garber plenary - facing our risk · r oyola i tennevet g coukos e gotovkin t vidarre t yamauchi y-s...
TRANSCRIPT
6/13/17
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What’s New in HBOC Research? PARPi in breast and ovarian cancer treatment:
Prevention in BRCA1/2 mutation carriers
Judy E. Garber, MD MPH Dana Farber Cancer Institute
Boston, MA 10 June 2017
10th Annual Joining FORCEs Against Hereditary Cancer Orlando, FL
Disclosure of Information Speaker: Judy E. Garber, MD MPH
I have the following relationships to disclose: Co-Investigator Olympiad trial (olaparib metastatic) Co-PI, NRG-55 (OlympiA adjuvant olaparib trial) Consultant, Helix (Spouse: Novartis, GTx) Research support: Ambry Genetics
I will discuss the following off-label uses of the product in approved research protocols in my presentation : None
Background
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Mechanism of Action of PARP Inhibitors
Lord CJ, Ashworth A. Science 2017;355:1152-1158
Randomized phase II studies of PARP
inhibitors in recurrent ovarian cancer
Evans T, Matulonits U. Ther Adv Med Onc 2017;9:253-267
Phase III Treatment trials of PARP inhibitors in Ovarian Cancer
Evans T, Matulonits U. Ther Adv Med Onc 2017;9:253-‐267
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Phase III Treatment trials of PARP inhibitors in Ovarian Cancer – cont’d
Evans T, Matulonits U. Ther Adv Med Onc 2017;9:253-‐267
Niraparib Maintenance Therapy in Platinum-Sensitive Ovarian Cancer
Mirza MR et al. NEJM 2016;375:2154-2164
A. Germline BRCA Mutation
B. No Germline BRCA Muation, HRD positive
HR 0.27
HR 0.38
C. No Germline BRCA Mutation
HR 0.45
Progression-Free Survival: A. BRCA Carriers: 21.0 v 5.5 months B. Non-BRCA,+HRD: 12.9 v 3.8 months C. Non-BRCA: 9.3 v 3.9 months
Slide 80
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Examples of trials combining PARP inhibitors with other biologics
Evans T, Matulonits U. Ther Adv Med Onc 2017;9:253-‐267
OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients with HER2-negative metastatic
breast cancer and a germline BRCA mutation Mark Robson,1 Seock-Ah Im,2 Elżbieta Senkus,3 Binghe Xu,4 Susan M Domchek,5 Norikazu Masuda,6
Suzette Delaloge,7 Wei Li,8 Nadine Tung,9 Anne Armstrong,10 Wenting Wu,11 Carsten Goessl,11 Sarah Runswick,12 Pierfranco Conte13
1Memorial Sloan Ke.ering Cancer Center, New York, USA; 2Seoul Na=onal University Hospital, Seoul, Korea; 3Medical University of Gdańsk, Gdańsk, Poland; 4Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; 5Basser Center, University of
Pennsylvania, Philadelphia, USA; 6Na=onal Hospital Organiza=on, Osaka Na=onal Hospital, Osaka, Japan; 7Ins=tut Gustave Roussy, Villejuif, France; 8The First Hospital of Jilin University, Changchun, China; 9Beth Israel Deaconess Medical Center, Dana-‐Farber Harvard
Cancer Center, Boston, USA; 10Chris=e Hospital NHS Founda=on Trust, Manchester, UK; 11AstraZeneca, Gaithersburg, USA; 12AstraZeneca, Macclesfield, UK; 13University of Padova and Is=tuto Oncologico Veneto IRCCS, Padova, Italy
ClinicalTrials.gov identifier: NCT02000622. This study was sponsored by AstraZeneca
Presented by: Mark Robson, MD 6/4/2017
Phase II studies of olaparib in breast cancer
Tu# et al1 (n=54)
Gelmon et al2 (n=26, 10 gBRCAm)
Kaufman et al3 (n=62)
PaKent populaKon Locally advanced/
metastaKc BRCAm BC, ≥1 chemotherapy regimen
Advanced metastaKc or recurrent BC, triple negaKve or known
BRCAm
Advanced BRCAm BC that progressed despite ≥3 previous lines of
chemotherapy for advanced/metastaKc BC
Prior lines of therapy for advanced disease 3 (median, including adjuvant) 3 (median, including adjuvant) 4.6 (mean, metastaKc only)
ORR 41% 0% (50% unconfirmed in BRCAm) 13%
Median DoR 144 days – 204 days
1. Tutt A et al Lancet 2010;376:235–244; 2. Gelmon KA et al Lancet Oncol 2011;12:852–861;
3. Kaufman B et al J Clin Oncol 2015;33:244–250
BC, breast cancer; DoR, duration of response; ORR, objective response rate
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Olaparib 300 mg tablets bd
OlympiAD study design
2:1 randomizaHon
Chemotherapy treatment of physician’s choice (TPC)
• Capecitabine • Eribulin • Vinorelbine
Primary endpoint: • Progression-‐free survival
(RECIST 1.1, BICR)
Treat u
nHl progression
• HER2-‐negaHve metastaHc BC ̶ ER+ and/or PR+ or TNBC
• Deleterious or suspected deleterious gBRCAm
• Prior anthracycline and taxane • ≤2 prior chemotherapy lines in metastaHc
se\ng • HR+ disease progressed on
≥1 endocrine therapy, or not suitable • If prior plaHnum use ̶ No evidence of progression during
treatment in the advanced se\ng ̶ ≥12 months since (neo)adjuvant
treatment
BICR, blinded independent central review; ER, estrogen receptor; HRQoL, health-related quality of life; PR, progesterone receptor; RECIST, response evaluation criteria in solid tumors; TNBC, triple negative breast cancer
Secondary endpoints: • Time to second progression or
death • Overall survival • ObjecHve response rate
• Safety and tolerability • Global HRQoL
(EORTC-‐QLQ-‐C30)
Primary endpoint: progression-free survival
Olaparib 300 mg bd
Chemotherapy TPC
Progression/deaths, n (%) 163 (79.5) 71 (73.2) Median PFS, months 7.0 4.2
HR 0.58 95% CI 0.43 to 0.80; P=0.0009
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
177 63
154 44
107 25
94 21
69 11
40 8
23 4
21 4
11 1
4 1
3 1
2 1
1 0
0 0
At risk, n 205 97
Olaparib 300 mg bd Chemotherapy TPC
Months
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100
0
10
20
30
40
50
60
70
80
90
PFS (%
)
Presented by: Mark Robson, MD
Overall survival (interim analysis; 46% data maturity)
0
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Olaparib 300 mg bd
Chemotherapy TPC
Deaths (%) 94 (45.9) 46 (47.4) Median OS, months 19.3 19.6
HR 0.90 95% CI 0.63 to 1.29; P=0.5665
Months 2 4 6 8 10 12 14 16 18 20 22 24 26 28
100
0
10
20
30
40
50
60
70
80
90
OS (%
)
205 92
199 85
189 78
178 74
159 69
146 62
109 50
78 34
46 24
30 13
18 9
14 7
8 4
4 2
At risk, n 205 97
0 0
Presented by: Mark Robson, MD
Olaparib 300 mg bd Chemotherapy TPC
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Subgroup analyses: Progression-Free Survival
6/4/2017 Presented by: Mark Robson, MD 16
PFS (%
)
Months 12 8 4 0 16 20 24 28
Months 12 8 4 0 16 20 24 28
Progression/ deaths, n (%)
Olaparib TPC
119 (81.5) 51 (73.9)
HR 0.65
95% CI 0.47 to 0.91
Progression/ deaths, n (%)
Olaparib TPC
44 (74.6) 20 (71.4)
HR 0.56
95% CI 0.34 to 0.98
PFS (%
)
100
80
60
40
20
0
100
80
60
40
20
0
Prior chemotherapy No prior chemotherapy
Subgroup analyses: Progression-Free Survival
6/4/2017 Presented by: Mark Robson, MD 17
PFS (%
)
Months 12 8 4 0 16 20 24 28
Months 12 8 4 0 16 20 24 28
Progression/ deaths (%)
Olaparib TPC
82 (79.6) 31 (63.3)
HR 0.82
95% CI 0.55 to 1.26
Progression/ deaths (%)
Olaparib TPC
81 (79.4) 40 (83.3)
HR 0.43
95% CI 0.29 to 0.63
PFS (%
)
100
80
60
40
20
0
100
80
60
40
20
0
ER+ and/or PR+ TNBC
Subgroup analyses: Progression-Free Survival
6/4/2017 Presented by: Mark Robson, MD 18
PFS (%
)
Months 12 8 4 0 16 20 24 28
Months 12 8 4 0 16 20 24 28
Progression/ deaths (%)
Olaparib TPC
50 (83.3) 21 (80.8)
HR 0.67
95% CI 0.41 to 1.14
Progression/ deaths (%)
Olaparib TPC
113 (77.9) 50 (70.4)
HR 0.60
95% CI 0.43 to 0.84
PFS (%
)
100
80
60
40
20
0
100
80
60
40
20
0
Prior plaHnum No prior plaHnum
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Adverse events (any grade) in ≥15% of patients
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 75 50 75 50 25 Adverse events (%)
Nausea Anemia VomiKng FaKgue Neutropenia Diarrhea Headache Cough
Decreased appeKte Pyrexia Increased ALT Increased AST Hand-‐foot syndrome
Olaparib 300 mg bd (N=205) Chemotherapy TPC (N=91)
Irrespective of causality. MedDRA preferred terms for adverse events have been combined for 1) anemia and 2) neutropenia ALT, alanine aminotransferase; AST, aspartate aminotransferase
Decreased white blood cells
B T Haddad A Aydiner A Santablla D Median R Villalobos Y Rai B Xu P F Conte A Lyss K Altundag M Ruiz D Grecea A Molina S-J Kim W Li A Santoro A Moreno I Çiçin S Menjon A Eniu A Gomez Q Ou F Cognetti
M Robson B Lash R Uslu R Andres C Idea T Vidaurre S Wang S De Placido S Domchek M Lee S Paydas Y Fermandes D Zob J Grados J Feng C Zamagni N Tung E Lower A Sevinç N Martinez J Salas L Landherr Z jiang M DeLaurentiis A Montero M Simon M Özkan J Haba O Meijia K Boer Q Zheng C Antonio S Vinayak M Mclaughlin E Sezer S Servitja I Lang T Sun M Barone A Rodriguez R Droder M Artaç B Cantos E Senkus M Dank H Li M Coleman A Pippas T Huzarski K Mezei Z Tong S Sundaram M Shum T Sarosiek A Armstrong Z Nagy Z Shao J Rainey R Blanchard I Ryniewicz-Zander C Poole L Hornyak K Shen T Cigler A Conlin D-C Yeh G Statsenko I Drab-Mazur J Stebbing L Li M Zimovjanova G Padula A Hossain L-M Tseng V Ivanov E Kalinka S Kelly K Petrakova D Anderson C M Jones C-S Huang S Tjulandin M Stelmaszuk MB Mukesh B Melichar J Nangia B Arrick S-C Chen M Mechaeva T McGoldrick S-A Im L Usha S Dakhill M-F Hou A Manikhas Y-H Park K Timcheva M Wood Y-C Chang E Topuzov J Sohn V Minchev E Hofsatter O Mikheeva M Philco E-K Cho K koynov G Shumaker R Paltuev C Desposorio N Masuda K-H Lee V Popov E Tanchiu S Delaloge S Cheporov H Gomez E Tokunaga J-H Kim A Dudov R Oyola I Tennevet G Coukos E Gotovkin T Vidarre T Yamauchi Y-S Chae T Koynova I Anderson W Jacot M Rabaglio P Skopin J Grados S Nakamura K-E Lee A Tomova S Brown C Levy S Stoll J Salas H Iwata P Lshkovka C Isaacs T Petit O Mejia M Takahashi C Alemany K Tamura
We thank all paKents who parKcipated in this study, their families, and the invesKgators:
Study Sponsor: AstraZeneca
Independent Data Monitoring Commifee
Acknowledgments
Debbi Gorman, medical writer, funded by AstraZeneca
Wendy Bannister, study staKsKcian contracted to AstraZeneca
6/4/2017 20 Presented by: Mark Robson, MD
Final Results of a Phase 2 Study of Talazoparib (TALA) Following Platinum or Multiple Cytotoxic Regimens in Advanced Breast Cancer Patients (pts) With Germline BRCA1/2 Mutations (ABRAZO)
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Background – Talazoparib
Maximal Percent Change in Target Lesions by BRCA Mutation Status
Maximal Percent Change in Target Lesions by Hormone Receptor Status
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Slide 15
OlympiA Schema
Randomize 1:1 Double blind N=1320
Olaparib 300 mg bid
12 month duration
Placebo 12 month duration
IDFS
Distant D
FS; OS
Post neoadjuvant gBRCA TNBC � Non-Path CR pts Assumptions: � Control arm 3 year EFS~60%
Post adjuvant gBRCA TNBC, � Node positive disease (any tumour size) OR � Node negative, primary >2cm Assumptions: � Control arm 3 year EFS~75%
Cancer Risks in Carriers of Mutations in BRCA1 and BRCA2
0
10
20
30
40
50
60
70
Female Breast
Male Breast Ovary Pancreas Prostate
BRCA1 BRCA2
54-‐84%
4% 7%
40-‐60%
15-‐20%
3% 7%
4-‐20%
20-‐34%
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BRCA-P: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center,
International Phase 3 Study to determine the Preventive Effect of Denosumab on
Breast Cancer in Women carrying a BRCA1 Germline Mutation
Nolan E et al. Nature Med 2016;22:933-939
b. Quantitative RT-PCR analysis of differentially expressed genes in reduction mammoplasties (n=3 pts per genotype) e. Box plots of RANK+ signatures scores by tumor subtype
Nolan E Nat Med 2016;22:933-939
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RankL inhibition markedly attenuates tumor onset in BRCA1 deficient mice
Nolan E et al. Nature Med2016;22:933-939
Cheng ML, Fong L. Front Oncol 204:3:1-8
BRCA-P: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center,
International Phase 3 Study to determine the Preventive Effect of Denosumab on
Breast Cancer in Women carrying a BRCA1 Germline Mutation
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BRCA-P Trial
• ABCSG: Christian Singer, MD, PI Austria • ANZBCTG Geoffrey Lindeman, MD Australia
Gareth Evans, MD United Kingdom Joan Brunet Vidal, MD Spain Rita Schmutzler, MD Germany Eitan Friedman, MD Israel
• Alliance Judy Garber, MD MPH United States
Study Type
Phase III, double-blind, prospective, randomized interventional prevention trial
Primary Objective
To evaluate the reduction in the risk of breast cancer (invasive or DCIS) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo
Primary Aim:
1. the reduction in the risk of invasive triple negative breast cancer (TNBC) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo
2. the reduction in the risk of ovarian and related cancers in women with germline BRCA1 mutation who are treated with denosumab compared to placebo
To determine the reduction in the risk of invasive breast cancer in women with germline BRCA1 mutation who are treated with denosumab compared to placebo
Secondary Aims:
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Secondary Aims (cont’d): To determine
3. To determine the reduction in the rates of breast biopsies and proliferative breast lesions in pre- and postmenopausal women with germline BRCA1 mutation during denosumab treatment compared to placebo
4. To determine the reduction in the risk of osteopenia,
osteoporosis and clinical fractures in pre- and postmenopausal women with germline BRCA1 mutation during denosumab treatment compared to placebo
Sample Size 2918 subjects, 1:1 randomized
Treatment Arms Arm A (Experimental): Denosumab 120 mg s.c., q6m
Arm B (Placebo Comparator): Placebo s.c., q6m
Study Design
Study Duration 10 years (event-driven design; recruitment phase of 2 years and treatment phase of 5 years needed to yield 167 primary endpoint events, 5 years follow up)
gBRCA1 Mutation
R 1:1
Denosumab s.c. 120 mg/q6m
Placebo s.c. 6qm
Biobanking, Imaging (if SoC); Translational
research program
Biobanking, Imaging (if SoC); Translational
research program
BCoccurrence
Eligibility Criteria • Women with a confirmed deleterious or likely deleterious BRCA1 germline
mutation (Variant class 4 or 5) • Age ≥ 25 years and ≤ 55 years at randomization • No evidence of breast cancer by MRI or MG and clinical breast examination
within the last 6 months • No clinical evidence of ovarian cancer at randomization • Negative pregnancy test at randomization for women of childbearing
potential • No preventive breast surgery planned at time of randomization • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 • Written informed consent before any study-specific procedure is performed
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Exclusion Criteria • Prior bilateral mastectomy
• History of ovarian cancer
• History of invasive breast cancer or DCIS
• History of invasive cancer except for basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or stage 1 papillary or follicular thyroid cancer
• Pregnant or lactating women (within 2 months of the date of consent )
• Unwillingness to use highly effective contraception method during and within at least 5 months after cessation of denosumab/placebo therapy in women of childbearing potential. Women of childbearing potential should be monitored for pregnancy prior to each denosumab/placebo injection
BZE/CEE compared with CEE and control in Monkey Mammary Tissue
Ethun KF et al. Menopause 2012;19:1242-1252
Ki67
ERἀ
60 women with BRCA2 mutations s/p RRSO within 4-6 wks of enrollment
Bazedoxifene 20mg/ Conjugated Estrogen 0.45mg as Duavee® repackaged for blinding po daily x 3 months
Conjugated Estrogen 0.45mg repackaged for blinding po daily x 3 months
Off study
Menopause symptom q’res
Menopause symptom q’res
US –guided breast core biopsy and blood sample
US –guided breast core biopsy and blood sample
Trial Schema