 II Platinum in TNBC BRCA+ vs BRCA-wt 55% vs 20% (p=0.02) 3.3 vs 2.8 (NS)
Tutt A, et al. Nat Med, 2018 Isakoff S, et al, JCO, 2015
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PARP Inhibitors
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PARP InhibitorsDual Activity – Catalytic and Trapping
• Work by catalytic enzyme activity and by trapping where they lock PARP onto the DNA
• Different PARP inhibitors with equal catalytic inhibition potency show markedly different PARP trapping ability which affects their potency
• Clinical PARP inhibitors can be ranked by their ability to trap PARP (from the most to the least potent): talazoparib >> niraparib > olaparib = rucaparib >> veliparib
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Proof of concept studies - Olaparib in BRCA+ BC
ORR
Tutt et al 41% At least 1 previousline of chemotherapy
Kaufman et al 13% Heavily pre-treated
Tutt et al, Lancet, 2010Kaufman et al , JCO 2015
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R
Potent PARP inhibitor at MTD as
continuous exposure
Physician Choice within SOC options
Capecitabineor
Vinorelbineor
Eribulinor
Gemcitabine
gBRCA1 / BRCA2 Carriers
Advanced anthracycline taxane
resistant breast cancer
Primary endpoint
PFS
Niraparib – BRAVO Trial EORTC / BIG
Talazoparib– EMBRACA - NCT01945775
Olaparib - OLYMPIAD NCT02000622
National Institutes of Health, Available at: https://clinicaltrials.gov/ct2/results?term=NCT01945775 and https://clinicaltrials.gov/ct2/results?term=NCT02000622 . Accessed: September 27, 2015.
How does PARP inhibition compare with SOC chemotherapy in ABC?
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PARP inhibitors in BRCA+ ABCPhase ORR (%) PFS (months)
OLYMPIAD III Olaparib vs TPC 60% vs 29% 7 vs 4.2
ABRAZO II Talazoparib after platinumTalazoparib after 3+ lines of Rx (& no platinum)
21%37%
45.6
EMBRACA III Talazoparib vs TPC 63% vs 27% 8.6 vs 5.6
BROCADE3 III Palclitaxel/Carboplatin+Veliparib/Placebo
78% vs 61%(p=0.027)
14.1 vs 12.3 (NS)
Robson et al, New Engl J Med 2017Turner et al, ASCO, 2017Litton et al, SABCS, 2017Dieras et al, ESMO, 2019
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2:1 randomization
Chemotherapy treatment of physician’s choice (TPC)• Capecitabine• Eribulin• Vinorelbine
Primary endpoint• Progression-free
survival (RECIST 1.1, BICR)
Secondary endpoints• Overall survival• Time to second
progression or death• Objective response rate• Global HRQoL
(EORTC-QLQ-C30)• Safety and tolerability
Olaparib 300 mg
tablets bd
Trea
t unt
il pr
ogre
ssio
n
• HER2-negative metastatic breast cancer – ER and/or PR positive (HR+) or– TNBC
• Deleterious or suspected deleterious gBRCAm
• ≤2 prior chemotherapy lines in metastatic setting
• Prior anthracycline and taxane• HR+ disease progressed on
≥1 endocrine therapy, or not suitable
• If prior platinum use– No evidence of progression
adjuvant treatment– ≥12 months since
(neo)adjuvant treatment
Robson et al, New Engl J Med 2017
Olaparib versus physicians’ choice: the phase III OLYMPIAD study
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Olaparib versus physicians’ choice: PFS
Robson et al, New Engl J Med 2017
Olaparib 300 mg bd
Chemotherapy TPC
Events (%) 163 (79.5) 71 (73.2)Median PFS,
months 7.0 4.2HR 0.58
95% CI 0.43 to 0.80; P=0.0009
Primary end point: centrally-evaluated PFS
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Overall survival in prespecified subgroupsPrior chemotherapy for mBC (2/3L)No prior chemotherapy for mBC (1L)
0 4 8 12 16 20 24 28 32 36 400.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time from randomization (months)0 4 8 12 16 20 24 28 32 36 40
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time from randomization (months)
Nominal P values calculated using a likelihood ratio test; OS stratification factors were prespecified but not alpha controlled1L, first line; 2/3L, second or third line; NS, not significant
Pro
babi
lity
of o
vera
ll su
rviv
al
Olaparib TPC
Deaths, n (%) 30 (50.8) 21 (75.0)Median OS, mo 22.6 14.7
HR 0.51 (95%CI 0.29–0.90; P=0.02)Alive at 6 mo, % 93.2 88.5
Alive at 18 mo, % 62.1 46.2Median follow-up, mo 25.5 26.9
Olaparib TPC
Deaths, n (%) 100 (68.5) 41 (59.4)Median OS, mo 18.8 17.2HR 1.13 (95%CI 0.79–1.64; P=NS)Alive at 6 mo, % 93.1 84.9
Alive at 18 mo, % 50.8 48.8Median follow-up, mo 25.2 26.0
Courtesy of Mark Robson
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37.9
25.1
33.3
15.0
020406080
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)
Delaloge et al, ESMO 2017 poster-discussion#243 PD
OLYMPIAD : additional efficacy data
ORR was 60% vs 29% favoring the Olaparib monotherapyMedian onset to response:Olaparib – 47 daysChemotherapy TPC – 45 days
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At 18 months 19% in the olaparib arm remained on treatment
*Data are cumulative and patients are included if their total duration (including dose interruptions) on study treatment is greater than or equal to that monthData Cutoff: 25th September 2017 1. AZ data on file (2018); 2. Robson et al. AACR, 2018
תרשים1
6 months6 months
12 months12 months
18 months18 months
24 months24 months
Olaparib
TPC
Percentage of patients (%)
Percentage of patients remaining on study treatment*
[].0
[].0
[]
60
27.5
27.8
9.9
19
2.2
8.8
1.1
Sheet1
OlaparibTPCSeries 3
6 months6027.52
12 months27.89.928.6666666667
18 months192.2317.333333333326
24 months8.81.15
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San Antonio Breast Cancer Symposium, December 5-9, 2017
This presentation is the intellectual property of the author/presenter. Contact her at jlitton@mdanderson.org for permission to reprint and/or distribute.
Study Design: EMBRACAPrimary endpoint• Progression-free survival by RECIST by
blinded central review
Key secondary efficacy endpoints • Overall survival (OS)• ORR by investigator• Safety
Exploratory endpoints • Duration of response (DOR) for objective
responders• Quality of life (QoL; EORTC QLQ-C30,
QLQ-BR23)Phase 3, international, open-label study randomized 431 patients in 16 countries and 145 sites
Abbreviations: CNS, central nervous system; EORTC, European Organisation for Research and Treatment of Cancer; HER2, human epidermal growth factor receptor 2; mets, metastases; PO, orally (per os); 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.*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.www.clinicaltrials.gov (NCT01945775)
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
Talazoparib1 mg PO daily
Physician's choice of therapy (PCT)‡:capecitabine,
eribulin, gemcitabine,or vinorelbine
R2:1
Treatment (21-day cycles) continues until progression or
unacceptable toxicity
Courtesy of Jennifer Litton
https://clinicaltrials.gov/ct2/show/NCT01945775?term=NCT01945775&rank=1
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San Antonio Breast Cancer Symposium, December 5-9, 2017
This presentation is the intellectual property of the author/presenter. Contact her at jlitton@mdanderson.org for permission to reprint and/or distribute.
Primary Endpoint: PFS by Blinded Central Review
TALA (n = 287)
Overall PCT(n = 144)
Events, no. (%) 186 (65%) 83 (58%)
Median, mo (95% CI) 8.6 (7.2, 9.3) 5.6 (4.2, 6.7)
Hazard ratio, 0.54, 95% CI, 0.41, 0.71P < .0001
TALAOverall PCT
1-Year PFS 37% vs 20% Median follow-up time: 11.2 months Courtesy of Jennifer Litton
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San Antonio Breast Cancer Symposium, December 5-9, 2017
This presentation is the intellectual property of the author/presenter. Contact her at jlitton@mdanderson.org for permission to reprint and/or distribute.
PFS: Subgroup Analysis
Courtesy of Jennifer Litton
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Study Design: BROCADE3 (NCT02163694)
• Advanced HER2-negative breast cancer
• Germline BRCA1 or BRCA2 mutation
• ≤2 prior lines cytotoxic therapy for metastatic disease
• ≤1 prior lines of platinum; no progression ≤12 months of completing
• Hormone Receptor Expression• Prior Platinum• CNS Metastasis
Patient Population
Stratification Factors Primary Endpoint: Investigator-assessed PFS per RECIST 1.1
2:1 Randomization
N=513
Veliparib + Carboplatin/paclitaxel
Placebo + Carboplatin/paclitaxel
Treat to progression:If carboplatin and paclitaxel were
discontinued prior to progression, dosing of
veliparib/placebo increased to 300mg BID
continuous, and then 400mg BID if tolerated
Optional open-label crossover
to veliparib
21-Day Cycles:• Carboplatin (C): AUC 6 on Day 1• Paclitaxel (P): 80 mg/m2 on Days 1, 8, 15• Veliparib or Placebo: 120mg BID on Days -2 to 5
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Statistical Design
Fixed Sequence Testing Procedure (α = 0.05)
Veliparib + C/P vs. Placebo + C/P in the ITT Population
ITT defined as all randomized patients with a centrally confirmed
gBRCA1/2 mutation
Investigator-assessed per RECIST 1.1
Progression-Free Survival(PFS – Primary Endpoint)
Overall Survival(OS)
Objective Response Rate(ORR)
Clinical Benefit Rate(CBR)
Progression on Subsequent Therapy (PFS2)
Pre-planned interim at time of primary analysis with final
analysis planned at 357 events
Investigator-assessed per RECIST 1.1
Assessed at 24 weeks
Time from randomization to disease progression on
subsequent therapy or death
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Primary Endpoint: PFS by Investigator Assessment
C/P: Carboplatin and Paclitaxel
PFS by Inv.14.5
[12.5, 17.7]12.6
[10.6, 14.4]Median PFS,months [95% CI]
217/337 132/172PFS Events, n/N
Placebo + C/P Veliparib + C/P HR 0.705 [95% CI 0.566-0.877], p = 0.002
Patie
nts
Free
from
Dis
ease
Pr
ogre
ssio
n or
Dea
th (%
)
Months from Randomization
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Overview of the Phase III PARPi studies in ABCOLYMPIAD EMBRACA BROCADE3
Prior Chemotherapy for MBC
71% 61% 19%
Prior platinum 29% 16% 8%
Control arm included platinum
0% 0% 100%
mPFS (months) 7 vs 4.2 8.6 vs 5.6 14.5 vs 12.6
ORR 60% vs 29% 63% vs 27% 75.8 vs 74.1%
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PARP Inhibitors – in EBC
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Study Design
Eligibility• Tumors > 1 cm• Clinical Stage I-III• Germline BRCA mutation• No previous therapy for invasive breast cancer
Exclusion• HER2 positive
Courtesy of Jennifer Litton
BiopsyUltrasound Residual Tissue Correlatives
Talazoparib1 mg orally daily
SurgerySystemic Therapy of Physician’s Choice
UltrasoundUltrasound
Primary Objectives
• pCR (ypT0/is ypN0)
• RCB-0 + RCB-I
Secondary Objective
• Evaluate toxicity
N=20*
*1 patient took 5 months of talazoparib and then refused biopsy and surgery and proceeded to chemotherapy** 1 cycle=28 days
0 2 4 6(Cycles**)
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Baseline Characteristics N = 20Characteristics Number of PatientsAge Median=38 (Range 23-58) 20
Race
White 7
Black 5
Hispanic 5
Asian 3
Clinical Stage
I 5
II 12
III 3
Histology
Ductal 18
Lobular 1
Metaplastic-chondrosarcomatous 1
Courtesy of Jennifer LittonJENNIFER K. LITTON, M.D.
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Pathologic Results
10
2
5
3
RCB-0 RCB-I RCB-II RCB-III
JENNIFER K. LITTON, M.D.
pCR (RCB-0): 10/19 = 53%, 95% CI = 32%, 73%RCB-0+I: 12/19 = 63%, 95% CI = 41%, 81%
Num
ber
of P
atie
nts
Courtesy of Jennifer Litton
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Platinum vs PARPi in the neo-adjuvant setting
Talazoparib Cisplatin
N 20 107
BRCA1 85% 100%
pCR 53% 61%
Litton et al, ASCO 2018Byrski et al, BCRT 2014
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Randomise 1:1Double blind
N=1500
IDFS
Distant D
FS; OS
Post neoadjuvant gBRCA TNBC,,HR+
Non-PathCR pts
Post adjuvant gBRCA TNBC,HR+
T2 or N+
Olaparib300 mg bd12 month duration
Placebo 12 month duration
Restricted to Germline Mutation carriers
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Long term safety of PARPi: hematological malignancies
Pujade Lauraine et al Lancet Oncol 2017, Mirza et al, New Engl J Med 2016, Robson et al New Engl J Med 2017
Trial Context Treatment arm Placebo arm
SOLO2 • Maintenance olaparib vs placebo, ovarian cancer
• Germline BRCA1/2 mutation
2% (med FU 22.2 months, med
treatment duration 19.1 months)
4% (med FU 22.1 months,
med treatmentduration 5.5 months)
NOVA • Maintenance niraparib vs placebo, ovarian cancer
• Both sporadic and GermlineBRCA1/2 mutation
1.4% (med FU 16.9 months)
1.1% (med FU 16.9 months)
OLYMPIAD • Olaparib vs placebo, breastcancer
• Germline BRCA1/2 mutation
0% (med FU 14.5 months)
0% (med FU 14.1 months)
Long term incidence of AML, MDS, CMML in germline mutant carriers in phase III studies :
FU: follow-up, med: median; AML: acute myeloblastic leukaemia, MDS: myelodysplatic syndrome, CMML: chronic myelomonocytic leukaemia
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Genomic Profiling – 21 Gene Recurrence Score
Courtesy of Rinat Yerushalmi
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Genomic Profiling – 21 Gene Recurrence Score
• BRCA1/2 - independent predictor for RS on MVA• 45 months median follow-up - 6.9% developed recurrent
disease• Oncotype-DX scores of patients with disease recurrence were
in the intermediate and low ranges - None of these patients had received adjuvant chemotherapy
Lewin et al BCRT 2016
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What next?
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Targeting Resistance to PARP inhibitors
Sonnenblick et al, Nat Rev Clin Onc 2015
• Restoration of HR function:- BRCA reversion mutations- Loss of TP53BP1- Reversal of epigenetic BRCA
silencing
• ↑ P glycoprotein efflux pumps
• ↓ levels of PARP-1 expression/activity
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Other compounds under investigation in BRCA+ BCCompounds
PARPi + ImmunotherapyChemotherapyRadiotherapy
Novel Agents+/- PARPi
ATR inhibitors, ATM inhibitors, WEE1 inhibitors, PI3Ki,VEGFi, HSP90, G-quadruplex interacting compounds
Novel chemotherapeuticagents
BTP-114, a novel platinum product
Other Lurbinectedin/Trabectedin - covalent DNA minor groove binderSacituzumab govitecan (IMMU-132) - anti-Trop-2-SN-38 Antibody-Drug Conjugate with topoisomerase I (Topo I)-inhibitory activity
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TOPACIO study : (Keynote 162)• Phase 2: Niraparib and Pembrolizumab• Met TNBC (n=46): 1L-3L• 33% (n=15) had tBRCAmut
Viniyak et al. J Clin Oncol 36, 2018 (suppl; abstr 1011)
ORRCR + PR
DCRCR+PR+SD
TNBC (all) n=46 28% 50%tBRCA mut n=15 60% 80%
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MEDIOLA – Ph II – Olaparib & IO in BRCA+ ABC
• Olaparib & Durvalumab (anti PDL1 antibody)
Domchek et al, ESMO 2019
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San Antonio Breast Cancer Symposium®December 4-8, 2018
BRCA1/2 mutants and PD-L1 IC+ are independent from each other (P = ns)a
Patients with BRCA1/2-mutant tumors derived clinical benefit (PFS/OS) only if their tumors were also PD-L1 IC+b
BEP (BRCA1/2): n = 612. Per FoundationOne BRCA1/2 testing, BRCA1/2 mutant: known and likely mutations. All P values are nominal.a Data derived from contingency table with Fisher exact tests. b Data interpretation limited by small number of BRCA1/2-mutant patients.
The clinical benefit derived by PD-L1 IC+ patients was independent of their BRCA1/2 mutation status
53
PD-L1 IC+49%
BRCA1/2mutant
15%
42% 7% 7%
BRCA1/2 non-mut/PD-L1 IC+ (n = 257)HR (95% CI) P Value
PFS 0.63 (0.48, 0.83) ≤ 0.005OS 0.62 (0.43, 0.91) 0.01
BRCA1/2 mut/PD-L1 IC+ (n = 45)HR (95% CI) P Value
PFS 0.45 (0.21, 0.96) 0.04OS 0.87 (0.26, 2.85) 0.82
BRCA1/2 mut/PD-L1 IC– (n = 44)HR (95% CI) P Value
PFS 0.77 (0.37, 1.61) 0.49OS 0.85 (0.29, 2.43) 0.76
Emens LA, et al. IMpassion130 biomarkers. SABCS 2018 (program #GS1-04)
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Conclusions
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Ongoing challenges
• Sequencing treatment in BRCA+ ABC & TNBC• Resistance & cross-resistance to platinum & PARPi• Clinical significance/application of:- Differences in BRCA1 & BRCA2- somatic BRCA mutations- loss-of-heterozygosity in BRCA-associated tumors- Homologous Recombination Defect (HRD) scoring• Cost of new therapies!
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Summary• Germline testing has therapeutic implications in the setting of ABC• Platinum agents superior in triple negative BRCA+ ABC• PARPi superior to TPC• Future studies – immunotherapy, overcoming PARPi resistance, novel
agents• Reproductive issues & tailoring risk reducing measures → further study
• All BRCA+ patients should be offered participation in clinical trials!!!
ABC=Advanced Breast CancerTPC= Treatment of Physician’s Choice
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Thank you
AcknowledgementsBella KaufmanKaren GelmonSybille LoiblJennifer LittonMark Robson
Management of BRCA mutation carriersDisclosuresSlide Number 3BackgroundBRCA-associated Breast Cancerimaging for screening and diagnosis in BRCA1/2Screening & Diagnosis: �MRI in women with high risk of breast cancerWhy is MRI superior to mammography in BRCA+?Impact of a BRCA1/2 mutation on treatment decisionsLocal therapy considerationsBCS vs MastectomyDoes CRRM improve survival?Why does presence of a BRCA1/2 mutation have an impact on systemic therapy?DNA Repair is more error-prone when brca1 or brca2 proteins are deficientSystemic Therapies in BRCA1/2+ Breast CancerChemotherapy�Platinum in the neo-adjuvant setting for BRCA+�Platinum in BRCA+ in ABCPARP InhibitorsPARP Inhibitors�Dual Activity – Catalytic and TrappingProof of concept studies - Olaparib in BRCA+ BCHow does PARP inhibition compare with SOC chemotherapy in ABC?PARP inhibitors in BRCA+ ABCSlide Number 25Slide Number 26Overall survival in prespecified subgroupsSlide Number 28At 18 months 19% in the olaparib arm remained on treatmentStudy Design: EMBRACA Primary Endpoint: PFS by Blinded Central ReviewPFS: Subgroup AnalysisStudy Design: BROCADE3 (NCT02163694)�Statistical Design�Primary Endpoint: PFS by Investigator Assessment�Slide Number 37Overview of the Phase III PARPi studies in ABCPARP Inhibitors – in EBCStudy DesignBaseline Characteristics N = 20Pathologic ResultsPlatinum vs PARPi in the neo-adjuvant setting���Long term safety of PARPi: hematological malignanciesGenomic Profiling – 21 Gene Recurrence ScoreGenomic Profiling – 21 Gene Recurrence ScoreWhat next?Targeting Resistance to PARP inhibitorsOther compounds under investigation in BRCA+ BC�TOPACIO study : (Keynote 162)MEDIOLA – Ph II – Olaparib & IO in BRCA+ ABCThe clinical benefit derived by PD-L1 IC+ patients �was independent of their BRCA1/2 mutation statusConclusionsOngoing challengesSummarySlide Number 57
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