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Maintenance Therapy for Ovarian Cancer – Do the Benefits Outweigh the Risks?

Maintenance Therapy for Ovarian Cancer – Do the Benefits Outweigh the Risks?. Bradley J. Monk, MD, FACS, FACOG Professor and Director Division of Gynecologic Oncology Department of Obstetrics and Gynecology

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Maintenance Therapy for Ovarian Cancer – Do the Benefits Outweigh the Risks?

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  1. Maintenance Therapy for Ovarian Cancer – Do the Benefits Outweigh the Risks? Bradley J. Monk, MD, FACS, FACOGProfessor and Director Division of Gynecologic Oncology Department of Obstetrics and Gynecology Creighton University School of Medicine atSt. Joseph’s Hospital and Medical Center,a Dignity Health Member University of Arizona Cancer Center-Phoenix Arizona USA bradley.monk@chw.edu

  2. Newly Diagnosed Advanced Ovarian Cancer

  3. Maintenance: The Stakes are High! Progression Diagnosis Evaluation ? SLL Secondary Surgery Chemo #2 Symptoms Chemotherapy #1 Chemo #3+ Maintenance What we know… • Rate of response is high (CR + PR) >75% • Second assessment operations find disease > 40% of CR’s • Clinical CR’s have >50% recurrence risk at 2 years • Pathological CR’s have >40% risk at 2 years • Option applies to CR’s and documented PR’s Supportive Care Staging

  4. Maintenance Strategies inEpithelial Ovarian Cancer • Anti-angiogenesis • Chemotherapy • Clinical trial – PARP inhibitor

  5. 4th Ovarian Cancer Consensus Conference 25 – 27 June 2010 UBC Life Sciences Institute, Vancouver, British Columbia B-2 What Are the Promising Targets for Future Therapeutic Approaches? • The most promising targets in clinical trials are angiogenesis and homologous recombination deficiency. Int J Gynecol Cancer 2011: 21; 756-762

  6. Maintenance Strategies inEpithelial Ovarian Cancer • Anti-angiogenesis • Chemotherapy • Clinical trial – PARP inhibitor

  7. GOG#218 ICON-7

  8. GOG-0218: Schema Arm Carboplatin (C) AUC 6 I • Front-line: Epithelial OV, PP or FT cancer • Stage III optimal (macroscopic) • Stage III • suboptimal • Stage IV • n=1800 (planned) Paclitaxel (P) 175 mg/m2 Placebo Carboplatin (C) AUC 6 1:1:1 II RANDOM I Z E Paclitaxel (P) 175 mg/m2 BEV 15 mg/kg Placebo Carboplatin (C) AUC 6 III Stratification variables: • GOG performance status (PS) • Stage/debulking status Paclitaxel (P) 175 mg/m2 BEV 15 mg/kg Maintenance (16 cycles) Cytotoxic (6 cycles) 15 months

  9. GOG-0218CA-125 To Determine Progression

  10. GOG-0218Ad Hoc Survival Analysis in Stage IV 1.0 0.8 0.6 Proportion Surviving CPP (n=153) CPB (n=165) CPB+B (n=165)) 0.4 0.2 HR 0.72, 95% confidence interval 0.53-0.97 0.0 0 12 24 36 48 60 72 Overall Survival (months) NEJM Data cut-off date August 26, 2011 (ASCO 2010 cut-off date February 5, 2010) Randall LM et al SGO 2013

  11. ICON7: a phase III Gynaecologic Cancer InterGroup (GCIG) trial of adding bevacizumab to standard chemotherapy in women with newly diagnosed epithelial ovarian, primary peritoneal or fallopian tube cancer 11 Tim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey, Philip Beale, Andreas Cervantes, Amit Oza on behalf of GCIG ICON7 collaborators (MRC/NCRI, AGO-OVAR, GINECO, NSGO, ANZGOG, GEICO, NCIC-CTG) ESMO 2010 N Engl J Med. 2011 Dec 29;365(26):2484-96.

  12. ICON7: Study Design Carboplatin AUC 6* • Front-line EOC, PP or FT cancer • Stage I-IIA (Gr 3 or CC) • Stage IIB/C • Stage III • Stage IV • n=1528 Arm A Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Paclitaxel 175 mg/m2 ArmB Carboplatin AUC 6* Paclitaxel 175 mg/m2 • Stratification variables: • Stage/surgery • Time since surgery • GCIG group Bevacizumab 7.5 mg/kg AVASTIN ** 12 months *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Perren, et al. ESMO 2010

  13. ICON 7 PFS Benefit: Academic Analysis 1.00 0.75 0.50 0.25 0 Proportion alive without progression CP CPB7.5+ 17.3 19.0 0 3 6 9 12 15 18 21 24 27 30 Time (months) Number at risk CP 764 723 693 556 464 307 216 143 91 50 25 CPB7.5+ 764 748 715 647 585 399 263 144 73 36 19 Perren, et al. ESMO 2010

  14. ICON 7Summary of Updated Results Kristensen G, et al. J Clin Oncol.2011;29: (suppl; abstr LBA5006)

  15. Phase III randomized, placebo-controlled, double-blind, multicenter N=940 patients randomized (1:1) from June 2009 to August 2010 Pazopanib administered at 800 mg daily for up to 24 months* AGO-OVAR 16 R ANDOM I Z E First-line surgery and chemotherapy (allowed: dose-dense, IP, neoadjuvant) Pazopanib 24 months If not PD + tumor < 2 cm Observation (to PD) Survival follow-up (post-PD) Placebo 24 months Median 7 months from diagnosis to randomization ICF *Original design was for 12 months and later amended to 24 months Du Bois A et al J Clin Oncol 31, 2013 (suppl; abstr LBA5503)

  16. Primary Endpoint: Progression-free Survival (RECIST) AGO-OVAR 16 Median time from Diagnosis: 7 months Δ= 5.6 months (months) Du Bois A et al J Clin Oncol 31, 2013 (suppl; abstr LBA5503)

  17. Adverse Events Grade 3-4 per Patient occurring in at least 1% in the Pazopanib Arm AGO-OVAR 16 Du Bois A et al J Clin Oncol 31, 2013 (suppl; abstr LBA5503)

  18. OCEANS Carboplatin AUC 4 Gemcitabine 1000 mg/m2 d1/8 Arm A Primary endpoint: PFS Secondary endpoints: ORR, OS, DR, safety Exploratory endpoints: IRC, CA 125 response, ascites IRC present Platinum-sensitive, recurrent OC, PP, FTC No prior bevacizumab n=480 Placebo to progression Arm B Carboplatin AUC 4 Gemcitabine 1000 mg/m2 d1/8 Bevacizumab 15 mg/kg to progression • Stratification variables: • Time to recurrence • Cytoreductive surgery ClinicalTrials.gov Identifier: NCT00434642 Aghajanian C et al J Clin Oncol 29: 2011 (suppl; abstr LBA5007)

  19. OCEANS: Primary analysis of PFS 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Months No. at risk CG + BV 242 203 92 33 11 0 CG + PL 242 177 45 11 3 0 ASCO 2011 Aghajanian C et al J Clin Oncol 29: 2011 (suppl; abstr LBA5007)

  20. OCEANS: OS Analyses First Interim Analysisa Second Interim Analysisb 1.0 1.0 0.8 0.8 0.6 0.6 GC + PL(n=242) GC + BV(n=242) Proportion surviving Proportion surviving 0.4 0.4 0.2 0.2 0.0 0.0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 48 54 Months Months aData cutoff date: Sept 17, 2010. Median follow-up of 24 months in both arms, with 141 deaths (29% of patients). bData cutoff date: Aug 29, 2011. Median follow-up 33.7 months in PL arm and 35.4 months in BV arm, with 235 deaths (49% of patients).

  21. Maintenance Strategies inEpithelial Ovarian Cancer • Anti-angiogenesis • Chemotherapy • Clinical trial – PARP inhibitor

  22. Maintenance Chemotherapy: GOG 178 R A N D O M I Z E Paclitaxel (3 hrs) 175 mg/m2 q28days x 3 EOC, FT, PP Stage III/IV Prior chemo 5–6 cycles Register 3–8 wks CCR Neuropathy ≤ grade II Paclitaxel (3 hrs) 175 mg/m2 q28days x 12 N = 450 anticipated Accrual closed 9/6/01 N = 277; 222 with FU 54 progression events End points • PFS • OS FU = follow-up. Markman et al, J Clin Oncol 2003.

  23. Unadjusted Log Rank p (1-sided) = .0035 Adjusted Log Rank p (1-sided) = .0023 Maintenance Chemotherapy: GOG 178 Markman et al, J Clin Oncol 2003.

  24. GOG-0212Phase III Maintenance Therapy Trial Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin ( N = 1100) Paclitaxel Every 28 days for up to 12 courses Paclitaxel poliglumex Every 28 days for up to 12 courses No treatment Primary endpoint: survivalSecondary endpoints: PFS, toxicity, QoL OPEN TO PATIENT ENTRY MARCH, 2005 CLOSED TO ENROLLMENT JANUARY, 2014 www.clinicaltrials.gov/ct2/show/NCT00108745.

  25. Maintenance Strategies inEpithelial Ovarian Cancer • Anti-angiogenesis • Chemotherapy • Clinical trial – PARP inhibitor

  26. DNA damage PNK 1 PNK 1 PARP PARP XRCC1 XRCC1 polβ polβ NAD+ PARP recruitment LigIII LigIII PARP poly (ADP-ribose) PARP activation and assembly of repair factors PARG PAR degradation via PARG End processing, gap filling, and ligation PARP and Base Excision Repair Vergote, ND; Khanna et al, 2001; Sanchez-Perez, 2006; Kennedy et al, 2006.

  27. DNA Repair Inhibitors in Cancer Cells: 2 Modes of Action • Potentiation • Inhibition of DNA repair following DNA-damaging agents • Original hypothesis • Synthetic lethality • Selected cancer cells lose DNA repair pathways, whereas normal cells remain unaffected • Targeting these defective cells may cause selective cell kill with an increased therapeutic ratio • May allow for a novel targeted approach to cancer treatment Bentle MS et al J Mol Histol. 2006 Sep;37(5-7):203-18

  28. PARPi in Phase III Development in Ovarian Cancer • AZD 2281 (KU-0059436) = Olaparib • MK-4827 = Niraparib • CO-338 (AG014699, PF-01367338) = Rucaparib • Others with randomized trials in devleopment • ABT-888 = Veliparib • BMN 673 No direct clinical comparisons!

  29. Dual Activities of PARP Inhibitors • Cell cytotoxicity greatest with niraparib • Dual mechanisms include catalytic inhibition of PARP and PARP trapping on DNA DT40: avian line with only PARP1: facilitates assessment of role of PARP trapping Murai J, et al.Cancer Res. 2012 Nov 1;72(21):5588-99.

  30. PARPi in Phase III Development in Ovarian Cancer • AZD 2281 (KU-0059436) = Olaparib • MK-4827 = Niraparib • CO-338 (AG014699, PF-01367338) = Rucaparib

  31. Olaparib Development • Oral small molecule PARPi (low nM) • Escalation Phase (N = 46) • All tumors • BRCA mutation not required (11 BRCA ovarian ca’s) • 10 Dose levels; administration 2 of 3 weeks up to bid continuously • PK and PD determined • DLT: Myelosuppression, N/V, CNS (mood changes) • MTD: 400 mg bid • Expansion Phase (N=52) • All confirmed BRCA mutation carriers (39 Ovarian ca’s) • DLT: fatigue, thrombocytopenia, somnolence • Administration 200 mg bid continuously 1Fong, ASCO 2006, 2007 2Yap, ASCO 2007

  32. Phase I: AZD 2281 (Olaparib)

  33. Clinical Activity: RECIST + GCIG (cont.) Fong et al, 2008.

  34. Phase II: AZD 2281 (Olaparib)

  35. Phase II: BRCA Mutation Ovarian Cohort Audeh et al, 2009.

  36. Who Will Benefit From PARPi Treatment? Sporadic tumors with intact BRCA function Courtesy of Robert Coleman, MD. Adapted from Coleman, 2009.

  37. Even Wider Catch: BRCAness “Profile” Konstantinopoulos PA, et al. J Clin Oncol. 2010;28:3555.

  38. BRCAness and Response to Chemotherapy Disease Free Survival Overall Survival 72 v 41 mo P = 0.006 34 v 15 mo P = 0.01 Konstantinopoulos PA, et al. J Clin Oncol. 2010;28:3555.

  39. Phase II study of the oral PARP inhibitor olaparib (AZD2281) versus liposomal doxorubicin in ovarian cancer patients with BRCA1 and/or BRCA2 mutations ESMO 2010 Stan Kaye,1 Bella Kaufman,2 Jan Lubinski,3 Ursula Matulonis,4 Charlie Gourley,5 Beth Karlan,6 Dianna Taylor,7 Mark Wickens,7 James Carmichael7 1. Royal Marsden Hospital, Sutton, Surrey, UK 2. Chaim Sheba Medical Center, Tel Hashomer, Israel 3. Pomeranian Medical University, Szczecin, Poland 4. Dana-Farber Cancer Institute, Boston, MA, USA 5. University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK 6. Cedars-Sinai Medical Center, Los Angeles, CA, USA 7. AstraZeneca, Alderley Park, Macclesfield, UK Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol. 2012 Feb 1;30(4):372-9. Clinicaltrials.gov number, NCT00628251

  40. Study Design Primary objective: Compare efficacy (PFS) of 2 dose levels of olaparib (200 mg and 400 mg bid) with pegylated liposomal doxorubicin (PLD) Olaparib 200 mg bid in 28-day cycles PD or withdrawal from treatment for other reason BRCA1/2 germline carriers with Ovarian Ca Progressive or recurrent disease < 12 months after previous platinum-based chemotherapy Olaparib 400 mg bid in 28-day cycles Randomized 1:1:1 As above or max lifetime cumulative dose reached PLD 50 mg/m2 IV every 4 weeks Stats: HR 0.55 (median PFS of 4 to 7.3 mos) N planned: 90 (30/arm) Patients in PLD group were allowed to cross over to olaparib 400 mg bid on confirmed PD Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol. 2012 Feb 1;30(4):372-9.

  41. 32 HR* vs PLD (80% CI) 33 1.0 Olaparib 400 mg PLD Olaparib 200 mg Number of patients at risk: 24 25 21 18 13 15 8 8 3 3 0 0 0 2 4 6 8 10 12 Olaparib 200 mg Olaparib 200 mg: 0.91 (0.60-1.39); P = 0.78 0.9 32 28 Olaparib 400 mg 21 17 12 1 0 Olaparib 400 mg: 0.86 (0.56-1.30); P = 0.63 Olaparib 200 mg + 400 mg: 0.88 (0.62-1.28); P = 0.66 0.8 *HR < 1 favors olaparib. 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Progression-Free Survival Median PFS (80% CI) Olaparib 200 mg: 6.5 (5.6-8.0) months Olaparib 400 mg: 8.8 (6.3-9.2) months PLD 50 mg/m2: 7.1 (5.5-7.8) months Proportion of Patients Progression Free Stats: HR 0.55 (median PFS of 4 to 7.3 mos) N planned: 90 (30/arm) Time From Randomization (months) PLD Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol. 2012 Feb 1;30(4):372-9.

  42. Patients Platinum-sensitive high-grade serous ovarian cancer ≥2 previous platinum regimens Maintained PR or CR following last platinum regimen Maintenance Olaparib:Study design (Study 19) Olaparib 400mg bid, orally (n=136) Primary endpoint PFS by RECIST Secondary endpoints TTP by CA-125 (GCIG criteria) or RECIST, OS, safety Randomized 1:1 Placebo (n=129) 82 sites in 16 countries Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003); N Engl J Med. 2012 Apr 12;366(15):1382-92.

  43. Study 19: Progression-free survival Placebo 93:129 (72.1) 4.8 Olaparib 60:136 (44.1) 8.4 1.0 No. of events: Total patients (%) Median PFS (months) 0.9 0.8 Hazard ratio 0.35 (95% CI, 0.25–0.49) P<0.00001 0.7 0.6 Proportion of patients progression free 0.5 0.4 0.3 0.2 Randomized treatment Placebo 0.1 Olaparib 400 mg bid 0 0 3 6 9 12 15 18 Time from randomization (months) At risk (n) Olaparib 136 104 51 23 6 0 0 Placebo 129 72 23 7 1 0 0 Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003); N Engl J Med. 2012 Apr 12;366(15):1382-92.

  44. Study 19:Common Adverse Events* Placebo (n=128) Olaparib 400 mg bid (n=136) Percentage of Patients Adverse event Any event Nausea Fatigue Vomiting Diarrhea Headache Decreased appetite Abdominal pain Anemia Dyspepsia Grade 1/2 61 66 42 29 21 18 18 16 12 16 Grade 3/4 35 2 7 2 2 0 0 2 5 0 Grade 1/2 70 35 34 13 20 11 13 23 4 9 Grade 3/4 20 0 3 1 2 1 0 3 1 0 *Adverse events graded according to maximum CTCAE version 3.0 grade, experienced by >15% of patients in either treatment group. Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003); N Engl J Med. 2012 Apr 12;366(15):1382-92.

  45. Presented by: Jonathan Ledermann et al at ASCO 2013 Study 19: PFS by BRCAm status • 82% reduction in risk of disease progression or death with olaparib 1.0 0.9 0.8 0.7 0.6 Proportion of patients progression-free 0.5 0.4 0.3 Olaparib BRCAm Placebo BRCAm 0.2 0.1 0 0 3 6 9 12 15 Time from randomization (months) Number at risk Olaparib BRCAm 74 59 33 14 4 0 Placebo BRCAm 62 35 13 2 0 0

  46. Study 19: PFS by BRCAm status 1.0 0.9 0.8 0.7 0.6 Proportion of patients progression-free 0.5 0.4 0.3 Olaparib BRCAm Placebo BRCAm 0.2 Olaparib BRCAwt 0.1 Placebo BRCAwt 0 0 3 6 9 12 15 Time from randomization (months) Number at risk Olaparib BRCAm 74 59 33 14 4 0 Placebo BRCAm 62 35 13 2 0 0 Olaparib BRCAwt 57 44 17 9 2 0 Placebo BRCAwt 61 35 10 4 1 0 BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance) Presented by: Jonathan Ledermann et al at ASCO 2013

  47. Study 19: OS in BRCAm patients 1.0 • OS in BRCAwt patients: HR=0.98; 95% CI, 0.62–1.55; P=0.946 • Median OS: olaparib, 24.5 months; placebo, 26.2 months • 14/62 (22.6%) placebo patients switched to a PARP inhibitor 0.9 0.8 0.7 0.6 Proportion of patients alive 0.5 0.4 0.3 Randomized treatment 0.2 Olaparib BCRAm 0.1 Placebo BRCAm 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time from randomization (months) Number at risk Olaparib BRCAm 74 71 69 67 65 62 57 54 50 48 39 36 26 12 7 Placebo BRCAm 62 62 58 52 50 46 39 36 33 29 29 27 21 12 4 Presented by: Jonathan Ledermann et al at ASCO 2013

  48. Study 19:Time to second subsequent therapy (PFS2) 1.0 0.9 0.8 0.7 0.6 Proportion of patients receiving study treatment or first subsequent therapy 0.5 0.4 0.3 Olaparib BRCAm Placebo BRCAm 0.2 0.1 0 0 5 10 15 20 25 30 35 40 45 Time from randomization (months) Number at risk Olaparib BRCAm 74 70 65 50 38 33 30 23 9 0 Placebo BRCAm 62 60 46 31 21 18 11 9 2 0 Presented by: Jonathan Ledermann et al at ASCO 2013

  49. Study 19:Time to second subsequent therapy (PFS2) 1.0 0.9 0.8 0.7 0.6 Proportion of patients receiving study treatment or first subsequent therapy 0.5 0.4 0.3 Olaparib BRCAm Placebo BRCAm 0.2 Olaparib BRCAwt 0.1 Placebo BRCAwt 0 0 5 10 15 20 25 30 35 40 45 50 Time from randomization (months) Number at risk Olaparib BRCAm 74 70 65 50 38 33 30 23 9 0 0 Placebo BRCAm 62 60 46 31 21 18 11 9 2 0 0 Olaparib BRCAwt 57 56 48 34 20 16 14 11 3 0 0 Placebo BRCAwt 61 58 48 28 18 8 6 4 2 1 0 BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance) Presented by: Jonathan Ledermann et al at ASCO 2013

  50. ORR post-olaparib = 36% (24/67) by RECIST • Platinum = 40% (19/48) by RECIST • ORR post-olaparib = 45% (35/78) by RECIST + GCIG • No evidence of secondary BRCA1/2 mutations detected in tumor samples of 6 PARPi-resistant patients

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