Clinical Data With PARP Inhibitors in Ovarian Cancer

Transcription

1 Clinical Data With PARP Inhibitors in Ovarian Cancer Thomas J. Herzog, MD, FACOG, FACS Paul & Carolyn Flory Professor Clinical Director, University of CincinnaD Cancer InsDtute CincinnaD, OH

2 Clinical Data With PARP Inhibitors in Ovarian Cancer Learning ObjecDve Evaluate the benefits and risks of emerging PARP inhibitors in the treatment of BRCA- deficient ovarian cancer Disclosures ScienDfic Advisor: AstraZenaca, Morphotek, J & J, Roche

3 PARP Inhibitors in the Clinic BRCA - /- 1x BRCA +/+ BRCA +/- 1. Bryant HE, et al. Nature. 25;434: Farmer H. Nature. 25;434: Specific killing of BRCA2- deficient tumors with inhibitors of poly(adp- ribose) polymerase 1 PARP inhibitors trigger γ- H2AX and RAD51 foci formadon In the absence of PARP1, spontaneous single- strand breaks collapse. replicadon forks and trigger homologous recombinadon for repair BRCA2- deficient cells are acutely sensidve to PARP inhibitors PARP1 acdvity is essendal in homologous recombinadon- deficient BRCA2 mutant cells. Treatment with PARP inhibitors is likely to be highly tumour specific TargeGng the DNA repair defect in BRCA- mutant cells as a therapeugc strategy 2 BRCA1 or BRCA2 dysfuncdon unexpectedly and profoundly sensidzes cells to the inhibidon of PARP enzymadc acdvity, resuldng in apoptosis The inhibidon of PARP leads to the persistence of DNA lesions normally repaired by homologous recombinadon Different pathways cooperate to repair damage, and suggest that the targeted inhibidon of pardcular DNA repair pathways may allow the design of specific and less toxic therapies for cancer

4 Phase I: AZD 2281 (olaparib) Enrolled and treated 6 padents; 22 were carriers of a BRCA1 or BRCA2 mutadon PharmacokineDc data indicated rapid absorpdon and eliminadon Pharmacodynamic studies confirmed PARP inhibidon in surrogate samples ObjecDve andtumor acdvity was reported only in mutadon carriers, all of whom had ovarian, breast, or prostate cancer and had received muldple treatment regimens CONCLUSION: Olaparib has few of the adverse effects of convendonal chemotherapy, inhibits PARP, and has andtumor acdvity in cancer associated with the BRCA1 or BRCA2 mutadon Fong PC, et al. N Engl J Med. 29;361:

5 Clinical AcDvity: RECIST + GCIG (cont) Fong PC, et al. N Engl J Med. 29;361:

6 Phase II Trial of the PARP Inhibitor Olaparib (AZD 2281) in BRCA- Deficient Advanced Ovarian Cancer: Efficacy Recurrent (stage IIIB/IIIC/IV), confirmed mutadon, aker failure of 1 pladnum- based chemotherapy Audeh MW, et al. J Clin Oncol 27:15s, 29 (suppl; abstr 55). Olaparib 4 mg bid (n = 33; %) Olaparib 1 mg bid (n = 24; %) Response by RECIST 11 (33) 3 (13) Platinum sensitive 1/7 (14) 2/8 (25) Platinum resistant 1/26 (38) 1/16 (6) Response by RECIST and/or GCIC 2 (61) 4 (17) Median DOR (range) 29 days ( ) 269 days ( ) Median PFS 5.8 months 1.9 months Grade 3/4 AEs (n = 33) (n = 24) Nausea 2 (6) 3 (13) Vomiting 2 (6) 2 (8) Discontinuation due to AEs 4 (12) 1 (4) Dose interruption due to AEs 12 (36) 4 (17)

7 Phase II BRCA MutaDon Ovarian Cohort Audeh MW, et al. J Clin Oncol 27:15s, 29 (suppl; abstr 55).

8 Phase II Monotherapy Studies: BRCA mut / Ovarian Cancer Study/size PaGents Agent/Dose Prior Treatment Response RECIST (n=; %) Audeh 1 BRCA mut n=33 Gelmon 2 BRCA mut (27%) n=17 Olaparib 4 mg BID n=24 Olaparib 1 mg BID BRCA wt N=47 Olaparib 4 mg BID Olaparib 4 mg BID Coleman 3 BRCA mut Veliparib 4 mg BID 1. Audeh MW, et al. J Clin Oncol 27:15s, 29 (suppl; abstr 55). 2. Gelmon KA, et al. Lancet Oncol. Sep 211;12: Coleman RL, et al. Gyne Oncol.137:3-4. Median 3 (1-1) 11/33 (33) Median 4 (1-16) 3/24 (13) Median 3 (1-1) 7/17 (41) Median 3 (1-8) 11/46 (24) Median 2 (1-3) (61% PlaGnum- resistant) 1/51 (2)

9 PARP Inhibitors as Maintenance Primary Therapy SOLO- 1 Olaparib (BRCA mut only) PlaDnum- sensidve Recurrence SOLO- 2 Olaparib (BRCA mut only) ARIEL 3 Rucaparib (PlaDnum- sensidve) NOVA Niraparib (BRCA mut & HGS)

10 Phase II Olaparib vs. PLD Primary objecdve: Compare efficacy (PFS) of 2 dose levels of olaparib (2 mg & 4 mg BID) with pegylated liposomal doxorubicin (PLD) PaDents: BRCA1/2 germline carriers with Ovarian Ca Progressive or recurrent disease <12 months aker previous pladnum- based chemotherapy Randomized 1:1:1 Olaparib 2 mg BID in 28- day cycles Olaparib 4 mg BIDin 28- day cycles PLD 5 mg/m 2 IV every 4 weeks PD or withdrawal from treatment for other reason As above or max lifedme cumuladve dose reached Stats: HR.55 (median PFS of 4 to 7.3 months) N planned: 9 (3/arm) PaGents in PLD group were allowed to X- over to olaparib 4 mg PD Kaye SB, et al. J Clin Oncol. 212;3:

11 PFS: Phase II Olaparib versus PLD ProporDon of padents progression free Stats: HR.55 (median PFS of 4 to 7.3 mos) HR* vs PLD (8% CI) Olaparib 2 mg:.91 ( ); P =.78 Olaparib 4 mg:.86 ( ); P =.63 Olaparib 2 mg + 4 mg:.88 ( ); P =.66 Median PFS (8% CI) Olaparib 2 mg: 6.5 (5.6 8.) months Olaparib 4 mg: 8.8 ( ) months PLD 5 mg/m 2 : 7.1 ( ) months Olaparib 2 mg Olaparib 4 mg PLD Number of pagents at risk: Olaparib 2 mg Olaparib 4 mg PLD *HR <1 favours olaparib Time from randomizagon (months) Kaye SB, et al. J Clin Oncol. 212;3:

12 Phase II RECIST Response Olaparib#4# Olaparib#2# 31% 26% Response#(PR)# SD# #4#mos# SD#2=4#mos# PD# PLD# 19% %# 2%# 4%# 6%# 8%# 1%# Odds rado (8% CI) Olaparib (2) vs PLD, 1.9 ( ); P=.313 Olaparib (4) vs PLD, 2.69 ( ); P=.18 Kaye SB, et al. J Clin Oncol. 212;3:

13 Maintenance Olaparib: Study 19 PaGents PlaDnum- sensidve high- grade serous ovarian cancer 2 previous pladnum regimens Maintained PR or CR following last pladnum regimen Olaparib 4 mg BID, orally (n = 136) Randomized 1:1 Placebo (n = 129) 82 sites in 16 countries Primary endpoint PFS by RECIST Secondary endpoints TTP by CA- 125 (GCIG criteria) or RECIST, OS, safety Ledermann, et al. J Clin Oncol. 211;29 (suppl; abstr 53). Ledermann, et al. N Engl J Med. 212;366:

14 Study 19: Progression- free survival ProporGon of pagents progression free At risk (n) Olaparib Placebo Randomized treatment Placebo Olaparib 4 mg BID Median PFS (months) Hazard ratio.35 P< Time from randomizagon (months) Olaparib Ledermann, et al. J Clin Oncol. 211;29 (suppl; abstr 53). Ledermann, et al. N Engl J Med. 212 Apr 12;366: Placebo 4.8

15 Adverse Events: Phase II Study of Maintenance Olaparib in PlaDnum- SensiDve Relapsed Ovarian Cancer (N = 265) Olaparib (%) Placebo (%) Adverse Event Any Grade Grade 3 Any Grade Grade 3 Nausea FaDgue VomiDng Diarrhea Headache Decreased appedte Abdominal pain Anemia Dyspepsia 16 9 Dysgeusia 14 6 No cases of leukemia or myelodysplasdc syndrome reported Ledermann, et al. J Clin Oncol. 211;29 (suppl; abstr 53). Ledermann, et al. N Engl J Med. 212 Apr 12;366:

16 Study 19: PFS by BRCAm status ProporGon of pagents progression- free Number at risk Olaparib BRCAm Placebo BRCAm Olaparib BRCAwt Placebo BRCAwt Olaparib BRCAm Placebo BRCAm Olaparib BRCAwt Placebo BRCAwt Events: total pts (%) BRCAm (n=136) Time from randomizagon (months) BRCAwt (n=118) Olaparib Placebo Olaparib Placebo 26:74 (35.1) 46:62 (74.2) 32:57 (56.1) 44:61 (72.1) Median PFS, months HR=.18 95% CI (.11,.31); P< HR=.53 95% CI (.33,.84); P=.7 BRCAwt, wild type (includes pagents with no known BRCAm or a mutagon of unknown significance) Ledermann J, et al. Lancet Oncol. 214 Jul;15(8):

17 Study 19: OS in BRCAm PaDents ProporGon of pagents alive Number at risk Olaparib BRCAm Placebo BRCAm Randomized treatment Olaparib BCRAm Placebo BRCAm Time from randomizagon (months) OS in BRCAwt padents: HR=.98; 95% CI, ; P=.946 Median OS: olaparib, 24.5 months; placebo, 26.2 months 14/62 (22.6%) placebo padents switched to a PARP inhibitor 48 Olaparib BRCAm (n=136) Placebo Deaths: total pts (%) 37:74 (5.) 34:62 (54.8) Median OS, months HR=.74 95% CI (.46, 1.19) P=.28 Ledermann J, et al. Lancet Oncol. 214;15:

18 Study 19: Time to Second Subsequent Therapy (PFS2) ProporGon of pagents receiving study treatment or first subsequent therapy Number at risk Olaparib BRCAm Placebo BRCAm Olaparib BRCAwt Placebo BRCAwt Olaparib BRCAm Placebo BRCAm Olaparib BRCAwt Placebo BRCAwt Time from randomizagon (months) BRCAm (n=136) BRCAwt (n=118) Olaparib Placebo Olaparib Placebo Events: total pts (%) 42:74 (56.8) 49:62 (79.) 42:57 (73.7) 55:61 (9.2) Median PFS, months HR=.46 95% CI (.3,.7); P<.3 HR=.64 95% CI (.42,.96); P=.32 BRCAwt, wild type (includes pagents with no known BRCAm or a mutagon of unknown significance) Ledermann J, et al. Lancet Oncol. 214;15:

19 PARPi in Phase III Development as Maintenance Therapy in PlaDnum- SensiDve Recurrence AZD 2281 (KU ) = Olaparib SOLO- 2 [NCT ] = PlaDnum- sensidve HGS maintenance in BRCAmut MK = Niraparib NOVA [NCT ] = PlaDnum- sensidve HGS maintenance in BRCAmut and BRCAwt CO- 338 (AG14699, PF ) = Rucaparib ARIEL- 3 [NCT ] = PlaDnum- sensidve HGS and endometrioid maintenance in BRCAmut and BRCAwt HGS = High grade serous

20 Niraparib: Phase 1/2 Ovarian Cancer AnD- tumor AcDvity 6 Percentage change from baseline in size of target lesions * * * * * * * * * * * * * * * * * * -8-1 PlaDnum Resistant PlaDnum Recommended Dose * PlaDnum SensiDve * BRCA1/2 mutadon carriers ReducDon in overall sum of measurable disease but new lesion seen (overall: PD) - Refractory padent (BRCA mutated) not included At recommended dose (29/3 mg), 3/4 (75%) pladnum sensidve padents achieved RECIST response RECIST response rate in pladnum- sensidve padents was 46% (6/13) Response rate (by RECIST and/or GCIG Ca125 criteria) in evaluable pladnum- resistant padents was 22% (6/27) Michie Co et al. J Clin Oncol. 213; 31 (suppl; abstr 2513).

21 Progression 6 months from last dose Pre-study Events Penultimate treatment course with a platinum-containing regimen (as per normal clinical practice) Last treatment course with a platinum containing regimen (as per normal clinical practice) NOVA Study Design Study Events Randomize patient within 8 weeks of last dose of platinum containing regimen based on centralized BRCA testing PRO/imaging gbrca mut Niraparib Placebo non-gbrca mut Niraparib Placebo No measurable disease > 2 cm; Normal CA125 or > 9% decrease during the last regimen (stable 7 days); PR/CR next to last/last platinum regimen Disease progression Off study treatment PRO Subsequent treatments Disease progression Off study treatment Subsequent treatments Patient can be considered for the study and consented ClinicalTrials.gov IdenDfier:NCT Survival Survival

22 Ph II Olaparib: Olaparib Monotherapy in PaDents with Advanced Cancer and a Germline BRCA1/2 MutaDon Results: A total of 298 padents received treatment and were evaluable. The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (6 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 5.% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, pancreadc, and prostate cancers, respecdvely. Stable disease 8 weeks was observed in 42% of padents (95% CI, 36. to 47.4), including 4% (95% CI, 33.4 to 47.7), 47% (95% CI, 34. to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with ovarian, breast, pancreadc, or prostate cancer, respecdvely. The most common adverse events (AEs) were fadgue, nausea, and vomidng. Grade 3 AEs were reported for 54% of padents; anemia was the most common (17%). Conclusion: Responses to olaparib were observed across different tumor types associated with germline BRCA1/2 mutadons. Olaparib warrants further invesdgadon in confirmatory studies. Kaufman B et al. J Clin Oncol. 215;33:

23 Primary Outcome: Cediranib/Olaparib Significantly Increased PFS Compared to Olaparib Alone Propor6on progression- free Olaparib Ced/Olap PFS events Median PFS 9. mo 17.7 mo p=.5 HR.42 (95% CI: ) Olaparib Cediranib/ olaparib Liu J, J Clin Oncol. 214; 32:5s (suppl; abstr LBA55).

24 Cediranib/olaparib Significantly Increased PFS in PaDents without a BRCA MutaDon BRCA mutagon carrier BRCA non- carrier/unknown Propor6on progression- free Cediranib/ olaparib Olaparib Propor6on progression- free Olaparib Cediranib/ olaparib BRCA MutaGon Carrier BRCA Non- carrier/unknown Olaparib Ced/Olap Olaparib Ced/Olap PFS events Median PFS 16.5 mo 19.4 mo 5.7 mo 16.5 mo p=.16 p=.8 HR.55 (95% CI: ) HR.32 (95% CI: ) Liu J. J Clin Oncol. 214; 32:5s (suppl; abstr LBA55).

25 Phase III: SOLO- 1 First- line Maintenance St III- IV Ov BRCA mutadon HG serous or endometrioid PR/CR & > 6 cycles R 2:1 Olaparib (PO) 3 mg tablet BID Placebo Primary endpoint: PFS Secondary: OS PFS2 QoL EsDmated Enrollment: 397 Study Start Date: Aug 213 ClinicalTrials.gov Id NCT EsDmated Study CompleDon Date: Jan 222 EsDmated enroll CompleDon: Jul 216 (Final data) Principle InvesDgators: P DiSilvestro & K Moore

26 Ph. III: SOLO- 2 Maintenance Relapsed Platsensitive Ov BRCA mutation > 2 prior platinum treatments Penultimate chemo = plat & > 6 mo after completion Last chemo with PR/CR & > 4 cycles R 2:1 Olaparib (PO) 3 mg tablet BID Placebo Primary endpoint: PFS Secondary: PFS2 OS QoL Primary endpoint Estimated Enrollment: 264 Study Start Date: June 213 ClinicalTrials.gov Id NCT Principal Investigator: E Pujade-Lauraine

27 Phase III: SOLO- 3 Relapsed PlaGnum- sensigve Ov BRCA mutadon >2 prior pladnum treatments Primary endpoint = PFS R Olaparib (PO) 3 mg tablet BID Physician's Choice Single Agent Chemo: Weekly paclitaxel Topotecan PLD Gemcitabine EsDmated Enrollment: 411 Study Start Date: Jan 215 EsDmated Study CompleDon Date: Dec 219 EsDmated CompleDon Date: Dec 217 (Final data) ClinicalTrials.gov IdenDfier: NCT22822 Principal InvesDgator: R Penson

28 PARP Inhibitors in Clinical Trials Agent AdministraGon Phase Comments AZD (olaparib) Oral I, II, III Single Agent and CombinaGon, BRCA and non- BRCA, PlaGnum- sensigve and resistant, Primary and Recurrent AZD Oral I FIH, Solid Tumors ABT- 888 (veliparib) Oral I, II Single Agent and CombinaGon, BRCA and non- BRCA, PlaGnum- sensigve and resistant, Primary and Recurrent (GOG- 9923, PIS14) CEP Oral I CombinaDon, Solid Tumors E716 Oral I CombinaDon, Solid Tumors MK4827 Oral I, II Single Agent and CombinaGon, BRCA and non- BRCA, PlaGnum- sensigve and resistant (DTM- 929) PF Oral I Single Agent and CombinaDon, Solid Tumors AG14699 IV II Single Agent, BRCA, PlaGnum- sensigve and resistant BSI- 21 (iniparib) IV II,III CombinaGon (Gem/Cis or Carbo), PlaGnum- sensigve and resistant INO- 11 IV Acute MI hyp:// Accessed 1/211

29 Veliparib CombinaDon Phase II Trial Histologically or cytologically confirmed high grade serous EOC Prior pladnum and < 4 prior cytotoxics Unlimited biologics allowed PlaDnum resistant TFI > 3 mo from last pladnum PlaDnum sensidve allowed R A N D O M I Z E 2:1 Veliparib PO 4 mg BID days 1-7 TMZ 15 mg/m 2 days 1-5 ungl disease progression PLD 5 mg/m 2 IV ungl disease progression if in tolerant BRCA mutagon not required Primary end point = RR (RECIST 1.1) N = 225 (15/75) Recruitment complete (results expected late 211) ClinicalTrials.gov IdenDfier: NCT753545

30 Phase II Veliparib & Metronomic CTX NCI Trial #8788 Germline BRCA or HG serous Plat- R Triple Neg Breast Cancer Low- Grade Non- Hodgkin

31 ENGOT Proposed Study: PAOLA 1 Phase III randomized, placebo-controlled, double-blind, multicenter Olaparib tablets administered at 6 mg daily for up to 2 years Stratification factors: First-line treatment outcome (complete resection after initial surgery and NED at screening, complete resection at interval debulking surgery and NED at screening, incomplete resection at initial or interval debulking surgery and in CR at screening, PR at screening) & gbrca status (yes, no, unknown)

32 PARP inhibitors: Recurrent Ovarian Regimen Status Trial ID Olaparib + CarboplaGn Phase I NCT Olaparib + BKM12 Phase I NCT Veliparib + PLD Phase II NCT Veliparib + Cyclophosphamide Veliparib + Temozolomide Phase II Phase I NCT13632 (completed) NCT (completed) Olaparib + Cediranib Phase I/II NCT ASCO 214

33 Summary and Key Points AcDve in those with BRCA germline mutadons Appear acdve in those with BRCA dysfuncdon Long- term safety data pending SyntheDc lethality is a new paradigm PARP inhibitors being studied in muldple se{ngs with chemotherapy and as single agents Ongoing trials with HRD markers and other biologics