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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  

6/4/2017   14  

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  

6/4/2017   15  

   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