Your Input Is Very Important! Sign-In   Sheets:  – Your attendance counts  – Please sign-in Chair’s   Practice Patterns ...
DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhancepatient outcomes and...
Disclosure of Conflicts of Interest                    Robert F. Ozols, MDReported a financial interest/relationship or af...
Learning Objectives             L       Upon completion of this activity, participants               should be better able...
Activity Agenda   Activity Overview (5 mins)   Current Treatments in Ovarian Cancer (25 mins)    – Case study 1: Integra...
Community and AcademicGround Rounds: Transforming Treatment in Ovarian Cancer
Newly Diagnosed Advanced                        Ovarian CancerCourtesy of Bradley J. Monk, MD, FACOG, FACS.
Ovarian Carcinoma:                      Incidence and Mortality            Incidence in US women               – 21,990 c...
Stage Distribution and 5-yr Relative                    Survival by Stage at Diagnosis                        (2001–2007, ...
Results of Treatment:                                 Advanced Disease       Parameter                                    ...
Results of Treatment:                         Advanced Disease (cont.)       Parameter (%)                                ...
First-Line Therapy                      Global Standard Treatment                                                    Surge...
Basis for Current Standard:                         Systemic Therapy           Studies showing paclitaxel/cisplatin super...
Case Study 1Integrating Personalized Approaches Into Treatment Planning and Management for            First-Line Therapy
Case Study 1       A      65-yr-old woman with diet controlled             diabetes and a past history (18 mos ago) of   ...
Based on Existing Evidence-Based              Data, What Options Might Be               Considered at This Point?        1...
JGOG: Dose-Dense Wkly Paclitaxel    EOC or PP                                                                            ...
JGOG: Dose-Dense Wkly Paclitaxel                        (cont.)Isonishi et al, 2008.
Justification for Neoadjuvant                            Chemotherapy        1. Extensive intra-abdominal ovarian cancer p...
NACT + IDS Vs. PDS                                         Ovarian, Tubal, or Peritoneal Cancer                           ...
NACT + IDS Vs. PDS (cont.)                             ITT AnalysisHR = hazard ratio.Vergote et al, 2010.
NACT + IDS Vs. PDS (cont.)      Surgical Characteristics                 PDS        NACT  IDS                            ...
Primary Therapy: IP                                           Median PFS                    HR         Median OS    HR    ...
GOG 172: Ovarian (Optimal III)         EOC         Optimal stage III         No prior therapy         Elective second-...
GOG Protocol 172                                                     RR of death = 0.75 (95% CI: 0.58, 0.97) p = .03      ...
GOG Protocol 172: Toxicity                                                        IV             IP                     Gr...
GOG 218: Schema                                                                                              Arm          ...
GOG 218: Patient Disposition                                                                  Arm I          Arm II       ...
GOG 218: Select AEs        Onset Between Cycle 2 and 30 Days After Date of Last Treatment                                 ...
GOG 218: Select AEs (cont.)                                           Treatment Phase                                     ...
GOG 218: Investigator-Assessed                                       PFS                                                  ...
GOG 218: Subgroup Analyses of PFS                      CP + Bev  Bev (Arm III) Vs. CP (Arm I)                            ...
GOG 218: OS Analysis                At Time of Final PFS Analysis (January 2010)                                  1.0     ...
ICON7: Study Design                                                                       C AUC 6a                        ...
Key Differences Between                             GOG 218 and ICON7            Trial            GOG 218                 ...
ICON7 Schema                                     Carboplatin AUC 5/6      Stratification Variables          1:1           ...
ICON7 PFS: Updated                                    17.4                                               19.8             ...
PFS: “High Risk” Subgroup (Ad Hoc Analysis)High Risk: Stage IIIC Suboptimal/Stage IV                                      ...
Interim Analysis of Overall SurvivalKristensen et al, 2011.
Case Study 2Optimally Managing Recurrent       Ovarian Cancer
Case Study 2   A 54-yr-old woman with ovarian cancer attains a    clinically-defined CR to primary    carboplatin/paclita...
The Traditional Treatment Paradigm                      Recurrence After First-Line Chemotherapy                       Pla...
Recurrent Ovarian Cancer:             Definition of Disease Sensitivity     P                          Time to Recurrence ...
Major Trials in                          Recurrent Ovarian Cancer              Paclitaxel vs. topotecan              Top...
19                                  64                                          Me                                        ...
Recurrence Regimens                              NCCN Preferred AgentsPlatinum-based combination therapy should be conside...
Phase III Study (Doublets): CALYPSO                               R   Paclitaxel 175 mg/m2                               A...
PFS: ITT                                                               CD            CP                                   ...
Intermediate Sensitive: 6–12 mos                                                                             CD           ...
PFS: Highly Platinum-Sensitive                          (PFI > 24 mos)                                         C-PLD   C-P...
CALPYSO: OS AnalysisMarth et al, 2011.
Bevacizumab: The First ActiveTargeted Agent in Ovarian Cancer   Case report of single-agent activity    – Monk et al, 200...
OCEANS: Study Schema       Platinum-Sensitive ROCa                  CG +                           Carboplatin AUC 4      ...
OCEANS: Patient Characteristics                                                             CG + PLA     CG + BEV         ...
OCEANS: Primary Analysis of PFS                                                                                     CG + P...
OCEANS: PFS Subgroup Analyses                                                Median PFS                                   ...
OCEANS: Interim OS                                1.0                                0.8         Proportion Alive (%)     ...
OCEANS: AEs of Special Interest                                                                          CG + PLA    CG + ...
OCEANS: Preliminary Conclusions             BEV + carboplatin + gemcitabine followed by              BEV until progressio...
Novel Therapies and Future Directions
PARP Inhibitors            Suggested Mechanism of Action  Chemotherapy inflicts DNA   damage via adducts and     DNA cross...
Phase II Study of Olaparib of Patients With              BRCA1 or BRCA2 Mutation        Two dosages tested in sequential ...
Study 19: Aim and Design             To assess the efficacy of olaparib (OLA) as a maintenance              treatment in ...
Patient Characteristics                                                 Olaparib                                          ...
Progression-Free Survival                                                                                                 ...
Preplanned Subgroup Analysis of PFS         Overall         BRCA mutation         BRCA status known         BRCA unknown  ...
Confluence of Multiple Advances                   PharmacogenomicsBioinformatics                        Translational     ...
Future Strategies in Ovarian Cancer                                                              Angiogenesis             ...
Transforming Treatment in Ovarian Cancer
Transforming Treatment in Ovarian Cancer
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Transforming Treatment in Ovarian Cancer

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This downloadable slidedeck, presented in a regional grand rounds series, focuses on increasing awareness about current and emerging treatment options for patients with newly diagnosed and recurrent ovarian cancer.

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  • This discussion in this grand rounds presentation will focus on the current front-line and second-line chemotherapeutic management of epithelial ovarian cancer and on promising new approaches in the treatment of this malignancy. Two cases will be presented, followed by specific questions that will be addressed in the subsequent discussion.
  • The ACS 2011, show an estimated 21,990 cases of ovarian cancer in the United States. Ovarian cancer is the ninth most common invasive cancer among women and the second most common gynecologic cancer in the United States. There are15,460 expected deaths attributed to ovarian cancer. These data reflect the fact that there is still no adequate early diagnostic test for ovarian cancer.
  • FIGO, International Federation of Gynecology and Obstetrics. The International Federation of Gynecology and Obstetrics staging system determines how to treat patients with the disease upfront. We will focus on stage III and IV disease, which accounts for 75% to 80% of all cases.
  • CR, complete response; PFS, progression-free survival; yr, year. This slide shows findings from the GOG database, which indicate what this approach will achieve. The second row and the last row on this slide are the 2 important rows. The second row shows that 95% of patients with small-volume disease and 50% of patients with large-volume disease will end their initial 6 cycles of paclitaxel/carboplatin with no clinical evidence of disease. They will be in a clinical complete remission. The combined data of those 2 columns results in an overall clinical complete remission rate of 75%. At 10 years, approximately 30% to 40% of patients with small-volume disease will be alive, and about 15% to 20% of patients with large-volume disease will be alive.
  • yr, year. A review of progress over a period of 3 decades from 1980 to the present shows that there is step-wise progress in 10-year overall survival (OS) for patients with large-volume disease from 0% to 10% and finally to 20%. For patients with small-volume disease, the progress increases from 7% to 20% and finally to 30% to 40%. This pattern reflects the addition of the platinum compounds first followed by the taxanes for frontline therapy for ovarian cancer.
  • Initial therapy of advanced ovarian cancer consists of debulking surgery followed by Platinum-taxane based chemotherapy
  • AGO, Arbeitsgemeinschaft Gynaekologische Onkologie ; EORTC, European Organisation for Research and Treatment of Cancer; GOG, Gynecologic Oncology Group; NCIC, National Cancer Institute of Canada. Systemic therapy is given based on 4 large studies conducted between 1993 and 2003. The first 2 studies compared cyclophosphamide/cisplatin with paclitaxel/cisplatin and showed that paclitaxel/cisplatin was superior. The second 2 studies compared paclitaxel/cisplatin with paclitaxel/carboplatin and showed equivalency or, in 1 case, borderline superiority for paclitaxel/carboplatin.
  • Three phase 3 randomized trials conducted by the Gynecologic Oncology Group have revealed improved progression-free and overall survival associated with the intraperitoneal administration of cisplatin (plus intraperitoneal paclitaxel in GOG 172) compared to intravenous administration of the agent
  • Intraperitoneal chemotherapy associated with increased toxicity compared to intravenous treatment.
  • 2008
  • Stage 3 optimal (n=434) 0.618 [0.466-0.820] Stage 3 suboptimal (n=496) 0.763 [0.620-0.939] Stage 4 (n=318) 0.698 [0.536-0.908] PS 0 (n=616) 0.710 [0.575-0.877] PS 1 or 2 (n=632) 0.690 [0.570-0.835] Age <60 (n=629) 0.680 [0.551-0.834] Age 60–69 (n=409) 0.763 [0.602-0.968] Age >=70 (n=210) 0.678 [0.480-0.957]
  • Slide summarizes the treatment paradigms in recurrent ovarian cancer. Treatment decisions are dependent upon whether the patient is considered platinum / refractory resistant or platinum sensitive In patents who are platinum resistant / refractory subsequent therapy uses a non-platinum agent For patients who are platinum-sensitive, retreatment with a platinum (either alone or as part of a combination) is the preferred option
  • 10
  • Seven drugs are approved by the US Food and Drug Administration (FDA) for treating epithelial ovarian cancer. This slide shows their dates of FDA approval.
  • Carbo/gem from AGO trial (identical dose and schedule), allowed up to 10 cycles in responding pts. Bev continued until progression in contrast to GOG-0218 and ICON7. All pts had measurable disease as defined by RECIST (older criteria). Stratification by cytoreductive surgery was probably not necessary as all pts had measurable disease – driven by thoughts that treatment paradigm was changing in US
  • Obs PATNUM AEPT AESOC AESICAT 4567 29223 INTESTINAL PERFORATION GASTROINTESTINAL DISORDERS Gastrointestinal Perforations 7314 29624 GASTRIC ULCER PERFORATION GASTROINTESTINAL DISORDERS Gastrointestinal Perforations Obs AEODT AERDT TXFDT TXLDT AEEMER 4567 21JUN2010 06JUL2010 19NOV2007 14APR2010 NO 7314 06APR2010 15APR2010 02JAN2008 31DEC2008 NO
  • Randomization stratification factors included: Time to disease progression on penultimate platinum therapy (>6 months to 12 months and >12 months) Objective response to last platinum therapy prior to enrolment (CR or PR) Ethnic descent (Jewish or non-Jewish)
  • Global interaction test showed no evidence of inconsistency across the subgroups ( P =0.282) Subgroups with <20 events were not statistically analysed (BRCA negative, Jewish descent)
  • The overarching concept that underpins personalized medicine is that information about a patient's protein, gene or metabolite profile could be used to tailor medical care to that individual's needs. A key attribute of personalized medicine is the development of so-called companion diagnostics, whereby specific molecular assays that measure levels of proteins or genes or specific mutations are used to stratify disease status, select from among different medications and tailor dosages, provide a specific therapy for an individual's condition, or initiate a preventative measure that is particularly suited to that patient at the time of administration. THE RIGHT MEDICINE FOR THE RIGHT PERSON AT THE RIGHT TIME The Cancer Genome Atlas Pilot Project cancergenome.nih.gov
  • Saracatinib (AZD0530) is a highly selective inhibitor of src and is being evaluated in phase 2 studies and in randomized trials.
  • Transforming Treatment in Ovarian Cancer

    1. 1. Your Input Is Very Important! Sign-In Sheets: – Your attendance counts – Please sign-in Chair’s Practice Patterns Research – Research data identifying common practices – Understanding knowledge gaps and training needs
    2. 2. DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhancepatient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. DISCLOSURE OF UNLABELED USEThis educational activity may contain discussion of published and/or investigational uses ofagents that are not indicated by the FDA. University of California, Irvine School of Medicine(UCI-SOM) and Institute for Medical Education & Research (IMER), do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of University of California, Irvine School of Medicine (UCI- SOM) and IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
    3. 3. Disclosure of Conflicts of Interest Robert F. Ozols, MDReported a financial interest/relationship or affiliation inthe form of: Consultant, AstraZeneca PharmaceuticalsLP, Johnson & Johnson Pharmaceutical Research &Development, LLC.
    4. 4. Learning Objectives L Upon completion of this activity, participants should be better able to: Outline evidence-based clinical decisions incorporating currently approved standard chemotherapeutic and biologic treatments for ovarian cancer Describe emerging clinical trial information that may facilitate individual treatment planning for ovarian cancer Explain the rationale for and implications of the use of novel therapies in ovarian cancer Discuss effective designs of treatment plans based upon individualized patient characteristics and other relevant clinical factors Identify ways to counsel patients on the availability of clinical trial participation when warranted
    5. 5. Activity Agenda Activity Overview (5 mins) Current Treatments in Ovarian Cancer (25 mins) – Case study 1: Integrating personalized approaches into treatment planning and management for first-line therapy • Updates on currently approved therapeutics Emerging Treatments in Ovarian Cancer (25 mins) – Case study 2: Optimally managing recurrent ovarian cancer in relation to platinum sensitivity/resistant disease • Novel therapies – Rationale for targets, relevant data, and impact on therapeutic landscape • Evidence-based updates and results from data presented at 2011 oncology meetings Questions and Answers (5 mins)
    6. 6. Community and AcademicGround Rounds: Transforming Treatment in Ovarian Cancer
    7. 7. Newly Diagnosed Advanced Ovarian CancerCourtesy of Bradley J. Monk, MD, FACOG, FACS.
    8. 8. Ovarian Carcinoma: Incidence and Mortality  Incidence in US women – 21,990 cases in 2011 – Ninth most common cancer – Second most common gynecologic cancer – 1.4% lifetime risk of developing ovarian cancer  Mortality in US women – 15,460 deaths in 2011 – Fifth most common cause of cancer death – Fourth leading cause of cancer deaths in women aged 40–59 yrs – Most common cause of death due to gynecologic cancer – 1.0% lifetime risk of dying of ovarian cancerUS = United States.ACS, 2011.
    9. 9. Stage Distribution and 5-yr Relative Survival by Stage at Diagnosis (2001–2007, all races)LNs = lymph nodes.Howlader et al, 2011.
    10. 10. Results of Treatment: Advanced Disease Parameter Small Volume Large Volume Response (%) 95 75 Clinical CR (%) 95 50 Pathologic CR (%) 50 25 PFS (mos) 25 18 Survival (mos) 50 36 10-yr Survival (%) 30–40 15–20CR = complete response; PFS = progression-free survival.Gynecologic Oncology Group Database (courtesy of J. Tate Thigpen, MD).
    11. 11. Results of Treatment: Advanced Disease (cont.) Parameter (%) Small Volume Large Volume 1980: 10-yr survival 7 0 1990: 10-yr survival 20 10 2008: 10-yr survival 30–40 15–20Gynecologic Oncology Group Database (courtesy of J. Tate Thigpen, MD).
    12. 12. First-Line Therapy Global Standard Treatment Surgery With Maximum Cytoreduction Effort IV Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) x 6IV = intravenous.Pfisterer & Ledermann, 2006.Courtesy of Bradley J. Monk, MD, FACOG, FACS.
    13. 13. Basis for Current Standard: Systemic Therapy  Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin – GOG Protocol 111 – EORTC-NCIC OV 10  Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy – AGO Trial – GOG Protocol 158GOG = Gynecologic Oncology Group; EORTC = European Organisation for Research and Treatment of Cancer;NCIC = National Cancer Institute of Canada; AGO = Arbeitsgemeinschaft Gynäkologische Onkologie.Ozols, 2008; Ozols et al, 2003; McGuire et al, 1996; Piccart et al, 2000; Du Bois et al, 2004.
    14. 14. Case Study 1Integrating Personalized Approaches Into Treatment Planning and Management for First-Line Therapy
    15. 15. Case Study 1 A 65-yr-old woman with diet controlled diabetes and a past history (18 mos ago) of an uncomplicated myocardial infarction presents to her PCP with a 1-mos history of increasing abdominal bloating and pain  Work-up reveals a 10-cm pelvic mass and extensive intra-abdominal ovarian cancerPCP = primary care physician.
    16. 16. Based on Existing Evidence-Based Data, What Options Might Be Considered at This Point? 1) Surgery + “standard” q3wk carboplatin + paclitaxel 2) Surgery + “standard” q3wk carboplatin + wkly paclitaxel 3) Neoadjuvant chemotherapy followed by surgery 4) Surgery + IP chemotherapy 5) Surgery + “standard” carboplatin + paclitaxel + bevacizumabIP = intraperitoneal.
    17. 17. JGOG: Dose-Dense Wkly Paclitaxel  EOC or PP Pac 180 mg/m2  Stage II–IV I x 6–9 Carb AUC = 6  No prior therapy  Stratified: Residual disease, stage, and histology  Primary end point: PFS Carb AUC = 6  Secondary end point: OS II Pac 80 mg/m2/wk x 3 x 6–9  Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy  Improved PFS with dose-dense wkly paclitaxel Accrual: 637 patients (ITT)EOC = epithelial ovarian cancer; PP = primary peritoneal cancer; OS = overall survival;JGOG = Japanese Gynecologic Oncology Group; ITT = intent-to-treat; AUC = area under curve.Isonishi et al, 2008.
    18. 18. JGOG: Dose-Dense Wkly Paclitaxel (cont.)Isonishi et al, 2008.
    19. 19. Justification for Neoadjuvant Chemotherapy 1. Extensive intra-abdominal ovarian cancer preventing, or increasing the risk for an unsuccessful “optimal” cytoreduction 2. Elderly patient or woman with significant comorbidity (eg, history of CHF) substantially increasing the risk associated with major abdominal surgeryCHF = congestive heart failure.Weinberg et al, 2010.
    20. 20. NACT + IDS Vs. PDS Ovarian, Tubal, or Peritoneal Cancer FIGO Stage IIIC/IV (N = 670) Randomization PDS NACT 3 x platinum-based CT 3 x platinum-based CT IDS IDS if no PD (not obligatory) ≥ 3 x platinum-based CT ≥ 3 x platinum-based CT Primary End Point: OS Secondary End Points: PFS, QOL, AEsNACT = neoadjuvant chemotherapy; IDS = interval debulking surgery; PDS = primary debulking surgery;FIGO = International Federation of Gynaecology and Obstetrics; CT = chemotherapy; PD = progressivedisease; QOL = quality of life; AEs = adverse events.Vergote et al, 2008, 2010.
    21. 21. NACT + IDS Vs. PDS (cont.) ITT AnalysisHR = hazard ratio.Vergote et al, 2010.
    22. 22. NACT + IDS Vs. PDS (cont.) Surgical Characteristics PDS NACT  IDS (n = 329) (n = 339) Postoperative mortality 2.5% 0.7% (< 28 days) Postoperative fever grade 3/4 8.1% 1.7% Fistula (bowel/GU) 1.2% / 0.3% 0.3% / 0.6% Operative time (mins) 180 180 RBC transfusion 51% 53% Hemorhage grade 3/4 7.4% 4.1% Venous grade 3/4 2.6% 0%GU = genitourinary; RBC = red blood cell.Vergote et al, 2008, 2010.
    23. 23. Primary Therapy: IP Median PFS HR Median OS HR (mos) (mos) IV IP IV IP 0.76 GOG 104 — — — 41 49 (p = .02) 0.78 0.81 GOG 114 22 28 (p = .01) 52 63 (p = .05) 0.80 0.75 GOG 172 18.3 23.8 (p = .05) 50 66 (p = .03)Alberts et al, 1996; Markman et al, 2001; Armstrong et al, 2006.
    24. 24. GOG 172: Ovarian (Optimal III)  EOC  Optimal stage III  No prior therapy  Elective second-look Pac 135 mg/m2 (24 hrs) I Cis 75 mg/m2 Day 2 Pac 135 mg/m2 (24 hrs) IV Day 1 II Cis 100 mg/m2 IP Day 2 Pac 60 mg/m2 IP Day 8 Open: 23-March-98 Closed: 29-January-01 Accrual: 415 patients (evaluable)Armstrong et al, 2006.
    25. 25. GOG Protocol 172 RR of death = 0.75 (95% CI: 0.58, 0.97) p = .03 By Treatment Group 1.0 0.9 IP median OS = 65.6 mos 0.8 0.7 0.6 IV median OS = 49.7 mos Proportion Surviving 0.5 0.4 0.3 0.2 Rx Group Lost to Alive Dead Total 0.1 Rx Group Follow-up Alive Dead Total IV IV 5 78 127 93 210 117 210 0.0 IP IP 11 93 101 117 205 88 205 0 12 24 36 48 60 Months on StudyRR = response rate; CI = confidence interval.Adapted from Armstrong et al, 2006.
    26. 26. GOG Protocol 172: Toxicity IV IP Grade (N = 210; %) (N = 201; %) 3/4 Leukopeniaa 64 76 3/4 Platelet 4 12 3/4 GIa 24 46 3/4 Renala 2 7 3/4 Neurologic eventa 9 19 3/4 Fatiguea 4 18 3/4 Infectiona 6 16 3/4 Metabolica 7 27 3/4 Paina 1 11 No difference in QOL at 12 mosp ≤ .05aGI = gastrointestinal.Armstrong et al, 2006.
    27. 27. GOG 218: Schema Arm C AUC 6 P 175 mg/m2 I Front-Line (CP) EOC, PP, or FT Placebo • Stage III optimal (macroscopic) 1:1:1 C AUC 6 • Stage III suboptimal P 175 mg/m2 II • Stage IV (CP + Bev) Bev 15 mg/kg Placebo N = 1,800 (planned) C AUC 6 Stratification variables – GOG PS P 175 mg/m2 III – Stage/debulking status (CP + Bev  Bev) Bev 15 mg/kg Cytotoxic Maintenance 15 mosFT = fallopian tube; PS = performance status; (6 cycles) (16 cycles)C = carboplatin; P = paclitaxel.Burger et al, 2010.
    28. 28. GOG 218: Patient Disposition Arm I Arm II Arm III CP CP + Bev CP + Bev Bev Characteristic (n = 625) (n = 625) (n = 623) Median (range) number Bev/placebo cycles 11 (0–22a) 12 (0–22a) 14 (0–21) On treatment at time of analysis, n (%) 86 (14) 82 (13) 117 (19) Completed regimen, n (%) 100 (16) 104 (17) 148 (24) Discontinued study treatment, n (%) Disease progression 299 (48) 264 (42) 164 (26) AEs 69 (11) 86 (14) 94 (15) Cycles 1–6 57 (9) 73 (12) 59 (9) Cycle ≥ 7 12 (2) 13 (2) 35 (6) Deaths 8 (1) 7 (1) 13 (2) Patient refusal 44 (7) 55 (9) 50 (8) Other 19 (3) 27 (4) 37 (6)  Percentages may not total 100% due to rounding or categorizationOne patient in each group received Bev/placebo in Cycle 1.aBurger et al, 2010.
    29. 29. GOG 218: Select AEs Onset Between Cycle 2 and 30 Days After Date of Last Treatment Arm I Arm II Arm III CP CP + Bev CP + Bev  Bev AE (grade when limited), n (%) (n = 601) (n = 607) (n = 608) GI eventsa (grade ≥ 2) 7 (1.2) 17 (2.8) 16 (2.6) Hypertension (grade ≥ 2) 43 (7.2)b 100 (16.5)b 139 (22.9)b Proteinuria (grade ≥ 3) 4 (0.7) 4 (0.7) 10 (1.6) Pain (grade ≥ 2) 250 (41.7) 252 (41.5) 286 (47.1) Neutropenia (grade ≥ 4) 347 (57.7) 384 (63.3) 385 (63.3) Febrile neutropenia 21 (3.5) 30 (4.9) 26 (4.3) Venous thromboembolic event 35 (5.8) 32 (5.3) 41 (6.7) Arterial thromboembolic event 5 (0.8) 4 (0.7) 4 (0.7) CNS bleeding 0 0 2 (0.3) Non-CNS bleeding (grade ≥ 3) 5 (0.8) 8 (1.3) 13 (2.1) RPLS 0 1 (0.2) 1 (0.2)Perforation/fistula/necrosis/leak.ap < .05bHTN = hypertension; CNS = central nervous system; RPLS = reversible posterior leukoencephalopathy syndrome.Burger et al, 2010.
    30. 30. GOG 218: Select AEs (cont.) Treatment Phase Arm I Arm II Arm III Select AEs (n) CP CP + Bev CP + Bev → Bev (grade when limited) Patients (n) (n = 601) (n = 483) (n = 607) (n = 457) (n = 608) (n = 464) Cycles (n) 2,906 4,059 2,911 4,204 2,891 4,677 Cytotoxic Maintenance Cytotoxic Maintenance Cytotoxic Maintenance Treatment phasea (Cycles 2–6) (Cycles ≥ 7) (Cycles 2–6) (Cycles ≥ 7) (Cycles 2–6) (Cycles ≥ 7) GI eventsb (grade ≥ 2) 6 1 16 1 15 1 HTN (grade ≥ 3) 3 7 24 12 25 38 Proteinuria (grade ≥ 3) 2 2 4 0 0 10 Pain (grade ≥ 3) 28 23 42 31 46 37 Neutropenia (grade ≥ 4) 345 2 382 2 385 0 Febrile neutropenia 21 0 30 0 26 0 Venous thromboembolic event 26 9 27 5 27 14 Arterial thromboembolic event 4 1 1 3 3 1 CNS bleeding 0 0 0 0 0 2 Non-CNS bleeding (grade ≥ 3) 3 2 8 0 10 3 RPLS 0 0 1 0 0 1Onset within 30 days of last treatment.aPerforation/fistula/necrosis/leak.bBurger et al, 2010.
    31. 31. GOG 218: Investigator-Assessed PFS Arm I Arm II Arm III CP CP + Bev CP + Bev  Bev 1.0 (n = 625) (n = 625) (n = 623) 423 418 360 0.9 Patients with event (n; %) (67.7) (66.9) (57.8) Median PFS (mos) 10.3 11.2 14.1 Proportion PFS (%) 0.8 0.908 0.717 Stratified analysis HR (95% CI) (0.759–1.040) (0.625–0.824) 0.7 One-sided p value (log rank) .080a < .0001a 0.6 0.5 0.4 0.3 CP (Arm I) + Bev (Arm II) 0.2 + Bev  Bev maintenance (Arm III) 0.1 0 12 24 36 0 Time (Mos Since Randomization)a p = .0116Burger et al, 2010.
    32. 32. GOG 218: Subgroup Analyses of PFS CP + Bev  Bev (Arm III) Vs. CP (Arm I) Experimental Arm (CP + Bev  Bev; Control Arm HR Arm III) Better (CP; Arm I) Better Stage III optimal (n = 434) 0.618 Stage III suboptimal (n = 496) 0.763 Stage IV (n = 318) 0.698 PS 0 (n = 616) 0.710 PS 1/2 (n = 632) 0.690 Age < 60 yrs (n = 629) 0.680 Age 60–69 yrs (n = 409) 0.763 Age ≥ 70 yrs (n = 210) 0.678 0.33 0.5 0.67 1.0 1.5 2.0 3.0 Treatment HRBurger et al, 2010.
    33. 33. GOG 218: OS Analysis At Time of Final PFS Analysis (January 2010) 1.0 0.9 0.8 Proportion Alive (%) 0.7 0.6 Arm I Arm II Arm III CP CP + Bev CP + Bev  Bev 0.5 (n = 625) (n = 625) (n = 623) Patients with 156 150 138 0.4 events (n; %) (25.0) (24.0) (22.2) 0.3 Median (mos) 39.3 38.7 39.7 0.2 HRa 1.036 0.915 (95% CI) (0.827–1.297) (0.727–1.152) 0.1 One-sided p value .361 .252 0 0 12 24 36 48 Time (Mos Since Randomization) No. at risk 625/625/623 442/432/437 173/162/171 46/39/40Stratified analysis.aBurger et al, 2010.
    34. 34. ICON7: Study Design C AUC 6a Primary end point: Front-Line A P 175 mg/m2 PFS m EOC, PP, or FT Ar Secondary end • Stage I/IIA (grade 3) • Stage IIB/C points: OS, RR, • Stage III QOL, safety, • Stage IV Ar cost-effectiveness, N = 1,520 (planned) m C AUC 6a translational B P 175 mg/m2 No IRC present  Stratification variables Bev 7.5 mg/kg – Stage/surgery 12 mos – Time since surgery – GCIG groupMight vary based on GCIG group.a GCIG = Gynecologic Cancer Intergroup; IRC = independent review committee. Kristensen et al, 2011.
    35. 35. Key Differences Between GOG 218 and ICON7 Trial GOG 218 ICON7  Double-blinded, placebo-controlled  Open-label Setting/  3-arm study  2-arm study Design  Bev for 15 mos  Bev for 12 mos  Bev dose: 5 mg/kg/wk  Bev dose: 2.5 mg/kg/wk  Stage III (suboptimal)  Stage I or IIA (grade 3/clear cell Patient  Stage III (optimal, visual/palpable) histology) Population  Stage IV  Stages IIB–IV (all)  Defined final OS analysis (end Additional  OS analysis (formal testing at time of PFS) 2012) End Point  IRC  No IRCBurger et al, 2010; Kristensen et al, 2011.
    36. 36. ICON7 Schema Carboplatin AUC 5/6 Stratification Variables 1:1 Paclitaxel 175 mg/m2  Stage and extent of debulking:  I–III debulked ≤ 1 cm R  Stage I–III debulked > 1 cm Carboplatin AUC 5/6  Stage IV and inoperable stage III N = 1,528a  Timing of intended treatment start Paclitaxel 175 mg/m2 ≤ 4 vs. > 4 wks after surgery  GCIG group BEV 7.5 mg/kg q3wks 18 cycles  Academic-led, industry-supported trial to investigate use of Bev and to support licensingDecember 2006 to February 2009.aKristensen et al, 2011.
    37. 37. ICON7 PFS: Updated 17.4 19.8 Control ResearchKristensen et al, 2011.
    38. 38. PFS: “High Risk” Subgroup (Ad Hoc Analysis)High Risk: Stage IIIC Suboptimal/Stage IV Control Research 1.00 (n = 234) (n = 231) Proportion Alive Without Progression (%) Events, n (%) 173 (74) 158 (68) Median (mos) 10.5 15.9 0.75 Log-rank test p < .001 HR (95% CI) 0.68 (0.55–0.85) Restricted mean 13.3 16.5 0.50 0.25 Control Research 10.5 15.9 0 Time 0 3 6 9 12 15 18 21 24 27 30 (mos) Number At Risk Control 234 205 98 36 14 2 Research 231 213 159 56 10 1Kristensen et al, 2011.
    39. 39. Interim Analysis of Overall SurvivalKristensen et al, 2011.
    40. 40. Case Study 2Optimally Managing Recurrent Ovarian Cancer
    41. 41. Case Study 2 A 54-yr-old woman with ovarian cancer attains a clinically-defined CR to primary carboplatin/paclitaxel chemotherapy 10 mos following the completion of chemotherapy abdominal pain returns and a repeat CT scan reveals the presence of diffuse small IP masses What are the current antineoplastic drug options and the direction of future research in this clinical setting?
    42. 42. The Traditional Treatment Paradigm Recurrence After First-Line Chemotherapy Platinum Platinum Refractory/Resistant Sensitive < 6 Mos > 6 Mos Non-Platinum Chemotherapy Single Agent DoubletUshijima, 2010.
    43. 43. Recurrent Ovarian Cancer: Definition of Disease Sensitivity P Time to Recurrence (mos) R E V 0 3 6 12 18 24 I O U S Refractory T R E A Resistant T M Sensitive E Our Patient N T Highly SensitiveUshijima, 2010.
    44. 44. Major Trials in Recurrent Ovarian Cancer  Paclitaxel vs. topotecan  Topotecan vs. PLD  Platinum vs. platinum + paclitaxel  Carboplatin vs. carboplatin + gemcitabine  Carboplatin + paclitaxel vs. carboplatin + PLD  PLD vs. PLD + trabectedinPLD = pegylated liposomal doxorubicin.ten Bokkel Huinink et al, 1997, 2004; Gordon et al, 2004; Parmar et al, 2003;Pfisterer et al, 2006; Pujade-Lauraine et al, 2010; Monk et al, 2010.
    45. 45. 19 64 Me lp ha lan 19 74 Do xor ubNCCN, 2011; Shah et al, 2009. icin 19 Cis p 78 lati n 1 98 Ca 9 rb op lati n 199 0 Alt ret am ine 19 9 2 Pa clit axe l 19 9 6 To po tec 1 99 an 9 PL D (ac 2 Ovarian Cancer cel era 00 t 5 ed Lip ) oso mal d 20 FDA-Approved Drugs in 0 oxo 6 Ge rub (wi mcita icin th 2 car bin (fu 00 bo e ll) 9 Tra pla (wi bect tin) th ed PL in; D) EU on ly
    46. 46. Recurrence Regimens NCCN Preferred AgentsPlatinum-based combination therapy should be considered for platinum sensitive recurrences.aNCCN = National Comprehensive Cancer Network.NCCN, 2011.
    47. 47. Phase III Study (Doublets): CALYPSO R Paclitaxel 175 mg/m2 A Carboplatin AUC 5 Ovarian Cancer N q3wks – First relapse – Platinum-sensitive D O Relapse M I PLD 30 mg/m2 Z Carboplatin AUC 5 E q4wks Opened: 4/2005 Closed: 10/2007 N = 976Pujade-Lauraine et al, 2010.
    48. 48. PFS: ITT CD CP Median PFS (mos) 11.3 9.4 HR (95% CI) 0.82 (0.72, 0.94) Log-rank p (superiority) .005 p (non-inferiority) < .001CD = carboplatin-PLD.Pujade-Lauraine et al, 2010.
    49. 49. Intermediate Sensitive: 6–12 mos CD CP Median PFS (mos) 9.4 8.8 HR (95% CI) 0.73 (0.58, 0.90) Log-rank p value (superiority) .004 p value (non-inferiority) < .001 Months from RandomizationPujade-Lauraine et al, 2010.
    50. 50. PFS: Highly Platinum-Sensitive (PFI > 24 mos) C-PLD C-P HR p PFS 12.0 12.3 1.05 .73 mos mos (0.79–1.40) RR 42% 38% .46PFI = progression-free interval.Mahner et al, 2011.
    51. 51. CALPYSO: OS AnalysisMarth et al, 2011.
    52. 52. Bevacizumab: The First ActiveTargeted Agent in Ovarian Cancer Case report of single-agent activity – Monk et al, 2005 Phase II of single-agent activity – Burger et al, 2007 Phase II of combination therapy – Garcia et al, 2008 Randomized phase III trial (GOG 218) – Burger et al, 2010
    53. 53. OCEANS: Study Schema Platinum-Sensitive ROCa CG + Carboplatin AUC 4 PLA Gemcitabine 1,000 mg/m2  Measurable disease  ECOG 0/1 Days 1, 8  No prior chemotherapy for ROC PLA q3wks Until Progression  No prior BEV (N = 484) Carbopaltin AUC 4 Gemcitabine 1,000 mg/m2 CG + Days 1, 8 Stratification Variables BEV BEV 15 mg/kg q3wks Until Progression Platinum-free interval (6–12 vs. > 12 mos) CG for 6 (up to 10) cycles Cytoreductive surgery for recurrent disease (yes vs. no)EOC, PP, or FT cancer.aROC = recurrent ovarian cancer; ECOG = Eastern Cooperative Oncology Group.Aghajanian et al, 2011.
    54. 54. OCEANS: Patient Characteristics CG + PLA CG + BEV Characteristic (n = 242) (n = 242) Median age (yrs) 61 60 (range) (28−86) (38–87) Age ≥ 65 yrs (%) 38 35 Race (%) White 92 90 Other 8 10 ECOG PS 0 (%) 76 75 Histologic subtype (%) Serous 84 78 Mucinous/clear cell 3 5 Other 14 17 Platinum-free interval (%) 6–12 mos 42 41 > 12 mos 58 59 Cytoreductive surgery for recurrent disease (%) 10 12Aghajanian et al, 2011.
    55. 55. OCEANS: Primary Analysis of PFS CG + PLA CG + BEV (n = 242) (n = 242) Events, n (%) 187 (77) 151 (62) 1.0 Median PFS (mos) 8.4 12.4 (95% CI) (8.3–9.7) (11.4–12.7) Proportion PFS (%) 0.8 Stratified analysis 0.484 HR (95% CI) (0.388–0.605) Log-rank p value < .0001 0.6 0.4 ORR GC: 57.4% 0.2 GC+B: 78.5% p < .0001 0 0 6 12 18 24 30 Number At Risk Time (mos) CG + PL 242 177 45 11 3 0 CG + BV 242 203 92 33 11 0Aghajanian et al, 2011.
    56. 56. OCEANS: PFS Subgroup Analyses Median PFS (mos) CG + No. of CG + PLA CG + BEV BEV CG + PLA Baseline risk factor patients (n = 242) (n = 242) HR (95% CI) better better All patients 0.49 (0.40– 484 8.4 12.4 0.61) Platinum-free interval 0.41 (0.29– 6–12 202 8.0 11.9 (mos) 0.58) 0.55 (0.41– > 12 282 9.7 12.4 0.73) Cytoreductive surgery 0.50 (0.24– Yes 54 7.5 16.7 for recurrent disease 1.01) 0.49 (0.39– No 430 8.4 12.3 0.62) Age (yrs) 0.47 (0.36– < 65 306 8.5 12.5 0.62) 0.50 (0.34– ≥ 65 178 8.4 12.3 0.72) Baseline ECOG PS 0.47 (0.36– 0 367 8.6 12.5 0.60) 0.61 (0.39– 1 116 8.3 10.6 0.95) 0.2 0.5 1 2 5 HRAghajanian et al, 2011.
    57. 57. OCEANS: Interim OS 1.0 0.8 Proportion Alive (%) CG + PLA CG + BEV 0.6 (n = 242) (n = 242) Events, n (%) 78 (32) 63 (26) 0.4 Median OS (mos) 29.9 35.5 (95% CI) (26.4–NE) (30.0–NE) Stratified analysis 0.751 0.2 HR (95% CI) (0.537–1.052) Log-rank p value .094a 0 0 6 12 18 24 30 36 42 Time (mos) Number At Risk CG + PL 242 235 195 131 77 26 8 0 CG + BV 242 238 200 146 82 42 8 0p value does not cross pre-specified boundary of .001aNE = not estimable.Aghajanian et al, 2011.
    58. 58. OCEANS: AEs of Special Interest CG + PLA CG + BEV Patients (%) (n = 233) (n = 247) ATE, all grades 1 3 VTE, grade ≥ 3 3 4 CNS bleeding, all grades <1 1 Non-CNS bleeding, grades ≥ 3 1 6 CHF, grades ≥ 3 1 1 Neutropenia, grade ≥ 3 56 58 Febrile neutropenia, grade ≥ 3 2 2 HTN, grade ≥ 3 <1 17 Fistula/abscess, all grades <1 2 GI perforation, all grades 0 0a Proteinuria, grade ≥ 3 1 9 RPLS, all grade 0 1 Wound-healing complication, grades ≥ 3 0 1Two GI perforations occurred 69 days after last BEV dose.aATE = arterial thromboembolic event; VTE = venous thromboembolic event.Aghajanian et al, 2011.
    59. 59. OCEANS: Preliminary Conclusions  BEV + carboplatin + gemcitabine followed by BEV until progression provides a clinically meaningful benefit over chemotherapy alone in ROC – Improved PFS: HR 0.484 (p < .0001); median 8.4 → 12.4 mos – Improved ORR and duration of response – OS data not yet mature  Safety data consistent with BEV profile – No GI perforations and no new safety signalAghajanian et al, 2011.
    60. 60. Novel Therapies and Future Directions
    61. 61. PARP Inhibitors Suggested Mechanism of Action Chemotherapy inflicts DNA damage via adducts and DNA cross-linking PARP1 PARP Inhibitor Replication PARP1 fork collapse Inhibition of Double strand PARP1 PARP1 DNA break PARP1 Upregulation Disables DNA Base-excision repair of base-excision DNA damage repair BRCA1 BRCA2 CELL SURVIVAL CELL DEATHPARP = poly (ADP-ribose) polymerase; DNA = deoxyribonucleic acid.O’Shaughnessy et al, 2009.
    62. 62. Phase II Study of Olaparib of Patients With BRCA1 or BRCA2 Mutation  Two dosages tested in sequential cohorts of patients with recurrent, measurable disease  Primary end point: RR 400 mg BID 100 mg BID n = 33 n = 24 ORR = 33% ORR = 13%  AEs: Nausea, fatigue, anemiaBRCA = breast cancer gene; BID = twice daily; ORR = overall response rate.Audeh et al, 2010.
    63. 63. Study 19: Aim and Design  To assess the efficacy of olaparib (OLA) as a maintenance treatment in patients with platinum-sensitive high grade serous ovarian cancer  Randomized, double-blind, placebo-controlled phase II study  Multinational study; 82 sites in 16 countries Patient Eligibility  Platinum-sensitive high grade serous ovarian cancer OLA 400 mg po BID  ≥ 2 previous platinum regimens  Last chemotherapy: Platinum-based with a Treatment maintained response Randomized 1:1 until PD  Stable CA125 at trial entry  Randomization stratification factors – Time to PD on penultimate platinum therapy PLA po BID – Objective response to last platinum therapy – Ethnic descentpo = oral; PD = progressive disease.Ledermann et al, 2011.
    64. 64. Patient Characteristics Olaparib 400 mg bid Placebo (n = 136) (n = 129) Median age, yrs (range) 58 (21–89) 59 (33–84) Ethnicity, n (%) Jewish descent 20 (15) 17 (13) ECOG status, n 0 / 1 / 2 / unknown 110 / 23 / 1 / 2 95 / 30 / 2 / 2 BRCA mutation status, n (%)a BRCA1 25 (18) 20 (16) BRCA2 6 (4) 7 (5) BRCA1 and BRCA2 0 1 (1) Known negative 18 (13) 20 (16) Unknown 87 (64) 81 (63)a BRCA mutation status was not a requirement.Ledermann et al, 2011.
    65. 65. Progression-Free Survival Olaparib Placebo 1.0 No. of events: Total patients (%) 60:136 (44.1) 93:129 (72.1) 0.9 Median PFS (mos) 8.4 4.8 Proportion of PFS (%) 0.8 0.7 HR 0.35 (95% CI, 0.25–0.49) 0.6 p < .00001 0.5 0.4 0.3 0.2 Randomized Treatment 0.1 Placebo Olaparib 400 mg bid 0 0 3 6 9 12 15 18 Time from randomization (mos) At risk (n) Olaparib 136 104 51 23 6 0 0 Placebo 129 72 23 7 1 0 0Ledermann et al, 2011.
    66. 66. Preplanned Subgroup Analysis of PFS Overall BRCA mutation BRCA status known BRCA unknown Age < 50 Age ≤ 50 to < 65 Age ≥ 65 Race, white Non-Jewish descent CR at baseline PR at baseline TTP penultimate platinum regimen 6–12 mos TTP penultimate platinum regimen > 12 mos 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 HR (OLA: PLA) and 95% CI Favors OLA Global interaction test showed no evidence of inconsistency across the subgroups (p = .282) Size of circle is proportional to number of events; grey band represents 95% CI in overall populationPR = partial response; TTP = time to progression.Ledermann et al, 2011.
    67. 67. Confluence of Multiple Advances PharmacogenomicsBioinformatics Translational Genomics Personalized Medicine Molecular Companion Biology Diagnostics Pharmacometabonomics
    68. 68. Future Strategies in Ovarian Cancer Angiogenesis VEGF/VEGFR EGFR mTOR/Akt/PI3K ER FR PARP Targets CA125 Src PKC HSP90 PDGFR Repackaging Traditional Agents MoAbVEGF/R = vascular endothelial growth factor/receptor; EGFR = epidermal growth factor receptor; ER = estrogen receptor;PDGFR = platelet-derived growth factor receptor; MoAb = monoclonal antibody; mTOR = mammalian target of rapamycin;PI3K = phosphatidylinositol 3-kinase; FR = folate receptor; PKC = protein kinase C; HSP90 = heat shock protein-90.Banerjee et al, 2009.
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