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

Transcription

1 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

2 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

3 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.

4 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

5 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.

6 PARP1 in Breast Cancer PARP1 mrna level %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% HER % HER2-70.0% ER+/PR+/HER % ER-/PR-/HER2-80.0% *defined by percentage of samples exceeding the 95% UCL of normal tissue distribution BiPar Sciences, data on file.

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

8 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

9 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 (9737):235-44

10 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

11 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 (9737):235-44

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

13 400 mg BD 100 mg BD Nb Cohorts were not randomised Audeh et al The Lancet (9737):245-51

14 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

15 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 = prior chemotherapy regimens for metastatic disease - no prior chemo~60% No prior gemcitabine, carboplatin, cisplatin, PARP inhibitor Stable brain metastases allowed ECOG PS 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

16 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%) 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%) *P-values were not adjusted for multiple interim analyses. O Shaughnessy et al, ESMO 2010

17 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= (2.6, 5.2) Iniparib + Gem-Carbo N= (4.5, 7.2) HR (95% CI) 0.59 (0.39, 0.9) P-value* Overall Survival-Exploratory Gem-Carbo N = 62 Iniparib + Gem-Carbo N= (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* PFS months OS months *P-values were not adjusted for multiple interim analyses.

18 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?

19 PARP Inhibitors in Development Agent Company Route Clinical Status AG 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