New developments and controversies in breast cancer treatment: PARP Inhibitors: a breakthrough?

New developments and controversies in breast cancer treatment: PARP Inhibitors: a breakthrough? F. Cardoso, MD Champalimaud Cancer Center Lisbon, Portugal BBM 2010 Thank you to A Tutt & PRIME Oncology for help with slides

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 Produces large branched chains of poly(adp-ribose) Attracts and assists BER repair effectors XRCC1 PNK Polß Lig3 Tutt et al ASCO 2009

BRCA1 and BRCA2 Maintain Specialized DNA Repair Healthy cells in BRCA1 or BRCA2 carrier Cancer cells in BRCA1 or BRCA2 carrier A normal BRCA gene remains Wild-type BRCA allele is lost Specialized DNA repair continues Specialized DNA repair is lost Tutt A, et al. J Clin Oncol. 2009;27(18S): Abstract CRA501.

SYNTHETIC LETHALITY IN DNA REPAIR PATHWAYS normal BRCA1 or BRCA2 deficient DNA DAMAGE DNA DAMAGE HR NHEJ SSA BER NER etc x HR NHEJ SSA BER NER etc x x

Can We Target a BRCA1/BRCA2 Tumor s DNA Repair Weakness? BRCA1/BRCA2 carrier normal tissue cells Few normal tissue effects DNA repair BRCA1/BRCA2 carrier DNA normal tissue cells repair Base excision DNA repair Homologous recombination (HR) repair PARP inhibitor Base excision DNA repair HR repair HR repair BRCA1/BRCA2 carrier Tumor cells Specific tumor cell killing HR repair PARP inhibitor HR repair Base excision DNA repair Tutt A, et al. J Clin Oncol. 2009;27(18S): Abstract CRA501.

PARP1 in Breast Cancer PARP1 mrna level 700 600 500 400 300 200 100 0 99.9%UCL 99%UCL 95%UCL 90%UCL Mean Normal IDC Infiltrating ductal carcinoma (IDC) is a highly invasive tumor, accounting for 70% to 80% of all breast malignancies IDC shows statistically significant PARP1 upregulation in comparison with normal breast tissues: P = 2x10-27 PARP1 is upregulated in TNBC IDC Subtype % PARP1 Upregulation Normal 2.9% IDC 30.2% ER+ 22.9% ER- 55.6% PR+ 23.1% PR- 45.0% HER2+ 29.2% HER2-70.0% ER+/PR+/HER2+ 20.0% ER-/PR-/HER2-80.0% *defined by percentage of samples exceeding the 95% UCL of normal tissue distribution BiPar Sciences, data on file.

DNA repair Telomere maintenance 17 PARP Isoforms Courtesy of Prof Hilary Calvert

Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer Andrew Tutt, 1 Mark Robson, 2 Judy E Garber, 3 Susan Domchek, 4 M William Audeh, 5 Jeffrey N Weitzel, 6 Michael Friedlander, 7 James Carmichael 8 1 Breakthrough Breast Cancer Research Unit, Guy's Hospital, King's Health Partners, London, UK 2 Memorial Sloan-Kettering Cancer Center, New York, NY, USA 3 Dana-Farber Cancer Institute, Boston, MA, USA 4 University of Pennsylvania, Philadelphia, PA, USA 5 Cedars-Sinai Cancer Center, Los Angeles, CA, USA 6 City of Hope Comprehensive Cancer Center, Duarte, CA, USA 7 Prince of Wales Cancer Centre, Randwick, Sydney, New South Wales, Australia 8 AstraZeneca, Macclesfield, UK Study no: D0810C00008; KU36-44

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 Cohort 1 (enrolled first) Olaparib 400 mg po bid (MTD) 28-day cycles; n = 27 Cohort 2 Olaparib 100 mg po bid 28-day cycles; n = 27 Tutt et al The Lancet 2010 376(9737):235-44

Patient characteristics Olaparib 400 mg bid (n=27) Olaparib 100 mg bid (n=27) ECOG status, n 0/1/2 12/13/2 16/10/1 Prior chemotherapy regimens Median (range) Taxane and anthracycline, n (%) Taxane/anthracycline and capecitabine, n (%) Platinum, n (%) Hormonal status, n (%)* Triple negative ER+ HER2- ER+ HER2+ ER- HER2+ 3 (1 5) 25 (96) 10 (37) 6 (22) 13/26 (50) 11/27 (41) 1/27 (4) 1/27 (4) 3 (2 4) 19 (70) 11 (41) 8 (30) 16/25 (64) 4/26 (15) 4/26 (15) 1/26 (4) *Patients with an unknown hormone receptor status are not included in demographics

Efficacy & Toxicity ITT cohort Olaparib 400 mg bid (n=27) Olaparib 100 mg bid (n=27) Overall Response Rate, n (%) Complete Response, n (%) Partial Response, n (%) 11 (41)* 1 (4) 10 (37) 6 (22)* 0 6 (22) *An additional 1 patient in the 400 mg cohort and 3 patients in the 100 mg cohort had unconfirmed responses Main G3 side-effects : fatigue (6 pts), nausea (5 pts), vomiting (3 ps) Tutt et al The Lancet 2010 376(9737):235-44

Progression Free Survival Nb Cohorts were not randomised Median PFS (95% CI) 400 mg: 5.7 (4.6-7.4) ms 100 mg: 3.8 (1.9-5.5) ms Tutt et al The Lancet 2010 376(9737):235-44

400 mg BD 100 mg BD Nb Cohorts were not randomised Audeh et al The Lancet 2010 376(9737):245-51

ESMO 2010 HIGHLIGHTS: ADVANCED BREAST CANCER ADVANCES IN TN ABC: main messages Heterogeneous group of BC ( non-er+/non HER-2+ BC or target less BC ) needing to be sub-classified Different subgroups of TN ABC probably need different treatments New available drugs: PARPi, Cetuximab, Endo-TAG

Iniparib (BSI-201) Study Design Multi-center, open-label, randomized Phase II Metastatic TNBC - about 70% had prior chemotherapy for early BC Measurable disease -median number of metastatic sites = 3 0-2 prior chemotherapy regimens for metastatic disease - no prior chemo~60% No prior gemcitabine, carboplatin, cisplatin, PARP inhibitor Stable brain metastases allowed ECOG PS 0 1 - two thirds PS = 0 Randomization (1:1) O Shaughnessy et al, ESMO 2010 i.v. PARPi Gemcitabine 1000 mg/m 2, IV, d 1, 8 Carboplatin AUC 2, IV, d 1, 8 21 day cycles Iniparib 5.6 mg/kg, IV, d 1, 4, 8, 11 Gemcitabine 1000 mg/m 2, IV, d 1, 8 Carboplatin AUC 2, IV, d 1, 8 21 day cycles N=62* RESTAGING: Every 2 Cycles (RECIST) N=61 PRIMARY ENDPOINTS: SECONDARY ENDPOINTS: CBR = CR + PR + SD 6 mo, Safety DFS, ORR, Toxicity * 30 patients randomized to gem/carbo crossed over to receive gem/carbo + Iniparib (BSI-201) at disease progression

Iniparib: Response and Clinical Benefit Rates (ITT Population) Gem-Carbo N = 62 Iniparib + Gem-Carbo N=61 P-value* Overall response rate 20 (32.3%) 32 (52.5%) 0.023 Complete response 1 (1.6%) 2 (3.3%) Partial response 19 (30.6%) 30 (49.2%) Stable disease 13 (21.0%) 11 (18.0%) Progressive disease 18 (29.0%) 10 (16.4%) SD 6 months 1 (1.6%) 2 (3.3%) Clinical benefit rate (CBR) 21 (33.9%) 34 (55.7%) 0.015 *P-values were not adjusted for multiple interim analyses. O Shaughnessy et al, ESMO 2010

O Shaughnessy et al, ESMO 2010 Iniparib: Progression-Free and Overall Survival (ITT Population) Progression Free Survival Median PFS, months (95% CI) Gem-Carbo N=62 3.6 (2.6, 5.2) Iniparib + Gem-Carbo N=61 5.9 (4.5, 7.2) HR (95% CI) 0.59 (0.39, 0.9) P-value* 0.012 Overall Survival-Exploratory Gem-Carbo N = 62 Iniparib + Gem-Carbo N=61 12.3 (9.8, 21.5) Median OS, months (95% CI) 7.7 (6.5, 13.3) HR (95% CI) 0.57 (0.36, 0.90) P-value* 0.014 PFS + 2.3 months OS + 4.6 months *P-values were not adjusted for multiple interim analyses.

Phase II Study of the PARP Inhibitor Iniparib (BSI-201) WORDS OF CAUTION + PRAISE Small Phase 2 trial Late side effects? Need confirmation: phase 3 (>500 pts) finished accrual Predictive biomarker evaluation under way FUTURE/ONGOING RESEARCH Not all PARPi were born equal Is PARP really the main/only target?

PARP Inhibitors in Development Agent Company Route Clinical Status AG014699 Pfizer Iv (oral) Phase I/II Combos KU59436 AZD2281 Olaparib Veliparib ABT888 Iniparib BSI-201 AstraZeneca/ Kudos oral Phase II/III Combos Abbott oral Phase I/II Combos BiPar/ Sanofi-Aventis iv Phase II/III Combos INO-1001 Inotek iv Phase Ib complete GPI21016 MGI Pharma/ Eisai oral Phase I CEP-9722 Cephalon oral Phase I MK4827 Merck & Co oral Phase I BMN-673 Biomarin / LEAD Pharmaceuticals Preclinical