PARP inhibitors for breast cancer
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1 PARP inhibitors for breast cancer Mark Robson, MD Memorial Sloan Kettering Cancer Center
2 Agenda Mechanism of action Clinical studies Resistance mechanisms Future directions
3 Poly (ADP-ribose) Polymerases
4 PARP Involvement in DNA Repair Helleday, Mol Oncol 211
5 PARP Inhibition in BRCA-deficient cells BRCA1 BRCA2 Farmer et al, Nature 25
6 Challenges to model PARP1 not required for base excision repair Steady state level of single strand breaks not increased with PARPi PARP1 hyperactivated in HR-defective cells PARP1 involved in non-homologous end joining PARP1 involved in restart of stalled replication forks
7 Alternative models Helleday et al Mol Oncol 211
8 Alternative models Impairs BRCA1 recruitment PARP1 involvement in POLQ-dependent pathway of NHEJ on HR-deficient cells
9 PARPi under development Compound AKA Phase Olaparib (AZ) KU59436, AZD2281 III Veliparib (AbbVie) ABT888 II/III (upcoming) Rucaparib (Clovis) PF , AG14699 I/II Niraparib (Tesaro) MK4827 III Talazoparib (Medivation) MDV38, BMN-673 III CEP-9722 (Cephalon) E716 (Eisai) I I
10 Differences among PARPi Catalytic inhibition O > V > N B, BMN673; N, niraparib; O, olaparib; R, rucaparib (promiscuous); V, veliparib PARP Trapping N=O > V B > O B > R Cytotoxicity (specific systems) N > O > V B > O B> R Murai et al Cancer Res 212, Mol Cancer Therap 214
11 Differences among PARPi Catalytic inhibition O > V > N B, BMN673; N, niraparib; O, olaparib; R, rucaparib (promiscuous); V, veliparib PARP Trapping N=O > V B > O B > R Cytotoxicity (specific systems) N > O > V B > O B> R Murai et al Cancer Res 212, Mol Cancer Therap 214
12 CLINICAL STUDIES
13 Approaches Single agent ( synthetic lethality ) Leverages defects in homologous recombination Combination with CTX or RT Does not necessarily require HR defect
14 Single agent development Best response (ITT) Olaparib 4 bid (n=27) Olaparib 1 bid (n=27) CR 1 (4%) PR 1 (37%) 6 (22%) SD 12 (44%) 12 (44%) PD 4 (15%) 9 (33%) Median PFS 5.7 mo 3.8 mo MRD days Tutt, Lancet 21
15 Study 42 : single agent olaparib basket Tumour response rates (full analysis set) Tumor type Response status, n (%) Ovarian (n=193) Breast (n=62) Pancreas (n=23) Prostate (n=8) Other (n=12) Total (n=298) Tumor response rate CR* PR* 6 (31.1) 6 (3.1) 54 (28) 8 (12.9) 8 (13) 5 (21.7) 1 (4.3) 4 (17) 4 (5.) 4 (5) 1 (8.3) 1 (8.3) 78 (26.2) 7 (2.3) 71 (23.8) SD 8 weeks SD Unconfirmed PR 78 (4) 64 (33) 12 (6) 29 (47) 22 (36) 7 (11) 8 (35) 5 (22) 3 (13) 2 (25) 2 (25) 7 (58) 6 (5) 1 (8.3) 124 (42) 99 (33) 23 (8) PD RECIST progression Early death 41 (21) 33 (17) 8 (4) 23 (37) 16 (26) 7 (11) 9 (39) 6 (26) 3 (13) 2 (25) 1 (13) 1 (13) 3 (25) 3 (25) 78 (26) 59 (2) 19 (6) Not evaluable No follow-up assessments SD <8 weeks 14 (7) 12 (6) 2 (1) 2 (3) 2 (3) 1 (4) 1 (4) 1 (8.3) 1(8.3) 18 (6) 15 (5) 3 (1) Kaufman et al. J Clin Oncol 215;33:244-5
16 Olaparib + Cisplatin Phase 1 Could not find tolerable olaparib dose with 75/m2 cisplatin Olaparib 5 bid D1-5 + cisplatin 6/m2 tolerable Good OR (71% (12/17)) in BRCA-BC, including 2 durable responses > 2 yrs in patients on olaparib monotherapy after combination Balmaña et al, Ann Oncol 214 Olaparib-Topetecan also very toxic (Samol, Invest new Drug 212)
17 Other combinations *ispy success in neoadjuvant therapy of unselected TNBC*
18 PARPi + PIK3CAi in BRCA1-BC Jukevar et al, Cancer Discovery 212;2:148
19 Challenges to getting approval Single agent vs combination What combination? What endpoint? Cross-over (official/ unofficial) Companion diagnostic
20 Olaparib in platinum-sensitive ovarian (Maintenance after carboplatin/paclitaxel induction) Probability of progression-free survival No. at risk Olaparib Placebo Months since randomization Olaparib Placebo Hazard ratio,.35 (95% CI, ) P<.1 No. of patients/ Total no (%) 6/136 (44.1) 93/129 (72.1) Median Progression-free Survival (mo) PFS Analysis in gbrca (ODAC) HR.17 (95% CI.9-.32) PFS 11.2 v 4.1 mo No difference in OS (32.9 v 3.2 mo) Ledermann J et al. N Engl J Med 212;366:
21 Study 42 : single agent olaparib basket Tumour response rates (full analysis set) Tumor type Response status, n (%) Ovarian (n=193) Breast (n=62) Pancreas (n=23) Prostate (n=8) Other (n=12) Total (n=298) Tumor response rate CR* PR* 6 (31.1) 6 (3.1) 54 (28) 8 (12.9) 8 (13) 5 (21.7) 1 (4.3) 4 (17) 4 (5.) 4 (5) 1 (8.3) 1 (8.3) 78 (26.2) 7 (2.3) 71 (23.8) SD 8 weeks SD Unconfirmed PR 78 (4) 64 (33) 12 (6) 29 (47) 22 (36) 7 (11) 8 (35) 5 (22) 3 (13) 2 (25) 2 (25) 7 (58) 6 (5) 1 (8.3) 124 (42) 99 (33) 23 (8) PD RECIST progression Early death 41 (21) 33 (17) 8 (4) 23 (37) 16 (26) 7 (11) 9 (39) 6 (26) 3 (13) 2 (25) 1 (13) 1 (13) 3 (25) 3 (25) 78 (26) 59 (2) 19 (6) Not evaluable No follow-up assessments SD <8 weeks 14 (7) 12 (6) 2 (1) 2 (3) 2 (3) 1 (4) 1 (4) 1 (8.3) 1(8.3) 18 (6) 15 (5) 3 (1) Kaufman et al. J Clin Oncol 215;33:244-5
22 Phase III OLympiAD (OLaparib in Advanced Disease) Metastatic gbrca-bc Prior anthra/taxane -2 prior for mbc No prior platinum Physician s choice (capecitabine, vinorelbine, eribulin) Olaparib Primary endpoint: PFS (no cross-over) Secondary: OS, PFS2 Planned sample size: 31 patients Nearly identical studies planned with niraparib (BIG/EORTC) and BMN-673 (Industry-sponsored)
23 Expanding the use of PARPi Triple negative breast cancer 8% of BRCA1-BC are TNBC Most BRCA1-BC are basal-like Some sporadic TNBC have BRCA1 expression by IHC Sporadic TNBC have genomic instability similar to BRCA1-BC
24 Expanding beyond gbrca Olaparib 4 mg po BID 1 gbrca-bc and 16 non-brca TNBC Gelmon et al, Lancet Oncol 211
25 ATM Deficient Cancer Yung-Jue Bang et al. JCO 215;33:
26 Genomic Aberrations in DNA Repair in Patients with Metastatic, Castration-Resistant Prostate Cancer Mateo J et al. New Engl J Med 215;373:1697
27 RESISTANCE TO PARP INHIBITORS
28 Mechanisms of resistance Panagiotis A. Konstantinopoulos et al. Cancer Discov 215;5:
29 Platinum Cross-Resistance? Patients with gbrca1/2m ovarian cancer and measurable disease at baseline who had received 3 prior chemotherapy regimens (n = 137). Platinum Status Confirmed Responders ORR, % (95% CI) Median DoR, months (95% CI) Total (n=137) (26-42) 7.9 ( ) Plt Sensitive (n=39) Plt resistant (n=81) Plt refractory (n=14) (3-63) 8.2 ( ) 24 3 (2-41) 8. ( ) 2 14 (2-43) 6..4 ( ) Unknown (n=3) 2 67 (9-99) 6.3 ( ) Domchek et al, Gyn Oncology 216
30 Summary PARP inhibition is a novel therapeutic approach to BRCAm breast cancer Promising activity in early trials, but obtaining regulatory approval has been challenging Effectiveness outside of gbrcam setting a topic of active exploration Biomarkers of response beyond gbrcam sorely needed
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