1. Early Treatment of Relapsed Ovarian Cancer Based on CA125 Level Alone Versus Delayed Treatment Based on Conventional Clinical Indicators Results of the Randomized MRCOV05 and EORTC 55955 Trials Rustin G et al. ASCO 2009; Abstract 1. (Plenary Oral Presentation)

2. Source: Rustin G et al. ASCO 2009; Abstract 1. Introduction 80% of patients with advanced ovarian cancer (OC) will relapse after first line chemotherapy Most of these patients will benefit from further therapy Serial measurements of circulating tumor markers (CA125) have the potential for earlier detection of relapse It is unclear whether patients benefit from earlier treatment of chemical relapse Current study objectives: –Investigate the benefit of early chemotherapy for relapsed OC, based on raised CA125 level alone, versus delayed chemotherapy based on conventional clinical indicators

3. CA125 >2x upper limit of normal (ULN) RANDOMIZED N = 529 (37%) Trial Design Ovarian cancer in complete remission after first-line platinum based chemotherapy and a normal CA125 REGISTER: Blinded CA125 measured every 3 months N = 1,442 Early treatment (Clinician and patient informed) N=265 N=254 (96%) started second-line chemo Delayed treatment (Clinician not informed, treatment delayed until clinically indicated) N=264 N=233 (88%) started second-line chemo Source: Rustin G et al. ASCO 2009; Abstract 1. Clinical relapse/Death CA125 <2x ULN Consent withdrawal/Other

4. Primary Outcome: Overall Survival Source: With permission from Rustin G. ASCO 2009; Abstract 1. No difference in overall survival between early and delayed second-line chemotherapy

5. Secondary Outcome: Time from Randomization to Second- or Third-line Treatment (or Death) Source: Rustin G et al. ASCO 2009; Abstract 1. Outcome Measure Early (N=265) Months Delayed (N=264) Months Hazard ratio (95% CI)P value Time from randomization to second-line chemotherapy 0.85.6 0.29 (0.24-0.35) <0.00001 Time from randomization to third-line chemotherapy or death 12.517.1 0.69 (0.58-0.83) 0.0001

6. Quality of Life (QoL) Source: Rustin G et al. ASCO 2009; Abstract 1. Outcome Measure Early (N=190) Months Delayed (N=194) Months Hazard ratio (95% CI)P value Time from randomization to first deterioration of GHS or death 3.15.8 0.71 (0.57-0.87) 0.001 Overall time spent with “good” GHS 7.19.2NA 0.15 EORTC QLQ-C30 questionnaire Q 3 months from registration and prior to each cycle of chemo, until the end of third-line treatment “Good” Global Health Score (GHS): improved or <10%  from pre-randomization score Global Health deterioration: >10%  from pre-randomization score

7. Summary and Conclusions In patients receiving early treatment based on rise in CA125 –Second-line chemo commenced a median of 4.8 months earlier –Third-line chemo commenced a median of 4.6 months earlier This early treatment did not improve overall survival –Hazard Ratio: 1.00, p=0.98 Early treatment with chemotherapy does not improve QoL There appears to be no benefit from early detection of relapse by routine CA125 measurements Source: Rustin G et al. ASCO 2009; Abstract 1.

8. Practice Implications Recommend less frequent monitoring of CA125 values in asymptomatic patients Consider delaying palliative chemotherapy until clinical recurrence (even in the presence of rising CA125) Women can be offered informed choices in follow-up: –No routine CA125 measurement, but rapid access to CA125 testing if symptoms or signs of relapse –Regular CA125 measurements Source: Rustin G et al. ASCO 2009; Abstract 1; Karlan B. ASCO 2009; Discussion