PARP inhibitors for breast cancer

PARP inhibitors for breast cancer Mark Robson, MD Memorial Sloan Kettering Cancer Center

Agenda Mechanism of action Clinical studies Resistance mechanisms Future directions

Poly (ADP-ribose) Polymerases

PARP Involvement in DNA Repair Helleday, Mol Oncol 211

PARP Inhibition in BRCA-deficient cells BRCA1 BRCA2 Farmer et al, Nature 25

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

Alternative models Helleday et al Mol Oncol 211

Alternative models Impairs BRCA1 recruitment PARP1 involvement in POLQ-dependent pathway of NHEJ on HR-deficient cells

PARPi under development Compound AKA Phase Olaparib (AZ) KU59436, AZD2281 III Veliparib (AbbVie) ABT888 II/III (upcoming) Rucaparib (Clovis) PF1367338, AG14699 I/II Niraparib (Tesaro) MK4827 III Talazoparib (Medivation) MDV38, BMN-673 III CEP-9722 (Cephalon) E716 (Eisai) I I

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

CLINICAL STUDIES

Approaches Single agent ( synthetic lethality ) Leverages defects in homologous recombination Combination with CTX or RT Does not necessarily require HR defect

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 141-144 days Tutt, Lancet 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

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)

Other combinations *ispy success in neoadjuvant therapy of unselected TNBC*

PARPi + PIK3CAi in BRCA1-BC Jukevar et al, Cancer Discovery 212;2:148

Challenges to getting approval Single agent vs combination What combination? What endpoint? Cross-over (official/ unofficial) Companion diagnostic

Olaparib in platinum-sensitive ovarian (Maintenance after carboplatin/paclitaxel induction) Probability of progression-free survival No. at risk Olaparib Placebo 1..9.8.7.6.5.4.3.2.1. 3 6 9 12 15 Months since randomization 136 129 14 72 51 23 23 7 6 1 Olaparib Placebo Hazard ratio,.35 (95% CI,.25-.49) P<.1 No. of patients/ Total no (%) 6/136 (44.1) 93/129 (72.1) Median Progression-free Survival (mo) 8.4 4.8 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;366:1382-1392.

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)

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

Expanding beyond gbrca Olaparib 4 mg po BID 1 gbrca-bc and 16 non-brca TNBC Gelmon et al, Lancet Oncol 211

ATM Deficient Cancer Yung-Jue Bang et al. JCO 215;33:3858-3865

Genomic Aberrations in DNA Repair in Patients with Metastatic, Castration-Resistant Prostate Cancer Mateo J et al. New Engl J Med 215;373:1697

RESISTANCE TO PARP INHIBITORS

Mechanisms of resistance Panagiotis A. Konstantinopoulos et al. Cancer Discov 215;5:1137-1154

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) 46 34 (26-42) 7.9 (5.6-9.6) Plt Sensitive (n=39) Plt resistant (n=81) Plt refractory (n=14) 18 46 (3-63) 8.2 (5.6-13.5) 24 3 (2-41) 8. (4.8-14.8) 2 14 (2-43) 6..4 (5.4-7.4) Unknown (n=3) 2 67 (9-99) 6.3 (4.7-9.7) Domchek et al, Gyn Oncology 216

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