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Bradley J. Monk, MD, FACS, FACOG

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1 Advances in Treatment and Management of Ovarian Cancer: Emerging Concepts and Practical Guidance
Bradley J. Monk, MD, FACS, FACOG Professor, Division of Gynecologic Oncology Arizona Oncology (US Oncology Network) University of Arizona College of Medicine--Phoenix Creighton University School of Medicine at St Joseph’s Hospital Phoenix, Arizona

2 About These Slides Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients When using our slides, please retain the source attribution: These slides may not be published, posted online, or used in commercial presentations without permission. Please contact for details Slide credit: clinicaloptions.com Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3 Faculty Bradley J. Monk, MD, FACS, FACOG
Professor, Division of Gynecologic Oncology Arizona Oncology (US Oncology Network) University of Arizona College of Medicine--Phoenix Creighton University School of Medicine at St Joseph's Hospital Phoenix, Arizona Bradley J. Monk, MD, FACS, FACOG, has disclosed that he has received consulting fees from Advaxis, Amgen, AstraZeneca, Biodesix, Clovis, Gradalis, ImmunoGen, Insys, Mateon, Merck, Perthera, Pfizer, Precision Oncology, Roche/Genentech, and Tesaro; fees for non-CME/CE services from AstraZeneca, Clovis, Janssen/Johnson & Johnson, Roche/Genentech, and Tesaro; and funds for research support from Amgen, Array, Genentech, Janssen/Johnson & Johnson, Morphotek, Lilly, and Tesaro.

4 Initial Surgical Management of Ovarian Cancer

5 Newly Diagnosed Advanced Ovarian Cancer

6 Adequate Surgery Is Vital in Treating Ovarian Cancer
Maximal effort at primary cytoreduction Goal is R0 (complete resection = optimal) Imaging and perhaps laparoscopy to assess feasibility Decision requires gynecologic oncology input Role of lymphadenectomy controversial 3 cycles of neoadjuvant chemotherapy and interval debulking in unique circumstances Infirm and elderly unlikely to tolerate extensive surgery Carcinomatosis where R0 is unlikely Slide credit: clinicaloptions.com Wright AA, et al. J Clin Oncol. 2016;34:

7 LION (Lymphadenectomy In Ovarian Neoplasms): Study Design
A prospective, randomized phase III AGO study group led Gynecologic Cancer Intergroup trial (AGO OVAR OP3/ENGOT-ov31) All centers required to demonstrate surgical skill prior to participation; pts enrolled at least 1 day prior to surgery Primary endpoint: OS Secondary endpoints: PFS, QoL, number of resected LN Stratified by center, age, ECOG PS Pts with FIGO stage IIB-IV epithelial ovarian cancer, macroscopic complete resection, ECOG PS 0/1, and clinically/radiologically negative pelvic and para-aortic LN; no prior CT or LN dissection (N = 647) Lymphadenectomy (n = 323) No lymphadenectomy (n = 324) CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; LN, lymph node; PS, performance status; QoL, quality of life. Slide credit: clinicaloptions.com Harter P, et al. ASCO Abstract 5500.

8 LION: Characteristics of Surgery
Characteristic, n (%) LNE (n = 323) No LNE (n = 324) P Value Bilateral salpingo-oophorectomy* 319 (98.8) 320 (98.8) .99 Hysterectomy* 321 (99.4) 322 (99.4) Omentectomy .41 (Partial) peritonectomy Pelvis Paracolic Diaphragm 291 (90.1) 276 (85.5) 193 (59.8) 173 (53.6) 291 (89.8) 278 (85.8) 208 (64.2) 196 (60.5) GI tract resection/stoma 169 (52.3)/34 (10.5) 167 (51.5)/24 (7.4) .84/.17 Splenectomy 62 (19.2) 56 (17.3) .53 Porta hepatis/lesser omentum 61 (18.9) 69 (21.3) .44 Partial pancreatectomy 7 (2.1) Partial hepatectomy 27 (8.4) 28 (8.6) .90 Pleurectomy 20 (6.2) 24 (7.4) .54 Complete resection GI, gastrointestinal; LNE, lymphadenectomy Harter P, et al. ASCO Abstract 5500. *Includes procedures performed earlier.

9 LION: Intraoperative Outcomes
LNE (n = 323) No LNE (n = 324) Difference P Value Study procedure per randomization, n (%) 320 (99.1) 313 (96.6) Median total resected LN (IQR) Para-aortic Pelvic 57 (45-73) 22 (16-33) 35 (26-43) LN metastases, n (%) 180 (55.7) Median surgery duration, min (IQR) 340 ( ) 280 ( ) +1 hr < .001 Median blood loss, mL (IQR) 650 ( ) 500 ( ) +150 mL Transfusions, n (%) Massive (> 10 RBC/24 hrs) 205 (63.7) 7 (2.2) 181 (56.0) 2 (0.6) +8% .005 .09 Fresh-frozen plasma, n (%) 117 (36.3) 96 (29.7) +7% .07 Intermediate/intensive care unit, n (%) 250 (77.6) 223 (69.4) .01 IQR, interquartile range; LN, lymph node; LNE, lymphadenectomy; RBC, red blood cell. Slide credit: clinicaloptions.com Harter P, et al. ASCO Abstract 5500.

10 LION: Postoperative Outcomes
Outcome With Significant Difference Between Arms, n (%) LNE (n = 323) No LNE (n = 324) P Value Infections requiring antibiotics 83 (25.8) 60 (18.6) .03 Asymptomatic lymph cysts 14 (4.4) 1 (0.3) < .001 Symptomatic lymph cysts 10 (3.1) .001 Readmission 40 (12.4) 27 (8.3) .09 Relaparotomy for complications 21 (6.5) .01 60-day post-op mortality 3 (0.9) .049 Platinum/taxane chemotherapy 257 (79.6) 274 (84.6) LNE, lymphadenectomy. No statistically significant difference between arms in rates of fever, sepsis, thrombosis, pulmonary embolism, secondary wound healing, prolonged ileus, peripheral sensory/motor neurologic events, fistula Slide credit: clinicaloptions.com Harter P, et al. ASCO Abstract 5500.

11 LION: PFS and OS of All Pts
100 100 80 80 60 60 PFS (%) OS (%) 40 40 20 N = 647, 429 events Median PFS: 25.5 mos (95% Cl: ) N = 647, 274 events Median OS: 67.2 mos (95% Cl: ) 20 6 12 18 24 30 36 42 48 54 60 66 72 78 6 12 18 24 30 36 42 48 54 60 66 72 78 Mos Mos Pts at Risk, n Pts at Risk, n Pts with advanced ovarian cancer and complete resection have median PFS of 25.5 mos and median OS of 67.2 mos (5-yr OS rate: 55.9%) Slide credit: clinicaloptions.com Harter P, et al. ASCO Abstract 5500.

12 LION: PFS and OS (Primary Endpoint)
100 100 Events, n Median PFS, Mos LNE No LNE 80 80 60 60 PFS (%) OS (%) HR: ( ; P = .65) 40 40 20 Events Median OS, Mos LNE No LNE 20 LNE, lymphadenectomy. HR: (95% CI: ) 6 12 18 24 30 36 42 48 54 60 66 72 78 6 12 18 24 30 36 42 48 54 60 66 72 78 Mos Mos LNE No LNE LNE No LNE Slide credit: clinicaloptions.com Harter P, et al. ASCO Abstract 5500.

13 Systemic Treatment Options for Newly Diagnosed Advanced Epithelial Ovarian Cancer

14 What Is the Standard Systemic Tx for Newly Diagnosed Advanced Epithelial Ovarian Cancer?
Depends on many factors Fitness of the pt Histologic subtype Volume of disease (stage and ascites) Setting (neoadjuvant) Reimbursement and guidelines Tx, treatment.

15 What Is the Standard Systemic Tx for Newly Diagnosed Advanced Epithelial Ovarian Cancer?
For stage IV or large volume residual disease (suboptimal): carboplatin/paclitaxel Q3W + bevacizumab is preferred[1] Based on GOG 218,[2] ICON7[3] Ascites, angiogenesis phenotype (MVD/CD31 and tumor VEGF-A) predicts treatment benefit of bevacizumab[4,5] Reimbursement and cost effectiveness are challenges Alternative treatment is weekly chemotherapy Dose-dense paclitaxel in fittest pts (JGOG 3016: GOG 262)[6,7] Fractionated paclitaxel in infirm and weak pts (MITO-7)[8] Tx, treatment. 1. Ledermann JA, et al. Ann Oncol. 2013;24(suppl 6):vi24-vi Burger RA, et al N Engl J Med. 2011;365: Oza A, et al. Lancet Oncol. 2015;16: Ferriss JS, et al. Gynecol Oncol. 2015;139: Bais C, et al. J Natl Cancer Inst. 2017;109:djx Katsumata N, et al. Lancet Oncol. 2013;14: Chan JK, et al. N Engl J Med. 2016;374: Pignata S, et al Lancet Oncol. 2014;15: Slide credit: clinicaloptions.com

16 Angiogenesis as a Target: 9 Positive Phase III Ovarian Cancer Studies
Study Agent Setting PFS HR (95% CI) GOG 218[1] Bevacizumab Front line/maintenance 0.72 ( ) ICON7[2] 0.81 ( ) AGO-OVAR12[3] Nintedanib 0.84 ( ) AGO-OVAR16[4] Pazopanib Primary maintenance 0.77 ( ) AURELIA[5] Recurrence, platinum resistant, 1-2 priors 0.48 ( ) TRINOVA-1[6] Trebananib Recurrence, platinum resistant/sensitive, 1-3 priors 0.66 ( ) OCEANS[7] Recurrent, platinum sensitive, 1 prior 0.53 ( ) ICON6[8] Cediranib 0.57 ( ) GOG-213[9] 0.63 ( ) 1. Burger RA, et al. N Engl J Med. 2011;365: Perren TJ, et al. N Engl J Med. 2011;365: du Bois A, et al. Lancet Oncol. 2016;17: du Bois A, et al. ASCO LBA Pujade-Lauraine E, et al. J Clin Oncol. 2014;32: Monk BJ, et al. Lancet Oncol. 2014;15: Aghajanian C, et al. J Clin Oncol. 2012;30: Ledermann JA, et al. Eur J Cancer. 2013;49(suppl):LBA Coleman RL, et al. Lancet Oncol. 2017;18:

17 Phase III GOG 218: Addition of Bevacizumab for Primary Therapy in Stage III/IV Ovarian Cancer
Paclitaxel 175 mg/m2/3 hrs + Carboplatin AUC 6 Q21D x 6 Placebo Day 1 x 5 begin cycle 2 (n = 625) Placebo Q21D x 15 mos Pts with newly diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer; stage III optimal (macroscopic), stage III suboptimal, stage IV (N = 1873) Paclitaxel 175 mg/m2/3 hrs + Carboplatin AUC 6 Q21D x 6 Bevacizumab* Day 1 x 5 begin cycle 2 (n = 625) Placebo Q21D x 15 mos AUC, area under the curve. Paclitaxel 175 mg/m2/3 hrs + Carboplatin AUC 6 Q21D x 6 Bevacizumab* Day 1 x 5 begin cycle 2 (n = 623) Bevacizumab* Q21D x 15 mos *Bevacizumab 15 mg/kg IV. Slide credit: clinicaloptions.com Burger RA, et al. N Engl J Med. 2011;365:

18 GOG 218: Investigator-Assessed PFS
30 20 10 100 90 80 70 60 50 40 PFS (%) 12 24 36 Events, n (%) Median PFS, Mos Stratified HR (95% CI) P Value CP 423 (67.7) 10.3 CP + Bev 418 (66.9) 11.2 0.908 ( ) .16 CP + Bev  Bev 360 (57.8) 14.1 0.717 ( ) < .001 Bev, bevacizumab; C, carboplatin; P, paclitaxel. Mos Since Randomization Slide credit: clinicaloptions.com Burger RA, et al. N Engl J Med. 2011;365:

19 GOG 218: Impact of Using CA-125 as a Determinant of PFS
Outcome Protocol-Defined Analysis CA-125–Censored Analysis Median PFS, mos CP (Arm 1) 10.3 12.0 CP + Bev  Bev (Arm 3) 14.1 18.0 Absolute difference in median PFS, mos 3.8 6.0 HR 0.717 0.645 1-sided log-rank P value < .0001 Pts censored for CA-125, % 20 19 Bev, bevacizumab; C, carboplatin; P, paclitaxel. Slide credit: clinicaloptions.com Burger RA, et al. ASCO Abstract LBA1.

20 GOG 218: OS at Time of Primary PFS Analysis
100 90 80 70 60 OS (%) 50 40 Events, n (%) Median, Mos HR* (95% CI) P Value CP 156 (25.0) 39.3 CP + Bev 150 (24.0) 38.7 1.036 ( ) 0.76 CP + Bev  Bev 138 (22.2) 39.7 0.915 ( ) 0.45 30 Bev, bevacizumab; C, carboplatin; P, paclitaxel. 20 10 12 24 36 48 Mos Pts at Risk, n 625/625/623 442/432/437 173/162/171 46/39/40 *Stratified analysis. Slide credit: clinicaloptions.com Burger RA, et al. N Engl J Med. 2011;365:

21 GOG 218: Select Adverse Events
Adverse Event, n (%) CP (n = 601) CP + Bev (n = 607) CP + Bev  Bev (n = 608) GI events*† 7 (1.2) 17 (2.8) 16 (2.6) Hypertension† 43 (7.2) 100 (16.5)‡ 139 (22.9)‡ Proteinuria§ 4 (0.7) 10 (1.6) Pain† 250 (41.6) 252 (41.5) 286 (47.0) Neutropenia׀׀ 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) Wound disruption 22 (3.6) 18 (3.0) CNS bleeding¶ 2 (0.3) Non-CNS bleeding§ 8 (1.3) 13 (2.1) RPLS¶ 1 (0.2) Bev, bevacizumab; C, carboplatin; CNS, central nervous system; GI, gastrointestinal; P, paclitaxel; RPLS, reversible posterior leukoencephalopathy syndrome. Onset between cycle 2 and 30 days after date of last treatment; *Perforation/fistula/necrosis/anastomotic leak. †Grade ≥ 2. ‡P < .05. §Grade ≥ 3. ׀׀Grade ≥ 4. ¶All grades. Footnotes in slidenotes. Burger RA, et al. N Engl J Med. 2011;365: Slide credit: clinicaloptions.com

22 GOG 218: Ascites Predict Treatment Benefit of Bevacizumab
PFS in Pts With Ascites OS in Pts With Ascites 100 100 Median PFS, Mos 10.4 15.2 P < .001 Median OS, Mos 39.9 43.3 P = .035 80 CP CP + Bev  Bev 80 CP CP + Bev  Bev 60 60 PFS (%) OS (%) 40 40 20 20 Bev, bevacizumab; C, carboplatin; P, paclitaxel. 12 24 36 48 60 72 84 96 108 120 12 24 36 48 60 72 84 96 108 120 Mos Mos Arm 1 (chemo) Arm 3 (ext. bev) Arm 1 (chemo) Arm 3 (ext. bev) 80% had ascites (defined as peritoneal fluid > 50 cm3) Slide credit: clinicaloptions.com Ferriss JS, et al. Gynecol Oncol. 2015;139:17-22.

23 Angiogenesis Phenotype (Microvessel Density, Tumor VEGF-A) and PFS Benefit
100 CP + Bev  Bev high microvessel density 80 CP + Bev  Bev low microvessel density CP high microvessel density 60 CP low microvessel density PFS (%) 40 20 Bev, bevacizumab; C, carboplatin; P, paclitaxel. P interaction = .003 6 12 18 24 30 36 42 Mos CP + Bev  Bev high microvessel density CP + Bev  Bev low microvessel density CP high microvessel density CP low microvessel density Slide credit: clinicaloptions.com Bais C, et al. J Natl Cancer Inst. 2017;109:djx066

24 Phase III ICON7: Carboplatin/Paclitaxel ± Bev in Newly Diagnosed Ovarian Cancer
Stratified by HR status, nodal status Control (n = 764) Pts with epithelial ovarian, fallopian tube, or primary peritoneal cancer; stage I-IIA (grade 3 or clear cell) or stage IIB-IV (all grades/histologic types); surgically debulked histologically confirmed ovarian cancer (N = 1528) Carboplatin AUC 5 or 6 Paclitaxel 175 mg/m2 Treatment (CPB7.5+) (n = 764) Bevacizumab 7.5 mg/kg AUC, area under the curve; Bev, bevacizumab; PD, progressive disease. Bevacizumab concurrently Q3W x 5 or 6 cycles, followed by 12 additional cycles or until PD. Bevacizumab omitted in cycle 1 to avoid delayed wound healing if chemotherapy was started within 4 wks of surgery Slide credit: clinicaloptions.com Oza AM, et al. Lancet Oncol. 2015;16:

25 ICON7: PFS PFS (%) 17.5 19.9 Mos 100 CP CP + Bev Events, n (%)
526 (69) 554 (73) Restricted mean, mos 27.7 29.2 Median PFS, mos 17.5 19.9 Log-rank test P = .25 HR (95% CI) 0.93 ( ) PFS (%) 75 50 25 Bev, bevacizumab; C, carboplatin; P, paclitaxel. 17.5 19.9 6 12 18 24 30 36 42 48 54 60 Mos Pts at Risk , n CP CP + Bev 764 484 604 294 314 239 226 198 182 66 54 Slide credit: clinicaloptions.com Oza AM, et al. Lancet Oncol. 2015;16:

26 ICON7: Final OS OS (%) Mos 100 75 50 CP CP + Bev Total Deaths, n 352
362 714 (47) Restricted mean OS, mos 44.6 45.5 +0.9 Median OS, mos 58.6 58.0 -0.6 Log-rank test P = .85 HR (95% CI) 0.99 ( ) 25 Bev, bevacizumab; C, carboplatin; P, paclitaxel. 6 12 18 24 30 36 42 48 54 60 Mos Pts at Risk, n CP CP + Bev 764 676 707 578 618 476 502 397 401 117 124 Slide credit: clinicaloptions.com Oza AM, et al. Lancet Oncol. 2015;16:

27 ICON7: MRC Final OS Subgroup Analyses
Median OS, Mos HR (95% CI) n CP CP + Bev All pts 44.6 45.5 58.6 58.0 0.99 ( ) 1528 Stage I, II, III (0 cm) 52.3 51.9 NR 1.23 ( ) 725 Stage III >0, ≤1 cm 42.6 41.9 45.7 44.2 0.95 ( ) 301 Stage III >1 cm 36.1 40.2 32.1 39.7 0.84 ( ) 290 Stage IV 33.5 38.9 29.4 39.6 0.76 ( ) 182 Non-operable 24.9 34.5 20.8 40.4 0.52 ( ) 30 Nonhigh risk 49.7 48.4 67.2 1.14 ( ) 1026 High risk 39.3 30.3 0.78 ( ) 502 Restricted Mean OS, mos CP + Bev Better CP Better Disease Stage Trend P = .004 Bev, bevacizumab; C, carboplatin; P, paclitaxel. Risk Status Interaction P = .01 HR (95% CI) Oza AM, et al. European Cancer Congress Abstract LBA 6. Oza AM, et al. Lancet Oncol. 2015;16: Slide credit: clinicaloptions.com

28 ICON7: Final PFS in High-Risk Subgroup
100 CP CP + Bev Events, n (%) 228 (90) 223 (90) Restricted mean PFS, mos 15.9 20.0 Median PFS, mos 10.5 16.0 Log-rank test P = .001 HR (95% CI) 0.73 ( ) PFS (%) 75 50 High-risk subgroup: stage III suboptimally debulked, stage IV, or no debulking surgery, n = 502 25 Nonproportionality test: P < .0001 Bev, bevacizumab; C, carboplatin; P, paclitaxel. 6 12 18 24 30 36 42 48 54 60 Mos Pts at Risk, % CP CP + Bev 254 248 109 175 43 53 24 32 18 23 6 5 Slide credit: clinicaloptions.com Oza AM, et al. Lancet Oncol. 2015;16:

29 ICON7: Final OS in High-Risk Subgroup
CP CP + Bev Deaths, n (%) 174 (69) 158 (64) Restricted mean OS, mos 34.5 39.3 Median OS, mos 30.3 39.7 Log-rank test P = .03 HR (95% CI) 0.78 ( ) 100 75 OS (%) 50 Nonproportionality test: P = .0072 High-risk subgroup: stage III suboptimally debulked, stage IV, or no debulking surgery, n = 502 25 Bev, bevacizumab; C, carboplatin; P, paclitaxel. 9.4 6 12 18 24 30 36 42 48 54 60 Mos Pts at Risk, n CP CP + Bev 254 248 208 224 156 180 101 135 82 95 21 27 Slide credit: clinicaloptions.com Oza AM, et al. Lancet Oncol. 2015;16:

30 ICON7: AEs of Specific Interest (All Grades)
CP (n = 753) CP + Bev (n = 745) All Grades Grade ≥ 3 Pts (%) Pts (%) AE, adverse event; ATE, arterial thromboembolism; Bev, bevacizumab; C, carboplatin; CHF, congestive heart failure; GI, gastrointestinal; P, paclitaxel; RPLS, reversible posterior leukoencephalopathy syndrome; VTE, venous thromboembolism. Slide credit: clinicaloptions.com Perren TJ, et al. N Engl J Med. 2011;365:

31 What Is the Standard Systemic Tx for Newly Diagnosed Advanced Epithelial Ovarian Cancer?
Intraperitoneal is an option in the adjuvant setting when the volume of residual disease is < 1cm Advanced stage: 60% to 70% No symptoms because of large peritoneal cavity Peritoneal dissemination Not curative by surgery or radiation therapy Importance of chemotherapy delivery Infusing a high concentration of anticancer drugs appears to be a reasonable approach Tx, treatment. Slide credit: clinicaloptions.com

32 Historical Large IP Trials
Study IP Regimen IV Control PFS (IP vs IV) OS Critique SWOG 8501 (N = 546)[1] Cisplatin IP 100 mg/m2 Cyclophosphamide IV 600 mg/m2 Cisplatin IV 100 mg/m2 Cyclophosphamide IV 600 mg/m2 Not reported 49 vs 41 mos P = .02 No paclitaxel 0-2 cm residual disease GOG 114 (N = 462)[2] Carboplatin IV AUC 9 x 2  Paclitaxel IV 135 mg/m2 (24 hrs) D1 Cisplatin IP 100 mg/m2 D2 Paclitaxel IV 135 mg/m2 (24 hrs) D1 Cisplatin IV 75 mg/m2 D2 28 vs 22 mos 63 vs 52 mos P = .05 High-dose carboplatin One-tail P value for OS GOG 172 (N = 415)[3] Paclitaxel IP 60 mg/m2 D8 Paclitaxel IV 135 mg/m2 (24 hrs) D1 Cisplatin IV 75 mg/m2 D2 24 vs 18 mos HR: 0.80 66 vs 50 mos HR: 0.75 P = .03 D8 paclitaxel confounds AUC, area under the curve. 1. Alberts DS, et al. N Engl J Med. 2006;335: 2. Markman M, et al. J Clin Oncol. 2001;19: 3. Armstrong D, et al. N Engl J Med. 2006;354:34-43. Slide credit: clinicaloptions.com

33 IP Regimen Better IV Regimen Better
NCI Clinical Announcement: Preferred Treatment Methods for Advanced Ovarian Cancer (2006) Treatment HRs for OS IP vs IV therapy HR Var (In(HR)) IP Regimen Better IV Regimen Better SWOG/GOG 104 (1996) GONO (2000) GOG 114/SWOG (2001) Taiwan (2001) EORTC (2003) GOG 172 (2006) Pooled estimate 0.79 HR, hazard ratio; NCI, National Cancer Institute; Rel, relative. 0.33 0.50 0.67 1.00 1.50 2.00 3.00 Relative Hazard Slide credit: clinicaloptions.com National Cancer Institute

34 Long-term Survival and Prognostic Factors Associated With IP Chemo in Advanced Ovarian Cancer
876 pts from GOG 114 and 172 with median follow-up of 10.7 yrs 1.0 1.0 GOG 172 IP, 6 GOG 172 IP, 3-5 to IV GOG 172 IP, < 3 to IV GOG 172 IV, 6 Median OS, Mos 0.8 0.8 IP IV 0.6 0.6 Probability of OS Probability of OS 0.4 0.4 0.2 0.2 Adjusted HR: 0.77 (95% CI: ) P = .002 30 60 90 120 30 60 90 120 Mos Mos Pts at Risk, n GOG 172 IP, 6 GOG 172 IP, 3-5 to IV GOG 172 IP, < 3 to IV GOG 172 IV, 6 78 26 61 182 73 19 46 133 50 14 30 79 31 8 18 47 4 7 25 Pts at Risk, n IV IP 436 440 303 337 184 217 110 140 68 85 Slide credit: clinicaloptions.com Tewari D, et al. J Clin Oncol. 2015;33:

35 Phase III GOG 252: IV vs IP Chemotherapy + Bevacizumab in Stage II/III Ovarian Cancer
Cycles 1-6 Cycles 7-22 Carboplatin AUC 6 IV Paclitaxel 80 mg/m2 IV (1 hr) D1, 8, 15 Bevacizumab 15 mg/kg IV D1, C2-6 Bevacizumab D1, C7-22 Pts with stage II/III epithelial ovarian, fallopian tube, or primary peritoneal carcinoma and no prior therapy; R0 (N = 1560) Carboplatin AUC 6 IP Paclitaxel 80 mg/m2 IV (1 hr) D1, 8, 15 Bevacizumab 15 mg/kg IV D1, C2-6 Bevacizumab D1, C7-22 Paclitaxel 135 mg/m2 IV (3 hrs) D1 Cisplatin 75 mg/m2 IP D2 Paclitaxel 60 mg/m2 IP D8 Bevacizumab 15 mg/kg IV D1, C2-6 AUC, area under the curve; R0, complete resection. Bevacizumab D1, C7-22 Walker JL, et al. SGO Abstract LBA7. ClinicalTrials.gov. NCT Slide credit: clinicaloptions.com 35

36 GOG 252: Completion of Assigned Treatment
Arm Bev Cycles Completed, n Completed ≥ 6 Cycles of Platinum, % Completed ≥ 6 Cycles of Taxane, % IV Carboplatin 20 90 87 IP Carboplatin 19 88 IP Cisplatin 17 84 Twice as many pts stopped protocol-directed bevacizumab prior to completion of cycle 6 on Arm 3 (IP cisplatin; 30% vs 15%) Bev, bevacizumab. Slide credit: clinicaloptions.com Walker JL, et al. SGO Abstract LBA7.

37 GOG 252: PFS by Treatment Group
PFS in Stage II or Stage III Optimally Debulked (< 1 cm) PFS in Stage III With No Gross Residual Disease (R0) 100 100 Treatment Median, Mos 26.8 28.7 27.8 1: IV Carbo (n = 239) 2: IP Carbo (n = 239) 3: IP Cis (n = 239) Treatment Median, Mos 31.3 31.8 33.8 1: IV Carbo (n = 461) 2: IP Carbo (n = 464) 3: IP Cis (n = 456) 80 80 60 60 PFS (%) PFS (%) 40 40 20 HR IV Carbo vs IP Carbo: 0.95 (95% CI: ; P = .416) 20 HR IV Carbo vs IP Cis: 1.01 (95% CI: ; P = .727) Carbo, carboplatin; Cis, cisplatin. 12 24 36 48 60 72 12 24 36 48 60 72 Mos on Study Mos on Study Estimated HR, log-rank tests adjusted for stage of disease and size of residual disease (micro vs < 1 cm) CT required every 6 mos for surveillance (not required in GOG 114/172) Slide credit: clinicaloptions.com Walker JL, et al. SGO Abstract LBA7.

38 GOG 252: Toxicity AE, % IV Carboplatin IP Carboplatin IP Cisplatin
Grade 2 Grade ≥ 3 Febrile neutropenia 2.5 2.6 3.3 Neutropenia 71 68 64 Platelets 17.6 15.1 6.1 Hypertension 11.9 13.8 20.5 Thrombocytopenia 6.3 8.4 9.0 Nausea/vomiting 5.1 4.7 11.2 Fistula 5.3 3.7 4.3 Urine protein 2.7 3.1 1.6 Sensory neuropathy 24.1 5.7 22.6 4.5 21.3 5.5 AE, adverse event. Slide credit: clinicaloptions.com Walker JL, et al. SGO Abstract LBA7.

39 Did Inclusion of Bevacizumab Compromise PFS in GOG 252?
Lessons learned from GOG 262 With bevacizumab, dose-dense weekly chemotherapy does not prolong PFS Without bevacizumab, dose-dense weekly chemotherapy prolongs PFS Median PFS, Mos Median PFS, Mos Events, n Events, n Weekly paclitaxel (n = 346) Q3W paclitaxel (n = 346) Weekly paclitaxel (n = 55) Q3W paclitaxel (n = 57) 20 40 60 80 100 12 24 36 Mos PFS (%) HR: 0.89 (95% Cl: ; P = .18) 20 40 60 80 100 12 24 36 PFS (%) HR: 0.62 (95% Cl: ; P = .03) Mos bev, bevacizumab. PFS without bev PFS with bev Slide credit: clinicaloptions.com Chan JK, et al. N Engl J Med. 2016;374:

40 Did Inclusion of Bevacizumab Compromise PFS in GOG 252?
Adding bevacizumab should have exaggerated any difference between the treatments rather than mitigating any IP benefit No difference between the treatment arms in GOG 252, even with the inclusion of bevacizumab, shows that IP chemotherapy does not improve PFS Median PFS, Mos Median PFS, Mos Events, n Events, n Weekly paclitaxel (n = 346) Q3W paclitaxel (n = 346) Weekly paclitaxel (n = 55) Q3W paclitaxel (n = 57) 20 40 60 80 100 12 24 36 Mos PFS (%) 20 40 60 80 100 12 24 36 PFS (%) Mos HR: 0.89 (95% Cl: ; P = .18) HR: 0.62 (95% Cl: ; P = .03) bev, bevacizumab. PFS without bev PFS with bev Slide credit: clinicaloptions.com Chan JK, et al. N Engl J Med. 2016;374:

41 Phase II/III iPocc Trial: IV vs IP Paclitaxel/ Carboplatin in Stage II-IV Ovarian Cancer
Paclitaxel 80 mg/m2/1h IV, weekly, Cycles 1-6 Carboplatin AUC 6 IV, Day 1, Cycles 1-6 Pts with stage II-IV ovarian, primary peritoneal, or fallopian tube cancer; suboptimal cases included (Planned N = 654) Paclitaxel 80 mg/m2/1h IV, weekly, Cycles 1-6 Carboplatin AUC 6 IP, Day 1, Cycles 1-6 AUC, area under the curve; QoL, quality of life. Primary endpoint: PFS Secondary endpoints: OS, toxicity, QoL, cost/benefit Slide credit: clinicaloptions.com ClinicalTrials.gov. NCT

42 Considerations for Genetic Mutations in Patients With Ovarian Cancer

43 BRCA Mutations: Basic Concepts
Germline BRCA mutations Germline non-BRCA mutations in HR pathway proteins Sporadic (somatic) BRCA mutations Sporadic non-BRCA mutations in HR pathway proteins Mutations in HR pathway HR deficiency HR, homologous recombination Slide credit: clinicaloptions.com

44 Overview of BRCA1 and BRCA2
Risk of Developing Ovarian Cancer MUTATED BRCA1 39% MUTATED BRCA2 11% to 17% NORMAL BRCA 1.4% Enzymes that repair double- stranded DNA breaks Mutations in BRCA1 or BRCA2 Increased risk of breast and ovarian cancer Prognostic marker Predictive biomarker for PARP inhibitor activity Slide credit: clinicaloptions.com

45 Homologous Recombination Repair
DNA DSB MRN-mediated sensing of the DSB → ATM activation MRN-mediated 5’ to 3’ end resection End processing via BRCA1 & 2-containing complex → binds directly to RAD 51 Displacement of RPA and assembly of RAD51 onto ssDNA via BRCA2 Strand invasion into undamaged homologous DNA leading to repaired DNA HR is a complex process involving many gene products Cells with disruptive BRCA mutations are deficient in HR Other mediators of the HR pathway include MRE11, RAD50, NBS1, ATM, CtIP, PALB2, BRCA2, RAD51, RPA Disruptive mutations in other HR pathway genes can also result in HR deficiency HR, homologous recombination. Slide credit: clinicaloptions.com Hosoya N, et al. Cancer Sci. 2014;105:370–388.

46 Germline vs Somatic Mutations
Germline mutation Somatic mutation Parental gametes Parental gametes Embryo Embryo Entire organism carries mutation Mutation only in affected area ©Medscape, LLC ©Medscape, LLC Half of gametes carry mutation No gametes carry mutation Organism Organism Offspring gametes Offspring gametes Germline mutations are inherited and found in all cells Somatic mutations are not inherited and are found within the tumor Slide credit: clinicaloptions.com

47 Single-Gene vs Multigene (Panel) Testing
Single-Gene Testing Tests for mutation-specific gene PCR and direct sequencing Traditionally used when personal or FH suggests single inherited cancer syndrome Panel Testing Tests mutation status of multiple genes with one sample Most commonly using NGS Can be used in place of single-gene testing; should be considered when negative for single-gene test but FH suggests an inherited susceptibility FH, family history; NGS, next-generation sequencing. Slide credit: clinicaloptions.com

48 Genetic Testing: Timing Recommendations
Germline panel testing at diagnosis in all women with ovarian, peritoneal and fallopian tube cancer Somatic testing at recurrence BRCA, HRD, MSI, etc HRD, homologous recombination deficiency; MSI, microsatellite instability. Slide credit: clinicaloptions.com

49 Management Options for Patients With Recurrent Ovarian Cancer

50 Bevacizumab for Recurrent Ovarian Cancer: Clinical Data Summary
Trial Treatment ORR, % PFS, Mos PFS HR P Value OS, Mos OS HR Platinum-sensitive recurrent ovarian cancer GOG 213[1] (N = 673) Paclitaxel/carboplatin 59 10.4 0.628 P < .0001 37.3 0.829 P = .056 + bevacizumab 78 13.8 42.2 OCEANS[2,3] (N = 484) Gem/carboplatin 57 8.4 0.48 32.9 0.952 P = .65 Gem/carboplatin + bevacizumab 79 12.4 33.6 Platinum-resistant recurrent ovarian cancer AURELIA[4] (N = 361) Single-agent chemotherapy 13 3.4 P < .001 13.3 0.85 P < .174 Single-agent chemotherapy + bevacizumab 31 6.7 16.6 Gem, gemcitabine. 1. Coleman RL, et al. Lancet Oncol. 2017;18: Aghajanian C, et al. J Clin Oncol. 2012;30: Aghajanian C, et al. Gynecol Oncol. 2015;139: Pujade-Lauraine E, et al. J Clin Oncol. 2014;32: Slide credit: clinicaloptions.com

51 Phase III OCEANS Study: Second-line Gem/Carbo ± Bevacizumab in Recurrent Ovarian Cancer
Stratified by platinum-free interval (6-12 mos vs > 12 mos), cytoreductive surgery for recurrent disease (yes vs no) Pts with platinum-sensitive, recurrent ovarian cancer, progression on first-line chemotherapy, no prior bevacizumab, ECOG PS 0/1 (N = 484) Carboplatin AUC 4 Day 1 Gemcitabine 1000 mg/m2 Days 1, 8 Bevacizumab 15 mg/kg Day 1 21-day cycles Carboplatin AUC 4 Gemcitabine 1000 mg/m2 Days 1 ,8 Placebo Day 1 21-day cycles AE, adverse event; Carbo, carboplatin; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; Gem, gemcitabine; GI, gastrointestinal; PS, performance status Primary endpoint: PFS Secondary endpoints: ORR, DoR, OS, % of pts with GI perforation, AEs Slide credit: clinicaloptions.com Aghajanian C, et al. Gynecol Oncol. 2015;139:10-16.

52 OCEANS: PFS, ORR, and DoR Investigator-Assessed PFS 100
Outcome GC + Pbo (n = 242) GC + Bev PFS by investigator Median PFS, mos 8.4 12.4 Stratified HR (95% CI) 0.484 ( ) Log-rank P value < .0001 ORR and DoR by investigator ORR, % 57 79 Median DoR, mos 7.4 10.4 HR (95% CI) 0.53 ( ) 100 GC + placebo (n = 242) GC + bev (n = 242) 80 60 PFS (%) 40 Bev, bevacizumab; C, carboplatin; DoR, duration of response; G, gemcitabine; Pbo, placebo. 20 Data cutoff date: September 17, 2010 6 12 18 24 30 Mos Slide credit: clinicaloptions.com Aghajanian C, et al. J Clin Oncol. 2012;30:

53 OCEANS: Final OS Analysis
100 Median OS, Mos GC + placebo 32.9 GC + bev 33.6 80 60 OS (%) HR: (95% CI: ; log-rank P = .6479) 40 20 Bev, bevacizumab; C, carboplatin; G, gemcitabine. Data cutoff date: July 19, 2013; median follow-up: 56.4 mos in placebo arm and mos in bev arm, with 353 deaths (72.9% of pts) 6 12 18 24 30 36 42 48 54 60 66 72 78 Mos Pts at Risk, n GC + placebo 242 235 222 191 160 128 104 87 64 41 20 7 1 GC + bev 242 239 226 201 172 138 105 87 68 47 25 7 1 Slide credit: clinicaloptions.com Aghajanian C, et al. Gynecol Oncol. 2015;139:10-16.

54 OCEANS: AEs of Special Interest
AEs, n (%) GC + Placebo (n = 233) GC + Bev (n = 247) Arterial thromboembolic event (all grades) 1 (0.4) 6 (2.4) Venous thromboembolic event (grades ≥ 3) 6 (2.6) 11 (4.5) Bleeding (CNS) (all grades) 2 (0.9) 2 (0.8) Congestive heart failure (grades ≥ 3) Febrile neutropenia (all grades) 4 (1.7) 4 (1.6) Neutropenia (grades ≥ 4) 51 (21.9) 52 (21.1) Fistula/abscess (all grades)* Gastrointestinal perforation (all grades)* Reversible posterior leukoencephalopathy syndrome (all grades) Wound-healing complication (grades ≥ 3) Proteinuria (grades ≥ 3) 27 (10.9) Bleeding (non-CNS) (grades ≥ 3), mostly epistaxis 14 (5.7) Hypertension (grades ≥3) 45 (18.2) AE, adverse event; Bev, bevacizumab; C, carboplatin; CNS, central nervous system; G, gemcitabine. *Due to coding changes to using the gastrointestinal perforation (GIP) standardized medical query, this is different than the primary analysis, where no GI perforations were reported and fistula/abscess were reported in 1 patient in the GC + placebo arm and 4 patients in the GC + Bev arm. GIPs were reported in 2 additional patients outside the safety reporting window. Footnote in slidenotes. Aghajanian C, et al. Gynecol Oncol. 2015;139:10-16. Slide credit: clinicaloptions.com

55 Phase III GOG 213: Carbo/Pac ± Bevacizumab in Recurrent Ovarian Cancer
Surgical candidate Regimen I Carboplatin AUC 5 Paclitaxel 175 mg/m2 21-day cycles R A N D O M I Z E Surgery Pts with recurrent ovarian, peritoneal primary, or fallopian tube cancer and a treatment-free interval ≥ 6 mos (N = 674) Yes No Surgery No surgery Regimen II Carboplatin AUC 5 Paclitaxel 175 mg/m2 Bevacizumab 15 mg/kg 21-day cycles Maintenance Bevacizumab 15 mg/kg Q21D No Primary objectives: OS with addition of bevacizumab, OS with addition of secondary cytoreductive surgery Secondary objectives: PFS, carboplatin/paclitaxel hypersensitivity, HRQoL AUC, area under the curve; Carbo, carboplatin; HRQoL, health-related quality of life; Pac, paclitaxel. Slide credit: clinicaloptions.com Coleman RL, et al. Lancet Oncol. 2017;18:

56 GOG 213: PFS Adjusted HR: 0.628 (95% CI: 0.534-0.739; P < .0001)
100 Events, n Median PFS, Mos PC (n = 337) 304 10.4 80 PC + bev (n = 337) 296 13.8 Adjusted HR: (95% CI: ; P < .0001) 60 PFS (%) 40 20 Bev, bevacizumab; C, carboplatin; P, paclitaxel. 12 24 36 48 60 Mos on Study Pts at Risk, n PC 337 125 40 20 12 5 PC + bev 337 201 84 46 16 9 Slide credit: clinicaloptions.com Coleman RL, et al. Lancet Oncol. 2017;18:

57 GOG 213: OS Adjusted HR: 0.829 (95% CI: 0.683-1.005; P = .056)
Events, n Median OS, Mos PC (n = 337) 214 37.3 100 PC + bev (n = 337) 201 42.2 80 60 OS (%) 40 20 Bev, bevacizumab; C, carboplatin; P, paclitaxel. Adjusted HR: (95% CI: ; P = .056) 12 24 36 48 60 Pts at Risk, n Mos on Study PC 337 303 234 152 69 18 PC + bev 337 306 253 183 75 28 Slide credit: clinicaloptions.com Coleman RL, et al. Lancet Oncol. 2017;18:

58 GOG 213: Select AEs Related to Bevacizumab Tx
 AEs (All Grades Unless Otherwise Stated), % PC (n = 327) PC + Bev (n = 330) Any AE 23 72 Grade ≥ 3 8 30 Serious 6 15 Bleeding (CNS) 1 < 1 Bleeding (non-CNS) 11 42 CHF Grade 3/4 fistula/abscess (nongastrointestinal) Gastrointestinal perforations 2 Hypertension (any grade/grade ≥ 3) 3/1 41/12 Neutropenia and complications (any grade/grade ≥ 3) 8/4 12/7 Posterior reversible encephalopathy syndrome Proteinuria 17 Thromboembolic event, arterial 7 Thromboembolic event, venous Wound healing complication 3 Secondary primary malignancy Bev, bevacizumab; C, carboplatin; CHF, congestive heart failure; CNS, central nervous system; P, paclitaxel; Tx, treatment. *Medical review of embolism events in AdEERS reports and comments recorded in CRFs revealed that all 5 of the Grade 4 emboli were pulmonary emboli. Therefore, the pulmonary emboli were recategorized as VTEs. Medical review of 9 cases of deep vein thrombosis and pulmonary embolism initially classified under the ATE category were reclassified as Grade ≥3 VTEs. Slide credit: clinicaloptions.com Coleman RL, et al. Lancet Oncol. 2017;18:

59 AURELIA: Randomized Phase III Trial of Bev + CT for Platinum-Resistant Recurrent Ovarian Cancer
Stratified by selected chemotherapy, prior antiangiogenic therapy, platinum-free interval (< 3 vs 3-6 mos) Pts with platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer, ≤ 2 prior regimens, no bowel obstruction, GI perforation, or rectosigmoid involvement, ECOG PS 0/1 (N = 484) Chemotherapy (n = 182) Treat to PD or unacceptable toxicity Bevacizumab monotherapy permitted on clear evidence of progression Chemotherapy + Bevacizumab 10 mg/kg Q2W or 15 mg/kg Q3W (n = 179) Bev, bevacizumab; ECOG, Eastern Cooperative Oncology Group; CT, chemotherapy; GI, gastrointestinal; PD, progressive disease; PS, performance status; QoL, quality of life; RECIST, Response Evaluation Criteria in Solid Tumors. Investigators first selected chemotherapy, then pts were randomized to bevacizumab or no bevacizumab Chemotherapy (physician’s choice): Paclitaxel 80 mg/m2 Days 1, 8, 15, 22 Q4W Topotecan 4 mg/m2 Days 1, 8, 15 Q4W (or 1.25 mg/m2 Days 1-5 Q3W) Pegylated liposomal doxorubicin 40 mg/m2 Day 1 Q4W Primary endpoint: PFS (RECIST v1.0) Secondary endpoints: ORR, OS, QoL, safety Slide credit: clinicaloptions.com Pujade-Lauraine E, et al. J Clin Oncol. 2014;32: 59

60 AURELIA: PFS (ITT Population) and Secondary Outcomes
Median PFS, Mos Median OS, Mos ORR, % 100 Bev + CT (n = 179) 80 CT alone (n = 182) 60 PFS HR: 0.48 (95% CI: ; log-rank P < .001) PFS (%) 40 OS HR: 0.85 (95% CI: ) 20 Bev, bevacizumab; CT, chemotherapy; ITT, intent to treat. 3 6 9 12 15 18 21 24 Pts at Risk, n Mos CT alone 182 92 35 18 9 1 1 Bev + CT 179 144 91 51 19 6 4 1 Slide credit: clinicaloptions.com Pujade-Lauraine E, et al. J Clin Oncol. 2014;32:

61 AURELIA: Cohorts Treated With Paclitaxel— PFS and OS
Median OS, Mos 100 100 Median PFS, Mos CT (n = 55) CT (n = 55) Bev + CT (n = 60) 22.4 80 Bev + CT (n = 60) 10.4 75 60 PFS (%) OS (%) 50 40 25 Bev, bevacizumab; CT, chemotherapy. 20 HR: 0.46 (95% CI: ) HR: 0.65 (95% CI: ) 3 6 9 12 15 18 21 24 6 12 18 24 30 36 42 Mos Mos Slide credit: clinicaloptions.com Poveda AM, et al. J Clin Oncol. 2015;33:

62 AURELIA: Cohorts Treated With Topotecan— PFS and OS
Median OS, Mos 100 Median PFS, Mos 100 CT (n = 63) CT (n = 63) Bev + CT (n = 57) 13.8 Bev + CT (n = 57) 6.2 75 75 50% OS (%) 50 PFS (%) 50 HR: 0.24 (95% CI: ) 25 25 Bev, bevacizumab; CT, chemotherapy. 8% 13% HR: 1.09 (95% CI: ) 3 6 9 12 15 18 21 24 6 12 18 24 30 36 42 Mos Mos 1. Poveda AM, et al ESMO Congress. Abstract LBA26. 2. Witteveen P, et al European Cancer Congress. Abstract LBA 5. Slide credit: clinicaloptions.com

63 AURELIA: Cohorts Treated With PLD— PFS and OS
Median OS, Mos 100 Median PFS, Mos 100 CT (n = 64) CT (n = 64) Bev + CT (n = 62) 13.7 Bev + CT (n = 62) 5.1 75 75 OS (%) 50 PFS (%) 50 41% HR: 0.47 (95% CI: ) 25 Bev, bevacizumab; CT, chemotherapy; PLD, pegylated liposomal doxorubicin. 25 14% 23% 4% HR: 0.91 (95% CI: ) 3 6 9 12 15 18 21 24 6 12 18 24 30 36 42 Mos Mos 1. Poveda AM, et al ESMO Congress. Abstract LBA26. 2. Witteveen P, et al European Cancer Congress. Abstract LBA 5. Slide credit: clinicaloptions.com

64 AURELIA: Summary of Grade ≥ 3 (and Selected Grade ≥ 2) AEs of Special Interest
Grade ≥ 3 AE of Special Interest, % Bev + CT (n = 179) CT Alone (n = 181) Hypertension (grade 2) 7 (20) 1 (7) Proteinuria 2 GI perforation (grade 2) 2 (2) Fistula/abscess (grade 2) 1 (2) Bleeding 1 Arterial/venous thromboembolic event 2/3 0/4 Wound healing complication RPLS CHF Cardiac disorders AE, adverse event; Bev, bevacizumab; CHF, congestive heart failure; CT, chemotherapy; GI, gastrointestinal; PD, progressive disease; RPLS, reversible posterior leukoencephalopathy syndrome. In each arm, 5 deaths occurred that were not considered to be caused primarily by PD Slide credit: clinicaloptions.com Pujade-Lauraine E, et al. J Clin Oncol. 2014;32: REFERENCE: Bevacizumab® (bevacizumab) [prescribing information]. South San Francisco, CA: Genentech, Inc.; 2014.

65 PARP Inhibitor Summary: Current Indications
Olaparib[1] Niraparib[2] Rucaparib[3] Approval date December 2014, August 2017 March 2017 December 2016 Current indication Maintenance tx for recurrent disease in CR or PR to platinum tx gBRCA+ pts with ≥ 3 lines of tx Somatic or gBRCA+ pts with ≥ 2 lines of tx Dose and schedule 300 mg (two 150-mg tablets) PO BID 300 mg (three 100-mg capsules) PO QD 600 mg (two 300-mg tablets) PO BID Safety MDS/AML confirmed in 2% Pneumonitis, including fatal cases, occurred in < 1%  Thrombocytopenia (61%; 29% grade ≥ 3) Neutropenia (30%; 20% grade ≥ 3) Hypertension (20%; 9% grade ≥ 3) Elevated AST/ALT (75%; 5%-13% grade ≥ 3) Dysgeusia (39%) Most common tx-related AEs include fatigue (60% to 80%); GI symptoms: nausea (65% to 75%), vomiting (35% to 45%), diarrhea (20% to 35%), pain (30% to 40%); and anemia (35% to 50%) AE, adverse event; ALT, alanine aminotransferase; AML, acute myeloid leukemia; AST, aspartate aminotransferase; GI, gastrointestinal; MDS, myelodysplastic syndromes; Tx, treatment. 1. Olaparib [package insert] Niraparib [package insert] 3. Rucaparib [package insert] Slide credit: clinicaloptions.com

66 Treatment until PD with no crossover allowed
Phase III NOVA: Niraparib Maintenance in Platinum-Sensitive Ovarian Cancer Niraparib 300 mg QD (n = 136) Platinum-sensitive, recurrent ovarian, fallopian tube, or primary peritoneal cancer; ≥ 2 prior platinum-based regimens with CR/PR and progression > 6 mos after most recent platinum-based therapy (N = 553) Germline BRCA mutation cohort (n = 203) Placebo QD (n = 65) Treatment until PD with no crossover allowed Niraparib 300 mg QD (n = 231) No germline BRCA mutation cohort (n = 350) Placebo QD (n = 114) PD, progressive disease. Primary endpoint: PFS Secondary endpoints: chemotherapy-free interval, time to first subsequent therapy, PFS2, time to second subsequent therapy, OS Maintenance therapy initiated within 8 wks of last dose of platinum chemotherapy Slide credit: clinicaloptions.com Mahner S, et al. SGO Abstract 8084.

67 NOVA: PFS Results in Pt Subgroups
gBRCAmut (n = 203) Non-gBRCAmut Overall (n = 350) 100 2 4 6 8 10 12 14 16 18 20 24 22 100 75 50 25 Median PFS, Mos Median PFS, Mos Pbo 75 Nira Pbo 3.9 PFS (%) 50 PFS (%) Nira 9.3 25 HR: 0.27 (P < .001) HR: 0.45 (P < .001) 2 4 6 8 10 12 14 16 18 20 22 24 Mos Mos Non-gBRCAmut, HRD+ (n = 162) HRD Negative (n = 134) 2 4 6 8 10 12 14 16 18 20 24 22 100 75 50 25 2 4 6 8 10 12 14 16 18 20 24 22 100 75 50 25 Median PFS, Mos Median PFS, Mos HRD, homologous recombination deficiency; Nira, niraparib; Pbo, placebo. Pbo Pbo 3.8 PFS (%) Nira PFS (%) Nira 6.9 HR: 0.38 (P < .001) HR: 0.58 (P = .02) Mos Mos Slide credit: clinicaloptions.com Mahner S, et al. SGO Abstract Mirza MR, et al. N Engl J Med. 2016;375:

68 NOVA: Chemotherapy-Free Interval
Non-gBRCAmut Overall (n = 350) 100 Median CFI, Mos Pbo 75 Nira gBRCAmut (n = 203) PFS (%) 50 Median CFI, Mos 100 Pbo 25 HR: 0.5 (P < .0001) Nira 75 2 4 6 8 10 12 14 16 18 20 22 24 PFS (%) 50 Non-gBRCAmut, HRD+ (n = 162) 100 Median CFI, Mos 25 Pbo CFI, chemotherapy-free interval; HRD, homologous recombination deficiency; Nira, niraparib; Pbo, placebo. 75 HR: 0.26 (P < .0001) Nira 2 4 6 8 10 12 14 16 18 20 22 24 PFS (%) 50 Mos 25 HR: 0.31 (P < .0001) Mahner S, et al. SGO Abstract Mirza MR, et al. N Engl J Med. 2016;375: 2 4 6 8 10 12 14 16 18 Slide credit: clinicaloptions.com 20 22 24 Mos

69 NOVA: Impact on Efficacy of Next-Line Therapy
(PFS2 - PFS1) in the Pooled gBRCAmut and Non-gBRCAmut Cohorts Randomization Progression 100 Progression Niraparib Placebo Platinum Chemo Chemo 75 PFS1 PFS2-PFS1 PFS2 Estimated Survival Function 50 Niraparib Placebo 25 HR: 1.02 (95% CI: ) 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Mos Since Randomization Slide credit: clinicaloptions.com Mahner S, et al. SGO Abstract 8084.

70 Mos Since Randomization Mos Since Randomization
Niraparib in Pts With Recurrent Ovarian Cancer With PR to Last Platinum-Based Chemotherapy gBRCAmut Non-gBRCAmut 100 Niraparib/all Niraparib/PR Placebo/all Placebo/PR 100 Niraparib/all Niraparib/PR Placebo/all Placebo/PR 80 80 60 60 PFS (%) PFS (%) 40 40 20 20 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24 Mos Since Randomization Mos Since Randomization Nira/all Nira/PR Pbo/all Pbo/PR 138 67 65 32 125 62 52 22 107 50 34 14 98 45 21 9 89 41 12 3 79 37 8 3 63 27 6 1 44 19 2 28 10 2 26 9 2 16 5 1 3 1 1 Nira/all Nira/PR Pbo/all Pbo/PR 234 117 116 56 188 90 88 40 145 66 52 13 113 54 33 5 88 39 23 2 75 31 19 2 57 26 10 2 41 16 8 1 23 8 4 1 21 7 4 1 16 6 3 1 7 2 1 3 1 Slide credit: clinicaloptions.com Mirza M, et al. ASCO Abstract 5517.

71 NOVA: Summary of AEs AE, n (%) Niraparib (n = 367) Placebo (n = 179) Any TEAE 367 (100) 171 (95.5) Any related TEAE 358 (97.5) 127 (70.9) Any CTCAE grade ≥ 3 TEAE 272 (74.1) 41 (22.9) Any related CTCAE grade ≥ 3 TEAE 237 (64.6) 8 (4.5) Thrombocytopenia 124 (33.8) 1 (0.6) Anemia 93 (25.3) Neutropenia 72 (19.6) 3 (1.7) Fatigue 30 (8.2) Hypertension 4 (2.2) Any serious TEAE 110 (30.0) 27 (15.1) Any related serious TEAE 62 (16.9) 2 (1.1) Any TEAE leading to treatment interruption 253 (68.9) 9 (5.0) Any TEAE leading to dose reduction 244 (66.5) 26 (14.5) Any TEAE leading to treatment discontinuation 54 (14.7) Any TEAE leading to death MDS/AML occurred in 5 of 367 pts (1.4%) who received niraparib and 2 of 179 pts (1.1%) who received placebo No grade 3/4 bleeding AEs were associated with thrombocytopenia No grade 5 events occurred AE, adverse event; AML, acute myeloid leukemia; CTCAE, Common Terminology Criteria for Adverse Events; MDS, myelodysplastic syndromes; TEAE, treatment-emergent adverse event Grade 1-4 cardiac palpitations 10 2 Slide credit: clinicaloptions.com Mahner S, et al. SGO Abstract Mirza MR, et al. N Engl J Med. 2016;375:

72 NOVA: Pt-Reported Outcomes
gBRCAmut: FOSI gBRCAmut: EQ-5D-5L 30 1.0 Measured using FOSI and the EQ-5D-5L PRO surveys were collected at Screening visit Every other cycle through cycle 14 Postprogression Compliance rates high and similar between the 2 treatment arms Niraparib: FOSI completion rate ranged from 75.0% to 97.1% Placebo: FOSI completion rate ranged from 79.6% to 97.4% PROs were similar for niraparib compared with placebo 25 0.8 20 0.6 FOSI (Adjusted Means) ± SE EQ-5D-5L (Adjusted Means) ± SE 15 0.4 10 0.2 Screening C2 C4 C6 C8 C10 C12 C14 Post- Prog Screening C2 C4 C6 C8 C10 C12 C14 Post- Prog Non-gBRCAmut: FOSI Non-gBRCAmut: EQ-5D-5L 30 1.0 25 0.8 EQ-5D-5L, EuroQol five dimension questionnaire; FOSI, Functional Assessment of Cancer Therapy—Ovarian Symptom Index; PRO, patient-reported outcome; SE, standard error. 20 0.6 FOSI (Adjusted Means) ± SE EQ-5D-5L (Adjusted Means) ± SE 15 0.4 10 0.2 Screening C2 C4 C6 C8 C10 C12 C14 Post- Prog Screening C2 C4 C6 C8 C10 C12 C14 Post- Prog Niraparib Placebo Mahner S, et al. SGO Abstract Mirza MR, et al. N Engl J Med. 2016;375: Slide credit: clinicaloptions.com

73 Accelerated Approval for Olaparib: December 2014
Administration: 400 mg BID (capsules) Approval based on multicenter phase II trial in pts with a germline BRCA1/2 mutation and recurrent ovarian cancer after ≥ 3 lines of treatment (N = 137) DoR, duration of response. Slide credit: clinicaloptions.com Domchek SM, et al. Gynecol Oncol. 2016;140:

74 Number of Prior Lines of Therapy
Number of Prior Lines of Chemotherapy Predicts ORR With Olaparib in mBRCA+ Ovarian Cancer 100 90 80 70 60 50 40 30 20 10 3 4 5 6-14 Sensitive (n = 18) Resistant (n = 24) Number of Prior Lines of Therapy ORR (95% Cl) Slide credit: clinicaloptions.com Domchek SM, et al. Gynecol Oncol. 2016;140:

75 SOLO-2: Study Design International, randomized, double-blind phase III trial[1] Pts with recurrent serous OC and germline BRCA1/2 mutation, ≥ 2 prior lines of platinum-based therapy and responded to most recent platinum, CR or PR on most recent therapy (N = 295) Olaparib 300 mg BID (n = 196*) RECIST assessment Q12W ± 7 days up to 72 wks, then ~ Q24W until PD or unacceptable toxicity Placebo (n = 99) *n = 195 received treatment. Primary endpoint: investigator-assessed PFS Key secondary endpoints: safety/tolerability, PFS2, TFST, TSST, OS, HRQoL EQ-5D-5L, EuroQol five dimension questionnaire; FACT-O, Functional Assessment of Cancer Therapy-Ovarian; HRQoL, health-related quality of life; OC, ovarian cancer; PD, progressive disease; QAPFS, quality-adjusted PFS; RECIST, Response Evaluation Criteria in Solid Tumors; TFST, time to first subsequent therapy or death; TOI, trial outcome index; TSST, time to second subsequent therapy or death; TWiST, time without symptoms of disease or toxicity. HRQoL analyses: Primary: change in FACT-O TOI Secondary pt-centered benefits: QAPFS (PFS + EQ-5D-5L); TWiST (mean PFS - mean toxicity) 1. Pujade-Lauraine E, et al. SGO Abstract LBA2. 2. Ledermann JA, et al. ASCO Abstract Friedlander M, et al. ASCO Abstract 5507. Slide credit: clinicaloptions.com

76 SOLO-2: PFS by Investigator Assessment
100 Median PFS, Mos 90 Placebo 5.5 80 Olaparib 19.1 70 60 HR: 0.30 (95% CI: ; log-rank P < .0001) PFS (%) 50 40 30 20 10 Median follow-up: 22.1 mos in the olaparib group, 22.2 mos for placebo 3 6 9 12 15 18 21 24 27 30 Pts at Risk, n Mos Since Randomization Olaparib 196 182 156 134 118 104 89 82 32 29 3 Placebo 99 70 37 22 18 17 14 12 7 6 Slide credit: clinicaloptions.com Pujade-Lauraine E, et al. SGO Abstract LBA2.

77 SOLO-2: PFS Sensitivity Analysis Using BICR
100 Median PFS, Mos 90 Placebo 5.5 80 Olaparib 30.2 70 HR: 0.25 (95% CI: ; log-rank P < .0001) 60 PFS (%) 50 40 30 20 10 BICR, blinded independent central review. 3 6 9 12 15 18 21 24 27 30 33 Pts at Risk, n Mos Since Randomization Olaparib 196 176 148 128 112 103 88 82 30 28 3 1 Placebo 99 62 26 18 16 14 14 11 6 5 Slide credit: clinicaloptions.com Pujade-Lauraine E, et al. SGO Abstract LBA2.

78 SOLO-2: Secondary Endpoints (TFST, PFS2, TSST)
HR: 0.28 (95% CI: ; P < .0001) 27.9 TFST 7.1 Olaparib Placebo Median not reached HR: 0.50 (95% CI: ; P = .0002) PFS2 18.4 HR: 0.37 (95% CI: ; P < .0001) Median not reached TSST TFST, time to first subsequent therapy or death; TSST, time to second subsequent therapy or death. 18.2 10 20 30 Mos Slide credit: clinicaloptions.com Pujade-Lauraine E, et al. SGO Abstract LBA2.

79 SOLO-2: Most Common AEs AEs, % Olaparib (n = 195) Placebo (n = 99) All Grades Grade ≥ 3 Any 98.5 36.9 94.9 18.2 Nausea 75.9 2.6 33.3 Fatigue/asthenia 65.6 4.1 39.4 2.0 Anemia 43.6 19.5 8.1 Vomiting 37.4 19.2 1.0 Diarrhea 32.8 20.2 Dysgeusia 26.7 7.1 Headache 25.1 0.5 13.1 Abdominal pain 24.1 31.3 3.0 Decreased appetite 22.1 11.1 Constipation 20.5 23.2 AE, adverse events; AML, acute myeloid leukemia; MDS, myelodysplastic syndromes. MDS/AML occurred in 4 pts receiving olaparib (2.1%) and 4 cases in placebo group (4.0%) Friedlander M, et al. ASCO Abstract Ledermann JA, et al. ASCO Abstract Pujade-Lauraine E, et al. SGO Abstract LBA2. Slide credit: clinicaloptions.com

80 SOLO-2: QAPFS Using Health-Related Quality of Life
Significantly longer QAPFS with olaparib vs placebo Olaparib 1.0 Olaparib quality adjusted Placebo Outcome Olaparib (n = 185) Placebo (n = 94) Difference (95% CI) P Value Mean PFS, mos 17.55 8.94 8.61 (6.47 to 10.87) < .0001 Mean utility (mixed model) 0.80 0.81 (-0.05 to 0.02) .284 QAPFS, mos 13.96 7.28 6.68 (4.98 to 8.54) 0.8 Placebo quality adjusted 0.6 Probability 0.4 QAPFD, quality-adjusted PFS. 0.2 3 6 9 12 15 18 21 24 27 Mos From Randomization Slide credit: clinicaloptions.com Friedlander M, et al. ASCO Abstract 5507.

81 Mos From Randomization Mos From Randomization
SOLO-2: TWiST TWiST duration = mean PFS – mean toxicity Olaparib, Mos (n = 185) Placebo, Mos (n = 94) Difference (95% CI) P Value TWiST 13.5 7.21 (2.95 to 8.58) < .0001 Toxicity 3.69 0.71 (1.52 to 4.68) .0002 1.0 1.0 Olaparib 0.8 0.8 0.6 0.6 Probability Probability Placebo 0.4 0.4 TWiST TWiST 0.2 TWiST, time without symptoms of disease or toxicity. 0.2 Toxicity Toxicity 3 6 9 12 15 18 21 24 27 3 6 9 12 15 18 21 24 27 Mos From Randomization Mos From Randomization Slide credit: clinicaloptions.com Friedlander M, et al. ASCO Abstract 5507.

82 Accelerated Approval Cohort for Rucaparib, December 2016
Dose: 600 mg BID Pt population: N = 106 (from phase II ARIEL2 and a phase I/II trial) Recurrent ovarian cancer 2+ prior lines of treatment Germline or somatic BRCA mutations ORR: 54% Slide credit: clinicaloptions.com fda.gov/drugs/informationondrugs/approveddrugs/ucm htm

83 ARIEL2 Analysis: Pts With Mutated Germline or Somatic BRCA
ARIEL2 (n = 493) Germline/Somatic BRCAmut or BRCA WT ARIEL2: This Analysis (n = 134) Germline/Somatic BRCAmut Part 1 (n = 206) ≥ 1 prior platinum-based therapy Platinum as their last treatment Platinum sensitive Part 1 (n = 41) ≥ 1 prior platinum-based therapy Platinum as their last treatment Platinum sensitive WT, wild type. Part 2 (n = 287) 3 or 4 prior chemotherapies Platinum sensitive, platinum resistant, or platinum refractory Part 2 (n = 93) 3 or 4 prior chemotherapies Platinum sensitive, platinum resistant, or platinum refractory Slide credit: clinicaloptions.com Konecny GE, et al. SGO Abstract 1.

84 ARIEL2: PFS by Platinum Sensitivity
Median PFS, Mos 95% CI Pt-sensitive, last treatment pt-based; PFI ≥ 6 mos (n = 57) 12.7 Pt-sensitive, last treatment non-pt-based (n = 14) 7.4 Platinum resistant (n = 49) 7.3 Platinum refractory (n = 14) 5.0 100 80 60 PFS (%) 40 PFI, progression-free interval. 20 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Mos Slide credit: clinicaloptions.com Konecny GE, et al. SGO Abstract 1.

85 ARIEL2: PFS by Degree of Platinum Sensitivity (PFI)
95% CI PFI ≥ 18 mos (n = 9) 25.1 5.5-NR PFI ≥ 12 mos (n = 21) 16.9 PFI ≥ 6 mos (n = 57) 12.7 Last tx non-pt based (n = 14) 7.4 Median PFS, Mos 100 80 60 PFS (%) 40 NR, not reached; PFI, progression-free interval; tx, treatment. 20 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Mos Slide credit: clinicaloptions.com Konecny GE, et al. SGO Abstract 1.

86 ARIEL2: PFS in Platinum-Sensitive Pts by Germline vs Somatic BRCA Mutation
100 80 60 40 20 30 28 26 24 22 18 16 14 12 10 8 6 4 2 PFS (%) Mos Median PFS, Mos 95% CI Germline BRCAmut (n = 32) 12.8 Somatic BRCAmut (n = 19) 12.7 Indeterminate BRCAmut (n = 6) 7.1 5.5-NR Slide credit: clinicaloptions.com Konecny GE, et al. SGO Abstract 1.

87 ARIEL2: Treatment-Emergent AEs in ≥ 20% of Pts With BRCAmut HGOC (N = 134)
All Grades Grade 3/4 Nausea 78 5 Asthenia/fatigue 10 Vomiting 49 Anemia 48 29 Dysgeusia 40 ALT/AST increased 39 Decreased appetite 3 Abdominal pain 38 2 Constipation 35 <1 Diarrhea 34 Thrombocytopenia 25 7 Blood creatinine increased 23 Dyspnea Urinary tract infection 20 4 AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HGOC, high-grade ovarian cancer. Slide credit: clinicaloptions.com Konecny GE, et al. SGO Abstract 1.

88 Phase III ARIEL3: Rucaparib Maintenance in Platinum-Sensitive Ovarian Cancer
Stratified by HRD classification, response to platinum regimen, PFI after penultimate platinum Pts with high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer after ≥ 2 prior platinum regimens, sensitive to penultimate platinum regimen, response to most recent platinum regimen, CA-125 ≤ ULN, ECOG PS 0-1, no prior PARP inhibitor (Planned N = 540) Rucaparib 600 mg BID Placebo BID ECOG, Eastern Cooperative Oncology Group; HRD, homologous recombination deficiency; PFI, progression-free interval; PS, performance status; ULN, upper limit of normal. Primary endpoint: PFS in molecularly defined subgroups Secondary endpoints: OS PFS by independent radiology Pt-reported outcomes Safety Slide credit: clinicaloptions.com Clinicaltrials.gov. NCT

89 ARIEL3: Primary Efficacy Analyses
Analysis Population PFS by Investigator Review (Primary Endpoint) PFS by BICR (Key Secondary Endpoint) HR Median PFS, Mos Rucaparib vs Pbo Primary Analyses tBRCAmut (n = 196) 0.23; P < .0001 16.6 vs 5.4 0.20; P < .0001 26.8 vs 5.4 HRD positive (n = 354) 0.32; P < .0001 13.6 vs 5.4 0.34; P < .0001 22.9 vs 5.5 Intent to treat (n = 564) 0.36; P < .0001 10.8 vs 5.4 0.35; P < .0001 13.7 vs 5.4 Exploratory Analyses BRCAwt/HRD positive (n = 158) 0.44; P < .0001 9.7 vs 5.4 0.55; P = .0135 11.1 vs 5.6 BRCAwt/HRD negative (n = 161) 0.58; P = .0049 6.7 vs 5.4 0.47; P = .0003 8.2 vs 5.3 BICR, blinded independent central review; HRD, homologous recombination deficiency; Pbo, placebo. Press release, June An expanded description of the ARIEL3 results will be presented in a scientific session at a medical meeting in late 2017. Slide credit: clinicaloptions.com

90 Future Directions

91 Relationship Between MSI and Tumor-Associated Inflammatory Response
Robust tumor-associated inflammatory response Hypermutation (10x to 100x increase in mutational load vs MMR-proficient tumors) Many neoantigens expressed on tumor cells MSI-H High PD-1 and/or PD-L1 on tumor-infiltrating inflammatory cells High PD-L1 on tumor cells MMR, mismatch repair; MSI, microsatellite instability; MSI-H, microsatellite instability high. Slide credit: clinicaloptions.com Le DT, et al. N Engl J Med. 2015;372:

92 MSI Analysis Using Microsatellite Markers
175 189 203 217 231 245 330 Normal Amount of DNA 220 110 175 189 203 217 231 245 600 Tumor Amount of DNA 400 MSI, microsatellite instability. 200 Size of DNA Fragments (bp) Allelic shift in tumor demonstrated by presence of new peaks vs control normal tissue Slide credit: clinicaloptions.com

93 New Approval: Pembrolizumab
In May 2017, pembrolizumab received accelerated approval from FDA For MSI-H or MMR-deficient CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan For ALL unresectable or metastatic MSI-H or MMR-deficient SOLID TUMORS (pediatric and adult) that have progressed on prior treatment and with no satisfactory alternative treatment options CRC, colorectal cancer; MMR, mismatch repair; MSI-H, microsatellite instability high.

94 Pembrolizumab in Pts With Metastatic MSI-High or dMMR Tumors After PD on Prior Tx
Included data from KEYNOTE-016, -164, -012, -028, and -158 for total of 149 pts MMR testing using standard PCR-based assay for detection of MSI Additional pts not listed in table included 2 each of breast and prostate cancer; 1 each of bladder, esophageal, sarcoma, thyroid, retroperitoneal adenocarcinoma, SCLC, and RCC with 6 pts achieving CR or PR Tumor Type n ORR, % (95% CI) DoR Range, Mos CRC 90 36 (26-46) 1.6+ to 22.7+ Non-CRC 59 46 (33-59) 1.9+, 22.1+ Endometrial cancer 14 36(13-65) 4.2+ to 17.3+ Biliary cancer 11 27 (6-61) 11.6+ to 19.6+ Gastric or GEJ cancer 9 56 (21-86) 5.8+ to 22.1+ Pancreatic cancer 6 83 (36-100) 2.6+ to 9.2+ Small intestinal cancer 8 38 (9-76) 1.9+ to 9.1+) CRC, colorectal cancer; dMMR, mismatch repair deficiency; DoR, duration of response; GEJ, gastroesophageal junction; MMR, mismatch repair; MSI, microsatellite instability; PD, progressive disease; RCC, renal cell carcinoma; SCLC, small-cell lung cancer; Tx, treatment. Slide credit: clinicaloptions.com Pembrolizumab [package insert]

95 MSI-High and dMMR in Ovarian Cancer
MSI-H in Unselected Ovarian Cancers Histologic Subtype HNPCC MSI-High dMMR Pooled Proportion (95% CI) Serous 0.42 ( ) 0.36 ( ) 0.32 ( ) Nonserous 0.57 ( ) 0.063 ( ) 0.95 ( ) 0.68 ( ) Mucinous 0.16 ( ) 0.22 ( ) 0.26 ( ) 0.19 ( )  Endometrioid 0.25 ( ) ( ) 0.34 ( ) 0.29 ( )  Clear cell 0.17 ( ) 0.10 ( ) 0.35 ( ) 0.18 ( ) Undifferentiated 1 study 0.24 ( ) Allen et al 2000 Alvi et al 2001 Buller et al 2001 Codegoni et al 1999 Dallas et al 2004 Fujita et al 1995 Geisler et al 2001 Gras et al 2001 Han et al 1993 Iwabuchi et al 1995 King et al 1995 Kobayashi et al 1995 Krajinovic et al 1998 Osborne et al 1994 Shih et al 1998 Sood et al 1996 Sood et al 2001 Tangir et al 1996 Combined ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) dMMR, mismatch repair deficiency; HNPCC, hereditary nonpolyposis colorectal cancer; MSI, microsatellite instability. 0.2 0.4 0.6 Proportion (95% CI) Slide credit: clinicaloptions.com Pal T, et al. Clin Cancer Res. 2008;14:

96 Conclusions Cytotoxic chemotherapy still has a role in ovarian cancer
Differences in dose and schedule may be important Role of IP therapy becoming clearer Angiogenesis is an established target Bevacizumab now FDA approved PARP inhibitors are emerging as important therapy Olaparib, rucaparib, and niraparib now FDA approved Labels are expanding based on recently reported positive trials Role of immunotherapy promising in ovarian cancer Slide credit: clinicaloptions.com

97 Go Online for More CCO Coverage of Ovarian Cancer!
CME-certified text module with key data and expert perspective on managing ovarian cancer ClinicalThoughtTM Commentaries on ovarian cancer with expert discussion and insights clinicaloptions.com/oncology


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