1. Therapeutic Options for Recurrent Platinum-Sensitive Ovarian Cancer (PSOC)
GEMSTONE Educational Module
Last Update: April 9, 2018
GEMSTONE, a committee of ovarian cancer experts, provided direction and approval of the material in this educational resource. TESARO, Inc. provided writing and organizational support to GEMSTONE in the generation of this material.

2. Module Objectives
Understand sensitivity to platinum-based chemotherapy
Identify the potential role of surgery at recurrence
Review treatment options for PSOC, including the role of maintenance therapy
Review future treatment opportunities
PSOC, platinum-sensitive ovarian cancer.

3. Module Outline Defining Platinum-Sensitive Recurrent Disease
Treating Biochemical Recurrence
Secondary Cytoreductive Surgery
Key Platinum-Doublet Trials in Recurrent PSOC
Targeted Therapy Maintenance Treatment Trials in Recurrent PSOC
Evaluation of Anti-Angiogenic Agent and PARP Inhibitor Combination Approaches
Summary and Unresolved Questions
PARP, poly ADP ribose polymerase; PSOC, platinum-sensitive ovarian cancer.

4. Defining Platinum-Sensitive Recurrent Disease

5. Most Ovarian Cancers Will Recur, Leading to Poor Prognosis and Shorter Treatment Intervals
~80% of advanced ovarian cancers will recur during or after 1L treatment
Median PFS decreases after every recurrencea:
mPFS
10.2 mo
(9.6–10.7)
6.4 mo (5.9–7.0)
5.6 mo
(4.8–6.2)
4.4 mo (3.7–4.9)
4.1 mo (3.0–5.1)
18.2 mo
(17.3–19.1) 5L 6L 4L 3L 2L 1L
Fourth
Recurrence
Fifth
Third
Second
First
Note: Data depict historical mPFS of watch-and-wait, and do not represent PFS observed with maintenance treatment.
a mPFS values measured from beginning of chemotherapy (ie, day of randomization) to the first disease progression and, thereafter, from one progression to the subsequent one or to death.
L, line; mPFS, median progression-free survival; PFS, progression-free survival.
Hanker LC, et al. Ann Oncol. 2012;23(10):

6. Improved Response to Salvage Therapy Increases PFS and OS
100 90 80 70 60 50 40 30 20 10
Response Rate
Response to Salvage Therapy (%) OS
PFS
0–3 mo PD
0–3 mo Non-PD
3–12 mo
12–18 mo
18+ mo
Treatment-Free Interval (TFI) After Prior Chemotherapy
OS, overall survival; PD, progressive disease; PFS, progression-free survival. 1. Pujade-Lauraine E. Presented at ASCO Annual Meeting, Abstract Pujade-Lauraine E. Recurrent disease. ESMO: Oncology Pro (Educational Portal for Oncologists) / /file/Advanced-Ovarian-Cancer Pujade-Lauraine.pdf. Accessed March 29, 2018.

7. Definitions of Platinum Sensitivity Are Based on Platinum-Free Interval
Platinum-free interval (PFI) defined from the last date of platinum dose until progressive disease1
Patient populations2,a:
Platinum-based therapy
Platinum-refractory
Platinum-resistant
Platinum-sensitive
<1
1–6 ≥6
Time from last platinum exposure while in complete remission (months)
a Adapted from definitions established by the 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer intergroup (GCIG) in 2010.
1. Stuart GC, et al. Int J Gynecol Cancer. 2011;21(4): Wilson MK, et al. Ann Oncol. 2017;28(4):

8. PFI Is a Reliable Predictor of Response to Subsequent Chemotherapy for Recurrence1
Time from last platinum exposure while in complete remissiona,1,2
<6 mo
≥6 mo
6 mo
Treatment
Completion
Platinum-Resistant/Refractory
Platinum-Sensitive
Platinum-based or non-platinum–based treatment for recurrence
Non-platinum–based treatment for recurrence
a For detailed recommendations (including recommended regimens for treatment of recurrent disease), see the complete version of the NCCN Guidelines for Ovarian Cancer.
PFI, platinum-free interval.
1. Wilson MK, et al. Ann Oncol. 2017;28: NCCN Guidelines® Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (V ). Available online at NCCN.org. Accessed March 29, 2018.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Guideline Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer V © National Comprehensive Cancer Network, Inc All rights reserved. Accessed March 29, To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

9. Evolution of Patient Subgroups to Reflect a New Treatment Landscape: GCIG Consensus Statementsa
With increasing use of non-platinum and biologic agents, previous definitions of recurrent disease may be inadequate to identify clinically relevant patient subgroups1,2
TFI categories2:
Additional criteria to consider for ROC subgroups in clinical trials2:
Histology
BRCA status (germline and somatic mutations)
Number/type of prior therapies
Outcome of prior surgery
Tumor volume
Patient-reported symptoms
TFI from last platinum dose (PFI)
TFI from last non-platinum therapy
TFI from last biological agent
TFIp
TFInp
TFIb
a From the 5th Ovarian Cancer Consensus Conference of the Gynecologic Cancer intergroup (GCIG) in 2015.
BRCA, breast cancer susceptibility gene; PFI, platinum-free interval; ROC, recurrent ovarian cancer; TFI, treatment-free interval.
1. Ganghadaran SGD. J Cancer Res Treatment. 2016;4(2): Wilson MK, et al. Ann Oncol. 2017;28(4):

10. Treating Biochemical Recurrence

11. Imaging and Biochemistry Can Help to Guide Assessment of Recurrencea
Rising CA-125 or clinical relapse
No prior chemotherapy
Imaging studies as clinically indicatedb:
C/A/P CT
MRI
PET/CT
PET
Tumor molecular testingc
Treat as per primary treatment pathway
Clinical relapse
Previous chemotherapy
See pathways for treatment of recurrence
Serially rising CA-125
Previous chemotherapy
Clinical trial or delay treatment until clinical relapse
a For detailed recommendations (including recommended regimens for treatment of recurrent disease), see the complete version of the NCCN Guidelines for Ovarian Cancer. b Surveillance imaging may be indicated when tumor markers are considered unreliable, the physical exam is unreliable, and/or there is a high risk of recurrence. C Validated molecular testing should be performed in a CLIA-approved facility using the most recent available tumor tissue. Testing should include at least: BRCA1/2, homologous recombination pathway genes, and microsatellite instability or DNA mismatch repair.
CA, cancer antigen; C/A/P, chest, abdomen, pelvis; CLIA, Clinical Laboratory Improvement Amendments of 1988; CT, computed tomography; MRI, magnetic resonance imaging; PD, progressive disease; PET, positron emission tomography.
NCCN Guidelines® Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (V ). Available online at NCCN.org. Accessed March 29, 2018.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Guideline Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer V © National Comprehensive Cancer Network, Inc All rights reserved. Accessed March 29, To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

12. MRC OV05/EORTC 55955 Study Showed No Benefit in OS From Treating Biochemical (CA-125) Recurrence
Physical and gynecologic examinations every 3 months, blinded to CA-125 measurements
Patients in complete remission after 1L platinum-based chemotherapy and normal CA-125 levels
Early
Delayed
Patients randomized if CA-125 >2× ULN
Months
Number at risk: Early
Delayed
Early
Delayed
mOS, mo (95% CI)
25.7 (23.0–27.9)
27.1 (22.8–30.9)
HR (95% CI)
0.98 (0.80–1.20)
P Value
0.85
Early Treatment:
Chemotherapy within 28 days
Delayed Treatment: Observation until clinical recurrence, then chemotherapy
No survival benefit observed, and deterioration of QoL was more rapid
Primary Outcome: OS
CA, cancer antigen; CI, confidence interval; EORTC, European Organisation for Research and Treatment of Cancer; HR, hazard ratio; L, line; mOS, median overall survival; MRC, Medical Research Council; OS, overall survival; QoL, quality of life; ULN, upper limit of normal.
Rustin GJ, et al. Lancet. 2010;376(9747):

13. Tamoxifen as an Option for Initial Management of Patients With Asymptomatic Recurrent Disease
Tamoxifen and other hormonally active agents are among the acceptable management options (category 2Ba) for patients with biochemical recurrence (ie, only rising CA-125 level as evidence of tumor progression) who previously received chemotherapy (prior to recurrence)1
For asymptomatic patients, goals of treatment differ from patients experiencing cancer-related symptoms2:
Slow time to subsequent progression
Do not negatively impact QoL
Delay time until patient requires treatment with chemotherapy
a Category 2B: Based on lower-level evidence, there is NCCN consensus that the intervention is appropriate.
CA, cancer antigen; QoL, quality of life.
1. NCCN Guidelines® Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (V ). Available online at NCCN.org. Accessed March 29, Markman M, et al. Gynecol Oncol. 2004;93(2):390-3.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Guideline Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer V © National Comprehensive Cancer Network, Inc All rights reserved. Accessed March 29, To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

14. Consider secondary cytoreductive surgery
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Recommendations for PSOC Differ for Clinical Relapse vs Biochemical Relapsea
Relapse
Surgical Options
Treatment Options
Treatment Options for Patients Who Received Platinum-Based Recurrence Therapy
Radiographic and/or clinical
Consider secondary cytoreductive surgery
Clinical trial
Combination platinum chemotherapy ×6 cycles (preferred for first recurrence)
Recurrence therapyb
Best supportive care
If partial or complete response:
Continue bevacizumab as maintenance therapyc
Consider PARPi maintenance therapyd
Observe
Biochemical (rising CA-125 and no radiographic evidence of disease) and previous chemotherapy
None
Delay treatment until clinical relapse (ie, observation)
Immediate treatment for recurrence with platinum- based or non-platinum–based therapy (category 2Be)
a For detailed recommendations (including recommended regimens for treatment of recurrent disease), see the complete version of the NCCN Guidelines for Ovarian Cancer. b Acceptable recurrence therapies include cytotoxic, targeted, hormonal, and radiation therapies. c If previously treated with chemotherapy + bevacizumab. d For patients with platinum-sensitive disease who have completed two or more lines of platinum-based therapy. e Category 2B: Based on lower-level evidence, there is NCCN consensus that the intervention is appropriate.
CA, cancer antigen; PARPi, poly ADP ribose polymerase inhibitor; PSOC, platinum-sensitive ovarian cancer.
NCCN Guidelines® Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (V ). Available online at NCCN.org. Accessed March 29, 2018.
Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Guideline Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer V © National Comprehensive Cancer Network, Inc All rights reserved. Accessed March 29, To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

15. Secondary Cytoreductive Surgery

16. Rationale for Cytoreductive Surgery Is Centered on Improving Opportunity for Next Therapy
May remove poorly vascularized tumor restricted from systemic therapy
Increase amount of cancer cells killed by removing large tumors in the plateau phase of growth
Small tumors require fewer cycles of chemotherapy, which may reduce risk of resistance
Immunocompetence toward tumor may be enhanced by removal of tumor bulk
Harter P, et al. Ann Surg Oncol. 2006;13(12):

17. Complete Resection (No Residuals) Any Postoperative Residuals
AGO DESKTOP I: Improved OS Was Observed With Secondary Debulking Surgery in a Retrospective Study
Retrospective study of 267 patients with recurrent ovarian cancer treated with cytoreductive surgery between 2000 and 2003
Complete Resection (No Residuals)
Any Postoperative Residuals
mOS, mo
45.2
19.7
HR (95% CI)
3.71 (2.27–6.05)
P Value
<0.0001
No Residuals
Residuals >10 mm
Residuals 1–10 mm
Months From Randomization
AGO, Arbeitsgemeinschaft Gynaekologische Onkologie; CI, confidence interval; HR, hazard ratio; mOS, median overall survival; OS, overall survival.
Harter P, et al. Ann Surg Oncol. 2006;13(12):

18. AGO DESKTOP III: Improved PFS With Secondary Debulking Surgery
407 patients relapsing ≥6 months since platinum chemotherapy were randomly assigned to either undergo cytoreductive surgery prior to 2L chemotherapy or receive chemotherapy without surgery1
Surgery
No surgery
Selection Criteria2:
First recurrence of platinum- sensitive, invasive epithelial ovarian, fallopian tube, or primary peritoneal cancer of any initial stage
Positive AGO score:
PS ECOG 0
No residual tumor after primary surgery
Absence of ascites
No radiological signs suggesting presence of metastases not accessible to surgical removal
Surgery
No Surgery
mPFS, mo
19.6
14.0
HR (95% CI)
0.66 (0.52–0.83)
P Value
<0.001
Number at risk:
Surgery
No Surgery
AGO, Arbeitsgemeinschaft Gynaekologische Onkologie; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; L, line; mPFS, median progression-free survival; PFS, progression-free survival; PS, performance status.
1. du Bois A, et al. Presented at ASCO Annual Meeting, Abstract ClinicalTrials.gov. NCT Accessed March 29, 2018.

19. Surgery but With Residual Tumor Surgery With Complete Resection
DESKTOP III: Benefit of Secondary Cytoreductive Surgery Was Only Seen in Patients With Complete Resection
Surgery but With Residual Tumor
Surgery With Complete Resection
No Surgery
mPFS, mo
13.7
21.2
14.0
HR (95% CI)
0.98 (0.71–1.35)
0.56 (0.43–0.72)
P Value
0.8952
<0.0001
Surgery but With Residual Tumor
Surgery With Complete Resection
No Surgery
Number at risk:
Surgery With Complete Resection
Surgery but With Residual Tumor
No Surgery
CI, confidence interval; HR, hazard ratio; mPFS, median progression-free survival; PFS, progression-free survival.
du Bois A, et al. Presented at ASCO Annual Meeting, Abstract 5501.

20. mOS: Complete Resection1 mOS: Incomplete Resection1
Certain Factors May Predict Success of Secondary Cytoreductive Surgery and Benefit
Factor1
Good Prognosis Range
TFI
>12 mo
Distant metastases
Absent
Number of recurrent tumors
Solitary PS
mOS: Complete Resection1
mOS: Incomplete Resection1
3–4 factors
83 mo
67.5 mo
2 factors
41 mo
25 mo
0–1 factors
19 mo
Tian model for predicting complete SCR includes FIGO stage, ascites at recurrence, residual disease after primary cytoreduction, progression-free interval, ECOG PS, CA-1252
AGO model uses ECOG PS, ascites, and macroscopic complete resection in primary therapy to predict complete SCR3
DFI = disease-free interval; mo = months; SC = secondary cytoreduction.
AGO, Arbeitsgemeinschaft Gynaekologische Onkologie; CA, cancer antigen; ECOG, Eastern Cooperative Oncology Group; FIGO, Federation of Gynecology and Obstetrics; mOS, median overall survival; PS, performance status; SCR, secondary cytoreductive surgery; TFI, treatment-free interval.
1. Minaguchi T, et al. Int J Clin Oncol. 2016;21(3): Tian WJ, et al. Ann Surg Oncol. 2012;19(2): Harter P, et al. Int J Gynecol Cancer. 2011;21(2): 20 20

21. Considerations for Cytoreductive Surgery
Perioperative morbidity1
Complete surgical resection rate2
Time to initiation of chemotherapy3
Questionable benefit of surgery for patients with chemotherapy-refractory/-resistant disease4
1. Walters CL, et al. Int J Gynecol Cancer. 2013;23(6): Cowan RA, et al. Gynecol Oncol. 2017;145(2): Hofstetter G, et al. Gynecol Oncol. 2013;131(1): Corrado G, et al. Expert Rev Anticancer Ther ;17(12):

22. Key Platinum-Doublet Trials in Recurrent PSOC

23. Rationale for Doublet Chemotherapy to Improve Clinical Treatment Benefit
Improve treatment efficacy over monotherapy approaches
Minimize development of resistance to treatment
Maximize effect of differing mechanisms of action
Decrease toxicity by reducing dosage of each agent
Bukowska B, et al. Contemp Oncol (Pozn). 2015;19(5):350-3.

24. Chemotherapy Doublets Were Shown Beneficial Compared to Monotherapy in PSOC
ICON41 (N=802)
Paclitaxel + Platinum (n=392)
Conventional Treatment (n=410)
HR (95% CI)
P Value
mPFS, mo 12 9
0.76 (0.66–0.89)
0.0004
mOS, mo 29 24
0.82 (0.69–0.97)
0.02
Intergroup Phase III Trial2 (N=356)
Gemcitabine + Carboplatin (n=178)
Carboplatin (n=178)
HR (95% CI)
P Value
mPFS, mo
8.6
5.8
0.72 (0.58–0.90)
0.0031
mOS, mo
18.0
17.3
0.96 (0.75–1.23)
0.7349
SWOG S02003,a
(N=61)
PLD + Carboplatin (n=31)
Carboplatin (n=30)
HR (95% CI)
P Value
mPFS, mo 12 8
0.54 (0.32–0.93)
0.03
mOS, mo 26 18
0.46 (0.22–0.95)
The direct cross-study comparison of results from independently conducted clinical trials is not intended on this slide.
a Study closed early due to slow patient accrual.
CI, confidence interval; HR, hazard ratio; mOS, median overall survival; mPFS, median progression-free survival; PLD, pegylated liposomal doxorubicin; PSOC, platinum-sensitive ovarian cancer.
1. Parmar MK, et al. Lancet. 2003;361(9375): Pfisterer J, et al. J Clin Oncol. 2006;24(29): Alberts DS, et al. Gynecol Oncol. 2008;108(1):90-4.

25. PLD + Trabectedin (n=218)b Carboplatin + Paclitaxel (n=509)
Chemotherapy Doublets Were Shown Beneficial Compared to Monotherapy in PSOC (continued)
OVA-3011,2 (N=430)a
PLD + Trabectedin (n=218)b
PLD (n=212)b
HR (95% CI)
P Value
mPFS, mo
9.2
7.5
0.73 (0.56–0.95)
0.0170
mOS, mo
27.0
24.1
0.83 (0.67–1.04)
0.106
CALYPSO3,4 (N=976)
Carboplatin + PLD (n=467)
Carboplatin + Paclitaxel (n=509)
HR (95% CI)
P Value
mPFS, mo
11.3
9.4
0.82 (0.72–0.94)
0.005
mOS, mo
30.7
33.0
0.99 (0.85–1.16)
0.94
Doublet approaches impact PFS but little OS effect has been observed to date in conclusive studies
The direct cross-study comparison of results from independently conducted clinical trials is not intended on this slide.
a Platinum-sensitive patient subgroup; full study N=672; PFS analysis total N=417. b PFS analysis: n=215 for PLD + trabectedin arm, n=202 for PLD-only arm.
CI, confidence interval; HR, hazard ratio; mOS, median overall survival; mPFS, median progression-free survival; OS, overall survival; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PSOC, platinum-sensitive ovarian cancer.
1. Monk BJ, et al. J Clin Oncol. 2010;28(19): Monk BJ, et al. Eur J Cancer. 2012;48(15): Pujade-Lauraine E, et al. J Clin Oncol. 2010;28(20): Wagner U, et al. Br J Cancer. 2012;107(4):

26. Targeted Therapy Maintenance Treatment Trials in Recurrent PSOC

27. Maintenance Therapy Is Extended Therapy With the Goal of Prolonging PFS Time
Multiple terms refer to extended treatment of a patient after primary therapy
Term
Definition
Additional Info
Consolidation therapy1
Treatment that is given after cancer has disappeared following the initial therapy. Consolidation therapy is used to kill any cancer cells that may be left in the body
Also called intensification therapy and postremission therapy
Maintenance therapy2
Treatment that is given to help keep cancer from progressing or coming back following the initial therapy; it may be given for a long time
May be used to slow growth of advanced cancer after initial treatment
Switch maintenance therapy3
Treatment with an agent with a different mode of action after completion of induction chemotherapy in patients whose tumors have not progressed
Definition based on maintenance therapy in NSCLC
NSCLC, non–small-cell lung cancer; PFS, progression-free survival.
1. NCI Dictionary of Cancer Terms. Consolidation therapy. terms/def/consolidation-therapy. Accessed March 29, ASCO. Understanding Maintenance Therapy. Cancer.net. Approved October Accessed March 29, Schmid-Bindert G. Transl Lung Cancer Res. 2012;1(2):

28. Landmark FDA Approvals in Ovarian Cancer Therapy1
Primary
Bevacizumab (platinum- sensitive)
Maintenance
Altretamine
Topotecan
Liposomal Doxorubicin (Full)
Bevacizumab (platinum- resistant)
Rucaparib (platinum- sensitive)
Cisplatin2
Carboplatin2
(1L)
1978
1989
1990
1991
1992
1996
1999
2005
2006
2014
2016
2017
2018
Niraparib (platinum- sensitive)
Carboplatin2
(palliative)
Paclitaxel
Liposomal Doxorubicin (Accelerated)
Gemcitabine
Olaparib (BRCAmut carriers)
Olaparib (platinum- sensitive)
Rucaparib (somatic + germline BRCAmut)
FDA, US Food and Drug Administration; L, line; mut, mutation.
1. FDA Approved Drug Products. Accessed March 29 and April 9, Kelland L. Nat Rev Cancer. 2007;7(8):

29. Study Designs of Key Anti-Angiogenic Maintenance Therapy Trials in PSOC
OCEANS1,2
(NCT )
GOG-02133,4
(NCT )
ICON65,6 (NCT ) N
484
1038a
486
Design
Phase 3, randomized, 2L therapy
Phase 3, randomized
Patient Population
Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer
Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients must be candidates for cytoreductive surgery
Study Arms
Active comparator: CG + PBO
Experimental: CG + BEV
Arm I : Chemob
Arm II: Chemob + BEV
Arm III: CG
Arm IV: CG + BEV
Arm A: Chemo + PBO  PBO
Arm B: Chemo + CED  PBO
Arm C: Chemo + CED  CED
Dosage
C AUC 4 IV day 1, G 1000 mg/m2 IV days 1 & 8, CG for 6 (up to 10) 21-day cycles; PBO q3w or BEV 15 mg/kg IV q3w until progression
Arm I/II: C AUC 5 IV day 1, P 175 mg/m2 IV day 1, CP for day cycles; BEV 15 mg/kg IV day 1 q3w until progression
6 cycles platinum-based chemo, CED 20 mg oral tablet daily; maintenance treatment continued for 18 mo or until progression
1° Endpoint
PFS
OS for secondary cytoreduction in addition to adjuvant chemo, OS for addition of BEV relative to 2L CP alone
PFS (arm A vs arm C)
2° Endpoint
ORR, DOR, OS, safety
PFS, safety, QoL
OS, toxicity, QoL
Stratification Factors
PFI, cytoreductive surgery for recurrent disease
PFI, cytoreductive surgery for recurrent disease
PFI, 1L chemo regimen, previous BEV treatment
a Estimated enrollment. b Paclitaxel or docetaxel and carboplatin; for portion of trial with data output, paclitaxel and carboplatin.
AUC, area under the curve; BEV, bevacizumab; C, carboplatin; CED, cediranib; CG, carboplatin/gemcitabine; Chemo, chemotherapy; CP, carboplatin/paclitaxel; DOR, duration of response; G, gemcitabine; IV, intravenous; L, line; ORR, objective response rate; OS, overall survival; P, paclitaxel; PBO, placebo; PFI, platinum-free interval; PFS, progression-free survival; PSOC, platinum-sensitive ovarian cancer; q3w, every 3 weeks; QoL, quality of life.
1. ClinicalTrials.gov. NCT Accessed March 29, Aghajanian C, et al. J Clin Oncol. 2012;30(17): ClinicalTrials.gov. NCT Accessed March 29, Coleman RL, et al. Lancet Oncol. 2017;18(6): ClinicalTrials.gov. NCT Accessed March 29, Ledermann JA, et al. Lancet. 2016;387(10023):

30. Chemo + Conc./ Maint. CED (n=164)
Summary of Efficacy and Safety Data for Key Anti-Angiogenic Maintenance Therapy Trials
OCEANS1,2,a
(NCT )
GOG-02133
(NCT )
ICON64,5 (NCT )
CG + PBO
(n=242)
CG + BEV CP
(n=337)
CP + BEV (n=337)
Chemo + PBO
(n=118)
Chemo + Conc./ Maint. CED (n=164)
mPFS, mo (95% CI)
8.4
(8.3–9.7)
12.4
(11.4–12.7)
10.4
(9.7–11.0)
13.8
(13.0–14.7)
8.7
11.1
HR (95% CI) P Value
0.484 (0.388–0.605)
<0.0001
0.628 (0.534–0.739) <0.0001
0.57 (0.45–0.74) <
mOS, mo (95% CI)
32.9
33.6
37.3
(32.6–39.7)
42.2 (37.7–46.2)
19.9
27.3
0.952 (0.771–1.176)
0.6479
0.829 (0.683–1.005)
0.056
0.85 (0.66–1.10)
0.21
Most Common Serious AEs in Experimental Arm (%)
Neutropenia (Gr ≥4): 21.1
Hypertension (Gr ≥3): 18.2
Proteinuria (Gr ≥3): 10.9
Hypertension (Gr ≥3): 12
Fatigue (Gr ≥3): 8
Proteinuria (Gr ≥3): 8
Maintenance phase:
Diarrhea (Gr ≥3): 12
Fatigue (Gr ≥3): 6
Neutropenia (Gr ≥3): 6
The direct cross-study comparison of results from independently conducted clinical trials is not intended on this slide.
a Safety population: n=233 PBO arm, n=247 BEV arm.
AEs, adverse events; BEV, bevacizumab; CED, cediranib; CG, carboplatin/gemcitabine; Chemo, chemotherapy; CI, confidence interval; Conc., concurrent; CP, carboplatin/paclitaxel; Gr, grade; HR, hazard ratio; Maint., maintenance; mOS, median overall survival; mPFS, median progression-free survival; PBO, placebo.
1. Aghajanian C, et al. J Clin Oncol. 2012;30(17): Aghajanian C, et al. Gynecol Oncol. 2015;139(1): Coleman RL, et al. Lancet Oncol. 2017;18(6): Ledermann JA, et al. Presented at ASCO Annual Meeting, Abstract Ledermann JA, et al. Lancet. 2016;387(10023):

31. Anti-Angiogenic Maintenance Summary
Anti-angiogenic agents improve PFS for recurrent PSOC1-3
Significant durable effect on OS has not been shown consistently for anti-angiogenic agents2,4,5
Anti-angiogenic maintenance therapy was associated with increased vascular adverse reactions, bleeding events, and other AEs compared with placebo, and varied by agent used2-4
AEs, adverse events; OS, overall survival; PFS, progression-free survival; PSOC, platinum-sensitive ovarian cancer.
1. Aghajanian C, et al. J Clin Oncol. 2012;30(17): Coleman RL, et al. Lancet Oncol. 2017;18(6): Ledermann JA, et al. Lancet. 2016;387(10023): Aghajanian C, et al. Gynecol Oncol. 2015;139(1): Ledermann JA, et al. Presented at ASCO Annual Meeting, Abstract 5506.

32. Study Designs of Key PARPi Maintenance Therapy Trials in Recurrent Ovarian Cancer
NOVA1,2 (NCT )
Study 193,4
(NCT )
SOLO-25,6
(NCT )
ARIEL37,8
(NCT ) N
553
265
295
564
Phase 3 2
Design
Randomized, placebo-controlled, with patients who have received ≥2 previous courses of platinum-containing therapy
Patient population
Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer; both gBRCAmut and non-gBRCAmut cohorts
Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer
Platinum-sensitive relapsed high-grade serous ovarian, fallopian tube, or primary peritoneal cancer, or high-grade endometrioid cancer, with BRCA1mut or BRCA2mut
Platinum-sensitive relapsed high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancers
Dosage
Niraparib oral 300 mg daily until disease progression
Olaparib oral 400 mg bid until disease progression
Olaparib oral 300 mg (tablets) bid until disease progression
Rucaparib oral 600 mg bid until disease progression
1⁰ Endpoint
PFS by RECIST (BICR) or central clinical assessment
PFS by RECIST (investigator radiography assessment)
2⁰ Endpoint
PRO, PFS2, time to subsequent therapy, OS, safety
OS, ORR, DCR, DOR, % change tumor size wk 24, best % change CA-125 levels, response, TTP, QoL
OS, TTP, PFS2, QoL, TFST, TSST, TDT, PFS patients with deleterious BRCA variant, PK
PFS by RECIST (BICR), QoL, OS, safety, PK
Stratification factors
TTP after completion of penultimate platinum regimen, prior treatment with BEV, best response during last platinum regimen
TTP on penultimate platinum therapy, objective response to last platinum regimen, ethnic descent
Response to previous platinum therapy, PFI
Response to previous platinum therapy, PFI, HR repair gene mutation status
BEV, bevacizumab; BICR, blinded independent central review; bid, twice daily; DCR, disease control rate; DOR, duration of response; g, germline; HR, homologous recombination; mut, mutation; ORR, objective response rate; OS, overall survival; PARPi, poly ADP ribose polymerase inhibitor; PFI, platinum-free interval; PFS, progression-free survival; PFS2, time from randomization to second progression; PRO, patient-reported outcomes; qd, once daily; QoL, quality of life; RECIST, Response Evaluation Criteria In Solid Tumors; TFST, time to first subsequent therapy or death; TSST, time to second subsequent therapy or death; TTP, time to progression.
1. ClinicalTrials.gov. NCT Accessed April 9, Mirza MR, et al. N Engl J Med. 2016;375(22): ClinicalTrials.gov. NCT Accessed April 9, Ledermann J, et al. N Engl J Med. 2012;366(15): ClinicalTrials.gov. NCT Accessed April 9, Pujade-Lauraine E, et al. Lancet Oncol. 2017;18(9): ClincialTrials.gov. NCT Accessed April 9, Coleman RJ, et al. Lancet. 2017;390(10106):

33. PARP Inhibitor Maintenance Summary
PARP inhibitor maintenance therapy has been shown to improve PFS compared with placebo in patients in response to platinum therapy1-3
OS data are not yet mature in most of these studies1-3
PARP inhibitor treatment is associated with hematological and gastrointestinal AEs1-3
Management through dose reduction is often possible with oral agents1-3
PRN medications can be used to manage gastrointestinal symptoms, such as nausea and vomiting4
Please refer to the module on PARP inhibition for more efficacy and safety data
AEs, adverse events; OS, overall survival; PARP, poly ADP ribose polymerase; PFS, progression-free survival; PRN, pro re nata (when necessary).
1. Mirza MR, et al. N Engl J Med. 2016;375(22): Pujade-Lauraine E, et al. Lancet Oncol ;18(9): Coleman RJ, et al. Lancet. 2017;390(10106):  4. Friedlander M, et al. Asia Pac J Clin Oncol. 2016;12(4):

34. Evaluation of Anti-Angiogenic Agent and PARP Inhibitor Combination Approaches

35. Rationale for Combining PARP Inhibition With Anti-Angiogenic Agents Grounded in Hypoxia
Restricting angiogenesis can induce a hypoxic state
Hypoxia can generate a “BRCAness” state by decreasing BRCA1 and RAD51 expression
Reduction in HR can increase sensitivity to PARP inhibition
HR, homologous recombination; PARP, poly ADP ribose polymerase.
Dréan A, et al. Crit Rev Oncol Hematol. 2016;108:73-85.

36. Combined Angiogenesis and PARP Inhibition Showed an Improved OS Trend in Non-gBRCAmut Subgroup
Randomized phase 2 study with platinum-sensitive, relapsed, high-grade serous, or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, and other histologies with deleterious germline BRCA1/2 mutations (NCT )1,2
ITT (N=90)
Olaparib (n=46)
Olaparib + Cediranib (n=44)
HR (95% CI)
P Value
mPFS, mo
8.2
16.5
0.50 (0.30–0.83)
0.007
mOS, mo
33.3
44.2
0.64 (0.36–1.11)
0.11
gBRCAmut Carrier (n=47)
Olaparib (n=24)
Olaparib + Cediranib (n=23)
HR (95% CI)
P Value
mPFS, mo
16.5
16.4
0.75 (0.38–1.49)
0.42
mOS, mo
40.1
44.2
0.79 (0.38–1.67)
0.55
Non-gBRCAmut* (n=43)
Olaparib (n=22)
Olaparib + Cediranib (n=21)
HR (95% CI)
P Value
mPFS, mo
5.7
23.7
0.32 (0.16–0.66)
0.002
mOS, mo
23.0
37.8
0.48 (0.21–1.08)
0.074
In contrast with the ITT population and the non-gBRCAmut carrier subgroup, no significant PFS benefit was observed with olaparib + cediranib combination treatment in patients who are gBRCAmut carriers
* Non-gBRCAmut carrier or status unknown.
BRCA, breast cancer susceptibility gene; CI, confidence interval; g, germline; HR, hazard ratio; ITT, intent to treat; mOS, median overall survival; mPFS, median progression-free survival; mut, mutation; OS, overall survival; PARP, poly ADP ribose polymerase; PFS, progression-free survival.
1. Liu JF, et al. Lancet Oncol. 2014;15(11): Liu JF, et al. Presented at ASCO Annual Meeting, Abstract 5535.

37. Ongoing Trials Exploring Anti-Angiogenic Agents and PARP Inhibitors Together in PSOC
Active Comparator
Experimental Therapy
Study Ph
Est. Enrollment
Patient Population
Prior Therapies
1° Outcomes
Est. 1° Completion Date
Maintenance niraparib
Maintenance niraparib + bevacizumab
AVANOVA (NCT )
1/2
108
Platinum-sensitive, recurrent epithelial ovarian, fallopian tube, or peritoneal cancer
Must have received platinum-containing therapy for primary disease
Part 1: safety and tolerability
Part 2: PFS
Nov 2018
Platinum- based chemotherapy
Olaparib or
olaparib + cediranib
NRG-GY004
(NCT ) 3
549
Platinum-sensitive, recurrent high-grade serous or high-grade endometrioid ovarian, primary peritoneal, or fallopian tube cancers; also high-risk histologies with documented BRCA1/2 mutations
Must have included a 1L platinum-based regimen
PFS
Dec 2019
Maintenance olaparib
Maintenance olaparib + cediranib
ICON9 (NCT )
618
Relapsed, platinum-sensitive ovarian, fallopian tube, or peritoneal cancer
Must have received 4–6 cycles of 2L platinum-based chemotherapy
PFS, OS
Dec 2023
Est., estimated; L, line; OS, overall survival; PARP, poly ADP ribose polymerase; PFS, progression-free survival; Ph, phase; PSOC, platinum-sensitive ovarian cancer.
ClinicalTrials.gov: NCT , NCT , and NCT Accessed March 29, 2018.

38. Summary and Unresolved Questions

39. Module Summary
Patients with ovarian cancer in complete remission whose disease recurs ≥6 months since treatment completion are typically considered platinum- or chemotherapy-sensitive1
Secondary cytoreductive surgery may be a valuable treatment option for some patients with recurrent PSOCa,2
Select combination platinum-based chemotherapy regimens are among the preferred options for treatment of recurrent PSOCa,2
Maintenance with select targeted therapies is a recommended option for select patients who respond to combination platinum-based chemotherapy for recurrent PSOCa,2
a For detailed recommendations (including regiments for treatment of recurrent disease), see the complete version of the NCCN Guidelines for Ovarian Cancer.
PSOC, platinum-sensitive ovarian cancer.
1. Ganghadaran SGD. J Cancer Res Treatment. 2016;4(2): NCCN Guidelines® Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (V ). Available online at NCCN.org. Accessed March 29, 2018.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Guideline Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer V © National Comprehensive Cancer Network, Inc All rights reserved. Accessed March 29, To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

40. Unresolved Questions
Are platinum-sensitivity and chemotherapy-sensitivity distinct concepts?
Do the most commonly used definitions of platinum-sensitivity still accurately capture today’s clinical reality?
What is the role of genetic/molecular testing for guiding treatment decisions for patients with platinum-sensitive disease?
How will emerging biomarkers for assessing HRD status (eg, LOH levels, somatic BRCA mutations, or composite assays evaluating multiple molecular markers associated with HRD) affect our understanding of PSOC?
Beyond anti-angiogenic agents and PARP inhibitors, which targeted therapies (eg, inhibitors of WNT signaling, agents targeting TP53 pathway) show promise in the evolving treatment landscape of PSOC?
BRCA, breast cancer susceptibility gene; HRD, homologous recombination deficiency; LOH, loss of heterozygosity; PARP, poly ADP ribose polymerase; PSOC, platinum-sensitive ovarian cancer; TP, tumor protein; WNT, wingless/proto-oncogene integration.

41. GEMSTONE
GEMSTONE, a committee of ovarian cancer experts, provided direction and approval of the material in this educational resource. TESARO, Inc. provided writing and organizational support to GEMSTONE in the generation of this material.
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